Function of GATA Factors in the Adult Mouse Liver

PubMed Central

Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

2013-01-01

GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

Acute Perioperative Comparison of Patient-Specific Instrumentation versus Conventional Instrumentation Utilization during Bilateral Total Knee Arthroplasty.

PubMed

Steimle, Jerrod A; Groover, Michael T; Webb, Brad A; Ceccarelli, Brian J

2018-01-01

Utilizing patient-specific instrumentation during total knee arthroplasty has gained popularity in recent years with theoretical advantages in blood loss, intraoperative time, length of stay, postoperative alignment, and functional outcome, amongst others. No study has compared acute perioperative measures between patient-specific instrumentation and conventional instrumentation in the bilateral total knee arthroplasty setting. We compared patient-specific instrumentation versus conventional instrumentation in the setting of bilateral total knee arthroplasty to determine any benefits in the immediate perioperative period including surgical time, blood loss, pain medication use, length of stay, and discharge disposition. A total of 49 patients with standard instrumentation and 31 patients with patient-specific instrumentation were retrospectively reviewed in a two-year period at one facility. At baseline, the groups were comparable with respect to age, ASA, BMI, and comorbid conditions. We analyzed data on operative time, blood loss, hemoglobin change, need for transfusion, pain medication use, length of stay, and discharge disposition. There was no statistically significant difference between groups in regards to these parameters. Patient-specific instrumentation in the setting of bilateral total knee arthroplasty did not provide any immediate perioperative benefit compared to conventional instrumentation.

Plant litter decomposition and nutrient release in peatlands

NASA Astrophysics Data System (ADS)

Bragazza, Luca; Buttler, Alexandre; Siegenthaler, Andy; Mitchell, Edward A. D.

Decomposition of plant litter is a crucial process in controlling the carbon balance of peatlands. Indeed, as long as the rate of litter decomposition remains lower than the rate of above- and belowground litter production, a net accumulation of peat and, thus, carbon will take place. In addition, decomposition controls the release of important nutrients such as nitrogen, phosphorus, and potassium, the availability of which affects the structure and the functioning of plant communities. This chapter describes the role of the main drivers in affecting mass loss and nutrient release from recently deposited plant litter. In particular, the rate of mass loss of Sphagnum litter and vascular plant litter is reviewed in relation to regional climatic conditions, aerobic/anaerobic conditions, and litter chemistry. The rate of nutrient release is discussed in relation to the rate of mass loss and associated litter chemistry by means of a specific case study.

Tissue Specific Expression Of Sprouty1 In Mice Protects Against High Fat Diet Induced Fat Accumulation, Bone Loss, And Metabolic Dysfunction

PubMed Central

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J.; Liaw, Lucy

2012-01-01

We recently characterized Sprouty1 (Spry1), a growth factor signaling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue specific Spry1 expression in mice resulted in increased bone mass and reduced body fat while conditional knockout of Spry1 had the opposite effect with decreased bone and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high fat diet-induced obesity, bone loss, and associated lipid abnormalities and demonstrate that Spry1 has a long-term protective effect on mice fed a high caloric diet. We studied diet-induced obesity in mice with fatty acid binding promoter (aP2)-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1 null mice, high fat diet increased body fat by 40%, impaired glucose regulation, and led to liver steatosis. However, over-expression of Spry1 led to 35% lower body fat, reduced bone loss, and normal metabolic function compared to single transgenics. This protective phenotype was associated with decreased circulating insulin (70%) and leptin (54%) compared to controls on a high fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45%. We show that conditional Spry1 expression in adipose tissue protects against high fat diet-induced obesity and associated bone loss. PMID:22142492

Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction.

PubMed

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J; Liaw, Lucy

2012-09-28

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

Plant diversity does not buffer drought effects on early-stage litter mass loss rates and microbial properties.

PubMed

Vogel, Anja; Eisenhauer, Nico; Weigelt, Alexandra; Scherer-Lorenzen, Michael

2013-09-01

Human activities are decreasing biodiversity and changing the climate worldwide. Both global change drivers have been shown to affect ecosystem functioning, but they may also act in concert in a non-additive way. We studied early-stage litter mass loss rates and soil microbial properties (basal respiration and microbial biomass) during the summer season in response to plant species richness and summer drought in a large grassland biodiversity experiment, the Jena Experiment, Germany. In line with our expectations, decreasing plant diversity and summer drought decreased litter mass loss rates and soil microbial properties. In contrast to our hypotheses, however, this was only true for mass loss of standard litter (wheat straw) used in all plots, and not for plant community-specific litter mass loss. We found no interactive effects between global change drivers, that is, drought reduced litter mass loss rates and soil microbial properties irrespective of plant diversity. High mass loss rates of plant community-specific litter and low responsiveness to drought relative to the standard litter indicate that soil microbial communities were adapted to decomposing community-specific plant litter material including lower susceptibility to dry conditions during summer months. Moreover, higher microbial enzymatic diversity at high plant diversity may have caused elevated mass loss of standard litter. Our results indicate that plant diversity loss and summer drought independently impede soil processes. However, soil decomposer communities may be highly adapted to decomposing plant community-specific litter material, even in situations of environmental stress. Results of standard litter mass loss moreover suggest that decomposer communities under diverse plant communities are able to cope with a greater variety of plant inputs possibly making them less responsive to biotic changes. © 2013 John Wiley & Sons Ltd.

Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice.

PubMed

Dworkin, Sebastian; Auden, Alana; Partridge, Darren D; Daglas, Maria; Medcalf, Robert L; Mantamadiotis, Theo; Georgy, Smitha R; Darido, Charbel; Jane, Stephen M; Ting, Stephen B

2017-06-01

The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3 -/- ), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3 flox/flox ), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 775-788, 2017. © 2017 Wiley Periodicals, Inc.

Deletion of Gαq in the telencephalon alters specific neurobehavioral outcomes.

PubMed

Graham, Devon L; Buendia, Matthew A; Chapman, Michelle A; Durai, Heather H; Stanwood, Gregg D

2015-09-01

G(αq) -coupled receptors are ubiquitously expressed throughout the brain and body, and it has been shown that these receptors and associated signaling cascades are involved in a number of functional outputs, including motor function and learning and memory. Genetic alterations to G(αq) have been implicated in neurodevelopmental disorders such as Sturge-Weber syndrome. Some of these associated disease outcomes have been modeled in laboratory animals, but as G(αq) is expressed in all cell types, it is difficult to differentiate the underlying circuitry or causative neuronal population. To begin to address neuronal cell type diversity in G(αq) function, we utilized a conditional knockout mouse whereby G(αq) was eliminated from telencephalic glutamatergic neurons. Unlike the global G(αq) knockout mouse, we found that these conditional knockout mice were not physically different from control mice, nor did they exhibit any gross motor abnormalities. However, similarly to the constitutive knockout animal, G(αq) conditional knockout mice demonstrated apparent deficits in spatial working memory. Loss of G(αq) from glutamatergic neurons also produced enhanced sensitivity to cocaine-induced locomotion, suggesting that cortical G(αq) signaling may limit behavioral responses to psychostimulants. Screening for a variety of markers of forebrain neuronal architecture revealed no obvious differences in the conditional knockouts, suggesting that the loss of G(αq) in telencephalic excitatory neurons does not result in major alterations in brain structure or neuronal differentiation. Taken together, our results define specific modulation of spatial working memory and psychostimulant responses through disruptions in G(αq) signaling within cerebral cortical glutamatergic neurons. © 2015 Wiley Periodicals, Inc.

YY1 Regulates Melanocyte Development and Function by Cooperating with MITF

PubMed Central

Bell, Robert J. A.; Tran, Thanh-Nga T.; Haq, Rizwan; Liu, Huifei; Love, Kevin T.; Langer, Robert; Anderson, Daniel G.; Larue, Lionel; Fisher, David E.

2012-01-01

Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP–seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1) gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF)—a general mechanism which may confer tissue-specific gene expression in multiple lineages. PMID:22570637

Neurotactin functions in concert with other identified CAMs in growth cone guidance in Drosophila.

PubMed

Speicher, S; García-Alonso, L; Carmena, A; Martín-Bermudo, M D; de la Escalera, S; Jiménez, F

1998-02-01

We have isolated and characterized mutations in Drosophila neurotactin, a gene that encodes a cell adhesion protein widely expressed during neural development. Analysis of both loss and gain of gene function conditions during embryonic and postembryonic development revealed specific requirements for neurotactin during axon outgrowth, fasciculation, and guidance. Furthermore, embryos of some double mutant combinations of neurotactin and other genes encoding adhesion/signaling molecules, including neuroglian, derailed, and kekkon1, displayed phenotypic synergy. This result provides evidence for functional cooperativity in vivo between the adhesion and signaling pathways controlled by neurotactin and the other three genes.

Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner.

PubMed

Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M; Strasser, Andreas; Heierhorst, Jörg

2018-01-01

The proapoptotic BH3-only protein BIM ( Bcl2l11 ) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre ) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre ) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim -deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro , conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc -driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions.

Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner

PubMed Central

Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M.; Strasser, Andreas; Heierhorst, Jörg

2018-01-01

The proapoptotic BH3-only protein BIM (Bcl2l11) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim-deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro, conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc-driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions. PMID:29623080

On-the-Job Productivity Losses Among Employees With Health Problems: The Role of Work Accommodations.

PubMed

Gifford, Brian; Zong, Yang

2017-09-01

Debates about the productivity impact of work accommodations typically focus on employment and labor force participation outcomes. This study considers whether accommodations mediate on-the-job productivity losses among employees who report health problems. The study uses ordered logistic regression to predict employees' self-reported productivity losses as a function of health problems and experiences with needed work accommodations. On average, the odds that an employee who did not get a needed accommodation reported higher levels of lost productivity are 5.11 times the odds for an employee who got a needed accommodation. Although health problems make it difficult for many employees to perform well on the job, accommodations could reduce productivity losses in some cases. Nonetheless, more research on the impact of specific kinds of accommodations for different chronic conditions is warranted.

Necroptosis: an emerging type of cell death in liver diseases.

PubMed

Saeed, Waqar Khalid; Jun, Dae Won

2014-09-21

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.

Meis2 is essential for cranial and cardiac neural crest development.

PubMed

Machon, Ondrej; Masek, Jan; Machonova, Olga; Krauss, Stefan; Kozmik, Zbynek

2015-11-06

TALE-class homeodomain transcription factors Meis and Pbx play important roles in formation of the embryonic brain, eye, heart, cartilage or hematopoiesis. Loss-of-function studies of Pbx1, 2 and 3 and Meis1 documented specific functions in embryogenesis, however, functional studies of Meis2 in mouse are still missing. We have generated a conditional allele of Meis2 in mice and shown that systemic inactivation of the Meis2 gene results in lethality by the embryonic day 14 that is accompanied with hemorrhaging. We show that neural crest cells express Meis2 and Meis2-defficient embryos display defects in tissues that are derived from the neural crest, such as an abnormal heart outflow tract with the persistent truncus arteriosus and abnormal cranial nerves. The importance of Meis2 for neural crest cells is further confirmed by means of conditional inactivation of Meis2 using crest-specific AP2α-IRES-Cre mouse. Conditional mutants display perturbed development of the craniofacial skeleton with severe anomalies in cranial bones and cartilages, heart and cranial nerve abnormalities. Meis2-null mice are embryonic lethal. Our results reveal a critical role of Meis2 during cranial and cardiac neural crest cells development in mouse.

Altered fronto-striatal functions in the Gdi1-null mouse model of X-linked Intellectual Disability.

PubMed

Morè, Lorenzo; Künnecke, Basil; Yekhlef, Latefa; Bruns, Andreas; Marte, Antonella; Fedele, Ernesto; Bianchi, Veronica; Taverna, Stefano; Gatti, Silvia; D'Adamo, Patrizia

2017-03-06

RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sleep loss and structural plasticity.

PubMed

Areal, Cassandra C; Warby, Simon C; Mongrain, Valérie

2017-06-01

Wakefulness and sleep are dynamic states during which brain functioning is modified and shaped. Sleep loss is detrimental to many brain functions and results in structural changes localized at synapses in the nervous system. In this review, we present and discuss some of the latest observations of structural changes following sleep loss in some vertebrates and insects. We also emphasize that these changes are region-specific and cell type-specific and that, most importantly, these structural modifications have functional roles in sleep regulation and brain functions. Selected mechanisms driving structural modifications occurring with sleep loss are also discussed. Overall, recent research highlights that extending wakefulness impacts synapse number and shape, which in turn regulate sleep need and sleep-dependent learning/memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Integrated Medical Model: A Probabilistic Simulation Model for Predicting In-Flight Medical Risks

NASA Technical Reports Server (NTRS)

Keenan, Alexandra; Young, Millennia; Saile, Lynn; Boley, Lynn; Walton, Marlei; Kerstman, Eric; Shah, Ronak; Goodenow, Debra A.; Myers, Jerry G.

2015-01-01

The Integrated Medical Model (IMM) is a probabilistic model that uses simulation to predict mission medical risk. Given a specific mission and crew scenario, medical events are simulated using Monte Carlo methodology to provide estimates of resource utilization, probability of evacuation, probability of loss of crew, and the amount of mission time lost due to illness. Mission and crew scenarios are defined by mission length, extravehicular activity (EVA) schedule, and crew characteristics including: sex, coronary artery calcium score, contacts, dental crowns, history of abdominal surgery, and EVA eligibility. The Integrated Medical Evidence Database (iMED) houses the model inputs for one hundred medical conditions using in-flight, analog, and terrestrial medical data. Inputs include incidence, event durations, resource utilization, and crew functional impairment. Severity of conditions is addressed by defining statistical distributions on the dichotomized best and worst-case scenarios for each condition. The outcome distributions for conditions are bounded by the treatment extremes of the fully treated scenario in which all required resources are available and the untreated scenario in which no required resources are available. Upon occurrence of a simulated medical event, treatment availability is assessed, and outcomes are generated depending on the status of the affected crewmember at the time of onset, including any pre-existing functional impairments or ongoing treatment of concurrent conditions. The main IMM outcomes, including probability of evacuation and loss of crew life, time lost due to medical events, and resource utilization, are useful in informing mission planning decisions. To date, the IMM has been used to assess mission-specific risks with and without certain crewmember characteristics, to determine the impact of eliminating certain resources from the mission medical kit, and to design medical kits that maximally benefit crew health while meeting mass and volume constraints.

The Integrated Medical Model: A Probabilistic Simulation Model Predicting In-Flight Medical Risks

NASA Technical Reports Server (NTRS)

Keenan, Alexandra; Young, Millennia; Saile, Lynn; Boley, Lynn; Walton, Marlei; Kerstman, Eric; Shah, Ronak; Goodenow, Debra A.; Myers, Jerry G., Jr.

2015-01-01

The Integrated Medical Model (IMM) is a probabilistic model that uses simulation to predict mission medical risk. Given a specific mission and crew scenario, medical events are simulated using Monte Carlo methodology to provide estimates of resource utilization, probability of evacuation, probability of loss of crew, and the amount of mission time lost due to illness. Mission and crew scenarios are defined by mission length, extravehicular activity (EVA) schedule, and crew characteristics including: sex, coronary artery calcium score, contacts, dental crowns, history of abdominal surgery, and EVA eligibility. The Integrated Medical Evidence Database (iMED) houses the model inputs for one hundred medical conditions using in-flight, analog, and terrestrial medical data. Inputs include incidence, event durations, resource utilization, and crew functional impairment. Severity of conditions is addressed by defining statistical distributions on the dichotomized best and worst-case scenarios for each condition. The outcome distributions for conditions are bounded by the treatment extremes of the fully treated scenario in which all required resources are available and the untreated scenario in which no required resources are available. Upon occurrence of a simulated medical event, treatment availability is assessed, and outcomes are generated depending on the status of the affected crewmember at the time of onset, including any pre-existing functional impairments or ongoing treatment of concurrent conditions. The main IMM outcomes, including probability of evacuation and loss of crew life, time lost due to medical events, and resource utilization, are useful in informing mission planning decisions. To date, the IMM has been used to assess mission-specific risks with and without certain crewmember characteristics, to determine the impact of eliminating certain resources from the mission medical kit, and to design medical kits that maximally benefit crew health while meeting mass and volume constraints.

Assessment of Rod, Cone, and Intrinsically Photosensitive Retinal Ganglion Cell Contributions to the Canine Chromatic Pupillary Response.

PubMed

Yeh, Connie Y; Koehl, Kristin L; Harman, Christine D; Iwabe, Simone; Guzman, José M; Petersen-Jones, Simon M; Kardon, Randy H; Komáromy, András M

2017-01-01

The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs. Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m2) and bright (400 cd/m2) blue light (for scotopic conditions) or bright red (400 cd/m2) light with 25-cd/m2 blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry. Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas. Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.

Etanercept Injection

MedlinePlus

... own joints, causing pain, swelling, and loss of function) in adults, psoriatic arthritis (condition that causes joint ... its own joints, causing pain, swelling, loss of function, and delays in growth and development) in children ...

The microRNA-processing enzyme Dicer is essential for thyroid function.

PubMed

Frezzetti, Daniela; Reale, Carla; Calì, Gaetano; Nitsch, Lucio; Fagman, Henrik; Nilsson, Ola; Scarfò, Marzia; De Vita, Gabriella; Di Lauro, Roberto

2011-01-01

Dicer is a type III ribonuclease required for the biogenesis of microRNAs (miRNAs), a class of small non-coding RNAs regulating gene expression at the post-transcriptional level. To explore the functional role of miRNAs in thyroid gland function, we generated a thyrocyte-specific Dicer conditional knockout mouse. Here we show that development and early differentiation of the thyroid gland are not affected by the absence of Dicer, while severe hypothyroidism gradually develops after birth, leading to reduced body weight and shortened life span. Histological and molecular characterization of knockout mice reveals a dramatic loss of the thyroid gland follicular architecture associated with functional aberrations and down-regulation of several differentiation markers. The data presented in this study show for the first time that an intact miRNAs processing machinery is essential for thyroid physiology, suggesting that deregulation of specific miRNAs could be also involved in human thyroid dysfunctions.

Psychosocial Adaptations to Dual Sensory Loss in Middle and Late Adulthood

PubMed Central

Brennan, Mark; Bally, Scott J.

2007-01-01

Concurrent losses of hearing and vision function, or dual sensory loss, affect a large number of individuals of all ages and particularly older adults. Dual sensory loss may present at any age as a result of genetic defect, accident, injury, disease, or environmental insult; however, most persons develop this condition as a result of age-related disease processes that rarely result in total deafness or blindness. This condition has wide-ranging implications for physical and psychological functioning and quality of life. In this article, we review the prevalence and causes of dual impairment and its effects on functioning for both individuals affected and their families. We examine psychosocial coping and adaptation to this condition using biopsychosocial–spiritual and ecological models and discuss various strategies for coping and adaptation. The impact of larger societal forces on psychosocial adaptation is presented, followed by recommendations for how rehabilitation and other professionals can meet the challenge of dual sensory loss that awaits us with the aging of the population. PMID:18003870

Stage-specific control of early B cell development by the transcription factor Ikaros

PubMed Central

Gültekin, Sinan; Dakic, Aleksandar; Axelsson, Elin; Minnich, Martina; Ebert, Anja; Werner, Barbara; Roth, Mareike; Cimmino, Luisa; Dickins, Ross A.; Zuber, Johannes; Jaritz, Markus; Busslinger, Meinrad

2018-01-01

Ikaros is an essential regulator of lymphopoiesis. Here, we studied the B-cell-specific function of Ikaros by conditional Ikzf1 inactivation in pro-B cells. B-cell development was arrested at an aberrant ‘pro-B’ cell stage characterized by increased cell adhesion and loss of pre-B cell receptor signaling. Ikaros was found to activate genes coding for pre-BCR signal transducers and to repress genes involved in the downregulation of pre-BCR signaling and upregulation of the integrin signaling pathway. Unexpectedly, derepression of Aiolos expression could not compensate for the loss of Ikaros in pro-B cells. Ikaros induced or suppressed active chromatin at regulatory elements of activated or repressed target genes. Notably, Ikaros binding and target gene expression was dynamically regulated at distinct stages of early B-lymphopoiesis. PMID:24509509

The impact of depression and diabetes mellitus on older workers' functioning.

PubMed

Stynen, D; Jansen, N W H; Kant, I J

2015-12-01

Using the International Classification of Functioning, Disability and Health as a framework, this study investigates the impact of depression and diabetes mellitus on older workers' functioning (problems with concentration, physical functioning, need for recovery and work and social participation restrictions). The study focuses on how these chronic conditions, in their interaction with the work context, affect older workers' functioning, which may be an important precursor of early retirement. Older workers (≥ 45years) with depression (n=127) or diabetes mellitus (n=107) enrolled in the prospective Maastricht Cohort Study (MCS) were followed between October 2008 and October 2012. Linear, logistic and Cox regression analyses were performed to investigate the effect of these health conditions on workers' functioning compared to a reference group of older workers without a chronic condition (n=1612). The interaction with participants' working conditions (psychological job demands, decision latitude and strenuous work) was also analysed. Compared to the reference group, depression and diabetes mellitus were (over time) positively related with need for recovery caseness and restrictions in social participation but not with restrictions in work participation. Depression was positively related with concentration problems and need for recovery, whereas diabetes mellitus was negatively related with physical functioning. Finally, the relationship between functioning and depression and diabetes mellitus depends on working conditions. Older workers with depression or diabetes mellitus are vulnerable to losses in specific domains of functioning. The impact on functioning varies across working conditions, providing insight for disease-tailored preventive measures. Copyright © 2015 Elsevier Inc. All rights reserved.

A rapid method to score stream reaches based on the overall performance of their main ecological functions.

PubMed

Rowe, David K; Parkyn, Stephanie; Quinn, John; Collier, Kevin; Hatton, Chris; Joy, Michael K; Maxted, John; Moore, Stephen

2009-06-01

A method was developed to score the ecological condition of first- to third-order stream reaches in the Auckland region of New Zealand based on the performance of their key ecological functions. Such a method is required by consultants and resource managers to quantify the reduction in ecological condition of a modified stream reach relative to its unmodified state. This is a fundamental precursor for the determination of fair environmental compensation for achieving no-net-loss in overall stream ecological value. Field testing and subsequent use of the method indicated that it provides a useful measure of ecological condition related to the performance of stream ecological functions. It is relatively simple to apply compared to a full ecological study, is quick to use, and allows identification of the degree of impairment of each of the key ecological functions. The scoring system was designed so that future improvements in the measurement of stream functions can be incorporated into it. Although the methodology was specifically designed for Auckland streams, the principles can be readily adapted to other regions and stream types.

Online Pairwise Learning Algorithms.

PubMed

Ying, Yiming; Zhou, Ding-Xuan

2016-04-01

Pairwise learning usually refers to a learning task that involves a loss function depending on pairs of examples, among which the most notable ones are bipartite ranking, metric learning, and AUC maximization. In this letter we study an online algorithm for pairwise learning with a least-square loss function in an unconstrained setting of a reproducing kernel Hilbert space (RKHS) that we refer to as the Online Pairwise lEaRning Algorithm (OPERA). In contrast to existing works (Kar, Sriperumbudur, Jain, & Karnick, 2013 ; Wang, Khardon, Pechyony, & Jones, 2012 ), which require that the iterates are restricted to a bounded domain or the loss function is strongly convex, OPERA is associated with a non-strongly convex objective function and learns the target function in an unconstrained RKHS. Specifically, we establish a general theorem that guarantees the almost sure convergence for the last iterate of OPERA without any assumptions on the underlying distribution. Explicit convergence rates are derived under the condition of polynomially decaying step sizes. We also establish an interesting property for a family of widely used kernels in the setting of pairwise learning and illustrate the convergence results using such kernels. Our methodology mainly depends on the characterization of RKHSs using its associated integral operators and probability inequalities for random variables with values in a Hilbert space.

Keeping Older Adults with Vision Loss Safe: Chronic Conditions and Comorbidities that Influence Functional Mobility

ERIC Educational Resources Information Center

Riddering, Anne T.

2008-01-01

Age-related macular degeneration (AMD) is a leading cause of vision loss in Americans aged 60 and older. The loss of central vision from AMD can decrease visual acuity, contrast sensitivity, glare sensitivity, color discrimination, and the ability to adapt to changes in lighting conditions. Older adults with vision loss often have other chronic,…

RAC-tagging: Recombineering And Cas9-assisted targeting for protein tagging and conditional analyses

PubMed Central

Baker, Oliver; Gupta, Ashish; Obst, Mandy; Zhang, Youming; Anastassiadis, Konstantinos; Fu, Jun; Stewart, A. Francis

2016-01-01

A fluent method for gene targeting to establish protein tagged and ligand inducible conditional loss-of-function alleles is described. We couple new recombineering applications for one-step cloning of gRNA oligonucleotides and rapid generation of short-arm (~1 kb) targeting constructs with the power of Cas9-assisted targeting to establish protein tagged alleles in embryonic stem cells at high efficiency. RAC (Recombineering And Cas9)-tagging with Venus, BirM, APEX2 and the auxin degron is facilitated by a recombineering-ready plasmid series that permits the reuse of gene-specific reagents to insert different tags. Here we focus on protein tagging with the auxin degron because it is a ligand-regulated loss-of-function strategy that is rapid and reversible. Furthermore it includes the additional challenge of biallelic targeting. Despite high frequencies of monoallelic RAC-targeting, we found that simultaneous biallelic targeting benefits from long-arm (>4 kb) targeting constructs. Consequently an updated recombineering pipeline for fluent generation of long arm targeting constructs is also presented. PMID:27216209

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis.

PubMed

Walck-Shannon, Elise; Lucas, Bethany; Chin-Sang, Ian; Reiner, David; Kumfer, Kraig; Cochran, Hunter; Bothfeld, William; Hardin, Jeff

2016-11-01

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis

PubMed Central

Lucas, Bethany; Chin-Sang, Ian; Reiner, David; Kumfer, Kraig

2016-01-01

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation. PMID:27861585

Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures

PubMed Central

Bohlen, Christopher J.; Bennett, F. Chris; Tucker, Andrew F.; Collins, Hannah Y.; Mulinyawe, Sara B.; Barres, Ben A.

2017-01-01

Summary Microglia, the resident macrophages of the central nervous system (CNS), engage in various CNS-specific functions that are critical for development and health. To better study microglia and the properties that distinguish them from other tissue macrophage populations, we have optimized serum-free culture conditions to permit robust survival of highly ramified adult microglia under defined-medium conditions. We find that astrocyte-derived factors prevent microglial death ex vivo and that this activity results from three primary components, CSF-1/IL-34, TGF-β2, and cholesterol. Using microglial cultures that have never been exposed to serum, we demonstrate a dramatic and lasting change in phagocytic capacity after serum exposure. Finally, we find that mature microglia rapidly lose signature gene expression after isolation, and that this loss can be reversed by engrafting cells back into an intact CNS environment. These data indicate that the specialized gene expression profile of mature microglia requires continuous instructive signaling from the intact CNS. PMID:28521131

Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures.

PubMed

Bohlen, Christopher J; Bennett, F Chris; Tucker, Andrew F; Collins, Hannah Y; Mulinyawe, Sara B; Barres, Ben A

2017-05-17

Microglia, the resident macrophages of the CNS, engage in various CNS-specific functions that are critical for development and health. To better study microglia and the properties that distinguish them from other tissue macrophage populations, we have optimized serum-free culture conditions to permit robust survival of highly ramified adult microglia under defined-medium conditions. We find that astrocyte-derived factors prevent microglial death ex vivo and that this activity results from three primary components, CSF-1/IL-34, TGF-β2, and cholesterol. Using microglial cultures that have never been exposed to serum, we demonstrate a dramatic and lasting change in phagocytic capacity after serum exposure. Finally, we find that mature microglia rapidly lose signature gene expression after isolation, and that this loss can be reversed by engrafting cells back into an intact CNS environment. These data indicate that the specialized gene expression profile of mature microglia requires continuous instructive signaling from the intact CNS. Copyright © 2017 Elsevier Inc. All rights reserved.

Studies of Cell-Mediated Immunity Against Immune Disorders Using Synthetic Peptides and Rotating Bioreactor System

NASA Technical Reports Server (NTRS)

Sastry, Jagannadha K.

1998-01-01

We conducted a series of experiments using mouse immune-precursor cells, and observed that bioreactor culturing results in the loss of antigen-specific cytotoxic T lymphocyte (CTL) function. The reason for the abrogation of CTL function is microgravity conditions in the bioreactor, but not the antigen per se or its MHC restriction. Similarly, we observed that allostimulation of human PBMC in the bioreactor, but not in the T flask, resulted in the blunting of both allo-CTL function and the NK activity, indicating that the microgravity-associated functional defects are not unique to the mouse system. These results provide further confirmation to the microgravity-associated immune dysfunction, and constitute ground-based confirmatory data for those related to space-travel.

Biomechanics of Reverse Shoulder Arthroplasty: 
Current Concepts.

PubMed

Lorenzetti, Adam J; Stone, Geoffrey P; Simon, Peter; Frankle, Mark A

2016-01-01

The evolution of reverse shoulder arthroplasty has provided surgeons with new solutions for many complex shoulder problems. A primary goal of orthopaedics is the restoration or re-creation of functional anatomy to reduce pain and improve function, which can be accomplished by either repairing injured structures or replacing them as anatomically as possible. If reconstructible tissue is lacking or not available, which is seen in patients who have complex shoulder conditions such as an irreparable rotator cuff-deficient shoulder, cuff tear arthropathy, or severe glenoid bone loss, substantial problems may arise. Historically, hemiarthroplasty or glenoid grafting with total shoulder arthroplasty yielded inconsistent and unsatisfactory results. Underlying pathologies in patients who have an irreparable rotator cuff-deficient shoulder, cuff tear arthropathy, or severe glenoid bone loss can considerably alter the mechanical function of the shoulder and create treatment dilemmas that are difficult to overcome. A better biomechanical understanding of these pathologic adaptations has improved treatment options. In the past three decades, reverse total shoulder arthroplasty was developed to treat these complex shoulder conditions not by specifically re-creating the anatomy but by using the remaining functional tissue to improve shoulder balance. Reverse total shoulder arthroplasty has achieved reliable improvements in both pain and function. Initial implant designs lacked scientific evidence to support the design rationale, and many implants failed because surgeons did not completely understand the forces involved or the pathology being treated. Implant function and clinical results will continue to improve as surgeons' biomechanical understanding of shoulder disease and reverse shoulder arthroplasty implants increases.

Assessing the Relationship Between Chronic Health Conditions and Productivity Loss Trajectories

PubMed Central

Pranksy, Glenn

2014-01-01

Objective: To examine the relationship between health conditions and the risk for membership in longitudinal trajectories of productivity loss. Methods: Trajectories of productivity loss from the ages of 25 to 44 years, previously identified in the National Longitudinal Survey of Youth (NLSY79), were combined with information on health conditions from the age 40 years health module in the NLSY79. Multinomial logistic regression was used to examine the relative risk of being in the low-risk, early-onset increasing risk, late-onset increasing risk, or high-risk trajectories compared with the no-risk trajectory for having various health conditions. Results: The trajectories with the greatest probability of productivity loss longitudinally had a greater prevalence of the individual health conditions and a greater total number of health conditions experienced. Conclusions: Health conditions are associated with specific longitudinal patterns of experiencing productivity loss. PMID:25479294

Helplessness and loss as mediators between pain and depressive symptoms in fibromyalgia.

PubMed

Palomino, Rand A; Nicassio, Perry M; Greenberg, Melanie A; Medina, Ernesto P

2007-05-01

This study evaluated the contribution of condition-specific helplessness and loss to depression in fibromyalgia (FM). Two models were tested. The first model examined whether loss, measured by the West Haven-Yale Multidimensional Pain Inventory (WHYMPI) Interference Scale, would mediate the relationship between disability and depression. The second model determined whether condition-specific helplessness and loss would mediate the relationship between pain and depression with disability controlled. Eighty patients with confirmed diagnoses of FM were recruited throughout Southern California from general medical clinics, newspaper advertisements, and rheumatology practices. The study design was cross-sectional, using self-report, observational, and interview measures. A composite measure of depression was adopted, consisting of the Center for Epidemiological Studies-Depression Scale and the Hamilton Rating Scale for Depression. Hierarchical multiple regression analyses were conducted using a path analytic framework to examine each model. In Model 1, loss fully mediated the relationship between disability and depression. In Model 2, condition-specific helplessness mediated the relationship between pain and depression, but the contribution of loss was not significant. The findings confirm the importance of helplessness and demonstrate that the cognitive meaning of having FM plays a more central role in predicting depressive symptomatology than illness-related stressors, such as pain or disability.

The functional and structural neural basis of individual differences in loss aversion.

PubMed

Canessa, Nicola; Crespi, Chiara; Motterlini, Matteo; Baud-Bovy, Gabriel; Chierchia, Gabriele; Pantaleo, Giuseppe; Tettamanti, Marco; Cappa, Stefano F

2013-09-04

Decision making under risk entails the anticipation of prospective outcomes, typically leading to the greater sensitivity to losses than gains known as loss aversion. Previous studies on the neural bases of choice-outcome anticipation and loss aversion provided inconsistent results, showing either bidirectional mesolimbic responses of activation for gains and deactivation for losses, or a specific amygdala involvement in processing losses. Here we focused on loss aversion with the aim to address interindividual differences in the neural bases of choice-outcome anticipation. Fifty-six healthy human participants accepted or rejected 104 mixed gambles offering equal (50%) chances of gaining or losing different amounts of money while their brain activity was measured with functional magnetic resonance imaging (fMRI). We report both bidirectional and gain/loss-specific responses while evaluating risky gambles, with amygdala and posterior insula specifically tracking the magnitude of potential losses. At the individual level, loss aversion was reflected both in limbic fMRI responses and in gray matter volume in a structural amygdala-thalamus-striatum network, in which the volume of the "output" centromedial amygdala nuclei mediating avoidance behavior was negatively correlated with monetary performance. We conclude that outcome anticipation and ensuing loss aversion involve multiple neural systems, showing functional and structural individual variability directly related to the actual financial outcomes of choices. By supporting the simultaneous involvement of both appetitive and aversive processing in economic decision making, these results contribute to the interpretation of existing inconsistencies on the neural bases of anticipating choice outcomes.

General Labour Code (Act No. 2 of 1986), 5 April 1986. [Selected provisions].

PubMed

1989-01-01

Guinea-Bissau's General Labor Code, Act No. 2 of 1986, requires that employers adopt non-discriminatory procedures in dealing with their employees, disallowing discrimination based on gender, race, national origin, religion, political ideology or inclination, or on whether or not an employee is affiliated to a worker's union. Women are guaranteed equality with men in work opportunity and employment treatment; they are assured access to any type of job, profession, or position which does not pose any potential or actual threat to their genetic functioning. Additional legislation shall establish the conditions and prohibitions for contracting woman for heavy labor, for jobs performed under insalubrious conditions, for underground work, and for other types of jobs which might endanger a woman's genetic functioning. Job offers must not discriminate, unless the restrictions or specifications are essential to the nature of the job, rendering the job qualitatively differentiable when performed by a man or a woman. The employer must ensure that female workers have the same job opportunity and treatment for professional training and career development. Different specific job categories may not be created for men and women if a woman's salary is inferior to that of a man performing equivalent work in a corresponding professional category. Protection during pregnancy and delivery guarantees a woman the right to decline medically inadvisable tasks without loss of wages; to decline overtime work; to be absent from work when necessary for maternal medical care without loss of wages; to interrupt daily work to nurse her children for 1 hour or 2 for half-hour periods for up to 1 year without the loss of wages. Every female employee has the right to 60 days pregnancy and maternity leave, without loss of wages, for whatever clinical type of delivery, including for still births and for births where the infant died shortly thereafter.

Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the Look AHEAD trial.

PubMed

Foy, Capri G; Lewis, Cora E; Hairston, Kristen G; Miller, Gary D; Lang, Wei; Jakicic, John M; Rejeski, W Jack; Ribisl, Paul M; Walkup, Michael P; Wagenknecht, Lynne E

2011-01-01

Lifestyle interventions have resulted in weight loss or improved physical fitness among individuals with obesity, which may lead to improved physical function. This prospective investigation involved participants in the Action for Health in Diabetes (Look AHEAD) trial who reported knee pain at baseline (n = 2,203). The purposes of this investigation were to determine whether an Intensive Lifestyle Intervention (ILI) condition resulted in improvement in self-reported physical function from baseline to 12 months vs. a Diabetes Support and Education (DSE) condition, and whether changes in weight or fitness mediated the effect of the ILI. Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and physical function subscales, and WOMAC summary score. ILI participants exhibited greater adjusted mean weight loss (s.e.) vs. DSE participants (-9.02 kg (0.48) vs. -0.78 kg (0.49); P < 0.001)). ILI participants also demonstrated more favorable change in WOMAC summary scores vs. DSE participants (β (s.e.) = -1.81 (0.63); P = 0.004). Multiple regression mediation analyses revealed that weight loss was a mediator of the effect of the ILI intervention on change in WOMAC pain, function, and summary scores (P < 0.001). In separate analyses, increased fitness also mediated the effect of the ILI intervention upon WOMAC summary score (P < 0.001). The ILI condition resulted in significant improvement in physical function among overweight and obese adults with diabetes and knee pain. The ILI condition also resulted in significant weight loss and improved fitness, which are possible mechanisms through which the ILI condition improved physical function.

Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function.

PubMed

Ryan, Scott D; Ferrier, Andrew; Sato, Tadasu; O'Meara, Ryan W; De Repentigny, Yves; Jiang, Susan X; Hou, Sheng T; Kothary, Rashmi

2012-02-01

Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of expression of neuronal dystonin isoforms (dystonin-a1/dystonin-a2) is sufficient to cause dt pathogenesis, the diverging function of each isoform and what pathological mechanisms are activated upon their loss remains unclear. Here we show that dt(27) mice manifest ultrastructural defects at the endoplasmic reticulum (ER) in sensory neurons corresponding to in vivo induction of ER stress proteins. ER stress subsequently leads to sensory neurodegeneration through induction of a proapoptotic caspase cascade. dt sensory neurons display neurodegenerative pathologies, including Ca(2+) dyshomeostasis, unfolded protein response (UPR) induction, caspase activation, and apoptosis. Isoform-specific loss-of-function analysis attributes these neurodegenerative pathologies to specific loss of dystonin-a2. Inhibition of either UPR or caspase signaling promotes the viability of cells deficient in dystonin. This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function.

Heathlands confronting global change: drivers of biodiversity loss from past to future scenarios

PubMed Central

Fagúndez, Jaime

2013-01-01

Background Heathlands are dynamic plant communities characterized by a high cover of sclerophyllous, ericoid shrubs that develop over nutrient-poor soils. Interest in the preservation of these habitats in Europe has increased over the last decades, but over this time there has been a general decline in habitat quality, affecting community structure, ecosystem functions and biodiversity. Negative drivers that trigger these changes include land-use changes (i.e. habitat destruction and fragmentation), pollution, climate change, natural succession and human management, as well as the presence of invasive exotic species. Scope Based on recent scientific literature, the effect of each of these potential drivers on a wide set of factors, including physiological traits, species richness and diversity, community structure, ecosystem functions and soil conditions, is reviewed. The effects of these drivers are generally understood, but the direction and magnitude of factor interactions, whenever studied, have shown high variability. Conclusions Habitat loss and fragmentation affect sensitive species and ecosystem functions. The nature of the surrounding area will condition the quality of the heathland remnants by, for example, propagule pressure from invasive species. The dominant ericoid shrubs can be out-competed by vigorous perennial grasses with increased atmospheric nitrogen deposition, although interactions with climate and management practices may either counteract or enhance this process. Grazing or periodic burning promotes heath loss but site-specific combined treatments maintain species diversity and community structure. Climate change alone moderately affects plant diversity, community structure and ecosystem functions. Combined with other factors, climatic changes will condition heath development, mainly with regard to key aspects such as seed set and seedling establishment, rare species occurrence and nutrient cycling in the soil. It is essential to address the effects of not only individual factors, but their interactions, together with land-use history, on heathland development and conservation in order to predict habitat response to future scenarios. PMID:23223202

Heathlands confronting global change: drivers of biodiversity loss from past to future scenarios.

PubMed

Fagúndez, Jaime

2013-02-01

Heathlands are dynamic plant communities characterized by a high cover of sclerophyllous, ericoid shrubs that develop over nutrient-poor soils. Interest in the preservation of these habitats in Europe has increased over the last decades, but over this time there has been a general decline in habitat quality, affecting community structure, ecosystem functions and biodiversity. Negative drivers that trigger these changes include land-use changes (i.e. habitat destruction and fragmentation), pollution, climate change, natural succession and human management, as well as the presence of invasive exotic species. Based on recent scientific literature, the effect of each of these potential drivers on a wide set of factors, including physiological traits, species richness and diversity, community structure, ecosystem functions and soil conditions, is reviewed. The effects of these drivers are generally understood, but the direction and magnitude of factor interactions, whenever studied, have shown high variability. Habitat loss and fragmentation affect sensitive species and ecosystem functions. The nature of the surrounding area will condition the quality of the heathland remnants by, for example, propagule pressure from invasive species. The dominant ericoid shrubs can be out-competed by vigorous perennial grasses with increased atmospheric nitrogen deposition, although interactions with climate and management practices may either counteract or enhance this process. Grazing or periodic burning promotes heath loss but site-specific combined treatments maintain species diversity and community structure. Climate change alone moderately affects plant diversity, community structure and ecosystem functions. Combined with other factors, climatic changes will condition heath development, mainly with regard to key aspects such as seed set and seedling establishment, rare species occurrence and nutrient cycling in the soil. It is essential to address the effects of not only individual factors, but their interactions, together with land-use history, on heathland development and conservation in order to predict habitat response to future scenarios.

Sarcopenia: An Undiagnosed Condition in Older Adults. Current Consensus Definition: Prevalence, Etiology, and Consequences

PubMed Central

2012-01-01

Sarcopenia, the age associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy on November 18, 2009 to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multi-factorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. While cachexia may be a component of sarcopenia, the two conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1.0 m·s−1. Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry (DXA) with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s−1 and an objectively measured low muscle mass (eg: appendicular mass relative to ht2 that is ≤ 7.23 kg/ m2 in men ≤ 5.67 kg/ m2 in men). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization and death. PMID:21527165

Conditional deletion of Cadherin 13 perturbs Golgi cells and disrupts social and cognitive behaviors.

PubMed

Tantra, M; Guo, L; Kim, J; Zainolabidin, N; Eulenburg, V; Augustine, G J; Chen, A I

2018-02-15

Inhibitory interneurons mediate the gating of synaptic transmission and modulate the activities of neural circuits. Disruption of the function of inhibitory networks in the forebrain is linked to impairment of social and cognitive behaviors, but the involvement of inhibitory interneurons in the cerebellum has not been assessed. We found that Cadherin 13 (Cdh13), a gene implicated in autism spectrum disorder and attention-deficit hyperactivity disorder, is specifically expressed in Golgi cells within the cerebellar cortex. To assess the function of Cdh13 and utilize the manipulation of Cdh13 expression in Golgi cells as an entry point to examine cerebellar-mediated function, we generated mice carrying Cdh13-floxed alleles and conditionally deleted Cdh13 with GlyT2::Cre mice. Loss of Cdh13 results in a decrease in the expression/localization of GAD67 and reduces spontaneous inhibitory postsynaptic current (IPSC) in cerebellar Golgi cells without disrupting spontaneous excitatory postsynaptic current (EPSC). At the behavioral level, loss of Cdh13 in the cerebellum, piriform cortex and endopiriform claustrum have no impact on gross motor coordination or general locomotor behaviors, but leads to deficits in cognitive and social abilities. Mice lacking Cdh13 exhibit reduced cognitive flexibility and loss of preference for contact region concomitant with increased reciprocal social interactions. Together, our findings show that Cdh13 is critical for inhibitory function of Golgi cells, and that GlyT2::Cre-mediated deletion of Cdh13 in non-executive centers of the brain, such as the cerebellum, may contribute to cognitive and social behavioral deficits linked to neurological disorders. © 2018 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo.

PubMed

Higashimori, Haruki; Schin, Christina S; Chiang, Ming Sum R; Morel, Lydie; Shoneye, Temitope A; Nelson, David L; Yang, Yongjie

2016-07-06

How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS. Copyright © 2016 the authors 0270-6474/16/367080-16$15.00/0.

Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice.

PubMed

Petkau, Terri L; Blanco, Jake; Leavitt, Blair R

2017-10-01

Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. We generated conditional progranulin-knockout mice that lack progranulin in nestin-expressing cells (Nes-cKO mice), which include most neurons as well as astrocytes. We confirmed near complete knockout of progranulin in neurons in Nes-cKO mice, while microglial progranulin levels remained similar to that of wild-type animals. Overall brain progranulin levels were reduced by about 50% in Nes-cKO, and no Grn was detected in primary Nes-cKO neurons. Nes-cKO mice aged to 12months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for most of these measures in Grn-null animals. We conclude that neuron-specific loss of progranulin is not sufficient to cause similar neuropathological changes to those seen in constitutive Grn-null animals. Our results suggest that increased lipofuscinosis and gliosis in Grn-null animals are not caused by intrinsic progranulin deficiency in neurons, and that microglia-derived progranulin may be sufficient to maintain neuronal health and homeostasis in the brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Association Between Depression and Functional Vision Loss in Persons 20 Years of Age or Older in the United States, NHANES 2005–2008

PubMed Central

Zhang, Xinzhi; Bullard, Kai McKeever; Cotch, Mary Frances; Wilson, M. Roy; Rovner, Barry W.; McGwin, Gerald; Owsley, Cynthia; Barker, Lawrence; Crews, John E.; Saaddine, Jinan B.

2013-01-01

Importance This study provides further evidence from a national sample to generalize the relationship between depression and vision loss to adults across the age spectrum. Better recognition of depression among people reporting reduced ability to perform routine activities of daily living due to vision loss is warranted. Objectives To estimate, in a national survey of US adults 20 years of age or older, the prevalence of depression among adults reporting visual function loss and among those with visual acuity impairment. The relationship between depression and vision loss has not been reported in a nationally representative sample of US adults. Previous studies have been limited to specific cohorts and predominantly focused on the older population. Design The National Health and Nutrition Examination Survey (NHANES) 2005–2008. Setting A cross-sectional, nationally representative sample of adults, with prevalence estimates weighted to represent the civilian, noninstitutionalized US population. Participants A total of 10 480 US adults 20 years of age or older. Main Outcome Measures Depression, as measured by the 9-item Patient Health Questionnaire depression scale, and vision loss, as measured by visual function using a questionnaire and by visual acuity at examination. Results In 2005–2008, the estimated crude prevalence of depression (9-item Patient Health Questionnaire score of ≥10) was 11.3% (95% CI, 9.7%–13.2%) among adults with self-reported visual function loss and 4.8% (95% CI, 4.0%–5.7%) among adults without. The estimated prevalence of depression was 10.7% (95% CI, 8.0%–14.3%) among adults with presenting visual acuity impairment (visual acuity worse than 20/40 in the better-seeing eye) compared with 6.8% (95% CI, 5.8%–7.8%) among adults with normal visual acuity. After controlling for age, sex, race/ethnicity, marital status, living alone or not, education, income, employment status, health insurance, body mass index, smoking, binge drinking, general health status, eyesight worry, and major chronic conditions, self-reported visual function loss remained significantly associated with depression (overall odds ratio, 1.9 [95% CI, 1.6–2.3]), whereas the association between presenting visual acuity impairment and depression was no longer statistically significant. Conclusions and Relevance Self-reported visual function loss, rather than loss of visual acuity, is significantly associated with depression. Health professionals should be aware of the risk of depression among persons reporting visual function loss. PMID:23471505

Separable roles of UFO during floral development revealed by conditional restoration of gene function.

PubMed

Laufs, Patrick; Coen, Enrico; Kronenberger, Jocelyne; Traas, Jan; Doonan, John

2003-02-01

The UNUSUAL FLORAL ORGANS (UFO) gene is required for several aspects of floral development in Arabidopsis including specification of organ identity in the second and third whorls and the proper pattern of primordium initiation in the inner three whorls. UFO is expressed in a dynamic pattern during the early phases of flower development. Here we dissect the role of UFO by ubiquitously expressing it in ufo loss-of-function flowers at different developmental stages and for various durations using an ethanol-inducible expression system. The previously known functions of UFO could be separated and related to its expression at specific stages of development. We show that a 24- to 48-hour period of UFO expression from floral stage 2, before any floral organs are visible, is sufficient to restore normal petal and stamen development. The earliest requirement for UFO is during stage 2, when the endogenous UFO gene is transiently expressed in the centre of the wild-type flower and is required to specify the initiation patterns of petal, stamen and carpel primordia. Petal and stamen identity is determined during stages 2 or 3, when UFO is normally expressed in the presumptive second and third whorl. Although endogenous UFO expression is absent from the stamen whorl from stage 4 onwards, stamen identity can be restored by UFO activation up to stage 6. We also observed floral phenotypes not observed in loss-of-function or constitutive gain-of-function backgrounds, revealing additional roles of UFO in outgrowth of petal primordia.

High frequency, high temperature specific core loss and dynamic B-H hysteresis loop characteristics of soft magnetic alloys

NASA Technical Reports Server (NTRS)

Wieserman, W. R.; Schwarze, G. E.; Niedra, J. M.

1990-01-01

Limited experimental data exists for the specific core loss and dynamic B-H loops for soft magnetic materials for the combined conditions of high frequency and high temperature. This experimental study investigates the specific core loss and dynamic B-H loop characteristics of Supermalloy and Metglas 2605SC over the frequency range of 1 to 50 kHz and temperature range of 23 to 300 C under sinusoidal voltage excitation. The experimental setup used to conduct the investigation is described. The effects of the maximum magnetic flux density, frequency, and temperature on the specific core loss and on the size and shape of the B-H loops are examined.

Missed losses loom larger than missed gains: Electrodermal reactivity to decision choices and outcomes in a gambling task.

PubMed

Wu, Yin; Van Dijk, Eric; Aitken, Mike; Clark, Luke

2016-04-01

Loss aversion is a defining characteristic of prospect theory, whereby responses are stronger to losses than to equivalently sized gains (Kahneman & Tversky Econometrica, 47, 263-291, 1979). By monitoring electrodermal activity (EDA) during a gambling task, in this study we examined physiological activity during risky decisions, as well as to both obtained (e.g., gains and losses) and counterfactual (e.g., narrowly missed gains and losses) outcomes. During the bet selection phase, EDA increased linearly with bet size, highlighting the role of somatic signals in decision-making under uncertainty in a task without any learning requirement. Outcome-related EDA scaled with the magnitudes of monetary wins and losses, and losses had a stronger impact on EDA than did equivalently sized wins. Narrowly missed wins (i.e., near-wins) and narrowly missed losses (i.e., near-losses) also evoked EDA responses, and the change of EDA as a function of the size of the missed outcome was modestly greater for near-losses than for near-wins, suggesting that near-losses have more impact on subjective value than do near-wins. Across individuals, the slope for choice-related EDA (as a function of bet size) correlated with the slope for outcome-related EDA as a function of both the obtained and counterfactual outcome magnitudes, and these correlations were stronger for loss and near-loss conditions than for win and near-win conditions. Taken together, these asymmetrical EDA patterns to objective wins and losses, as well as to near-wins and near-losses, provide a psychophysiological instantiation of the value function curve in prospect theory, which is steeper in the negative than in the positive domain.

Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice.

PubMed

Derksen, Patrick W B; Braumuller, Tanya M; van der Burg, Eline; Hornsveld, Marten; Mesman, Elly; Wesseling, Jelle; Krimpenfort, Paul; Jonkers, Jos

2011-05-01

Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30-40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10-15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.

Prenatal choline availability alters the context sensitivity of Pavlovian conditioning in adult rats

PubMed Central

Lamoureux, Jeffrey A.; Meck, Warren H.; Williams, Christina L.

2008-01-01

The effects of prenatal choline availability on Pavlovian conditioning were assessed in adult male rats (3–4 mo). Neither supplementation nor deprivation of prenatal choline affected the acquisition and extinction of simple Pavlovian conditioned excitation, or the acquisition and retardation of conditioned inhibition. However, prenatal choline availability significantly altered the contextual control of these learned behaviors. Both control and choline-deprived rats exhibited context specificity of conditioned excitation as exhibited by a loss in responding when tested in an alternate context after conditioning; in contrast, choline-supplemented rats showed no such effect. When switched to a different context following extinction, however, both choline-supplemented and control rats showed substantial contextual control of responding, whereas choline-deficient rats did not. These data support the view that configural associations that rely on hippocampal function are selectively sensitive to prenatal manipulations of dietary choline during prenatal development. PMID:19050158

Post Flight Reconditioning for US Astronauts Returning from the International Space Station

NASA Technical Reports Server (NTRS)

Nieschwitz, Bruce; Guilliams, Mark E.; Hoellen, David; Loehr, Jim

2011-01-01

Prior to spaceflight, each astronaut undergoes medical requirement testing to establish a preflight baseline for physiologic functions. Astronauts returning from the International Space Station can experience deficits in all or some of the following areas: aerobic capacity, muscular strength, power, endurance, stamina, bone, balance, agility, coordination, orthostatic tolerances, proprioception, neurovestibular function and flexibility. These losses occur from living in microgravity and are consistent with deficits seen in terrestrial, de-conditioning individuals. Since 2001, the Astronaut Strength, Conditioning and Rehabilitation (ASCR) specialists have administered a reconditioning program, focusing on all deficits, which improves the physical condition of all returning astronauts. In most cases, astronauts have reached or surpassed their preflight physical condition. Purpose: This presentation will describe and explain the postflight reconditioning program for returning astronauts. Methods: The postflight reconditioning program is designed to stress the body systems that affect the following: aerobic capacity, muscular strength, power, endurance, stamina, bone, balance, agility, coordination, orthostatic tolerances, proprioception, neurovestibular function and flexibility. Postflight reconditioning begins on landing day, is scheduled for two hours per day, 7 days a week for 45 days and is tailored to the specific needs of the astronaut. Initially the program focuses on basic ambulation, cardiovascular endurance, strength, balance, flexibility and proprioception. The program advances through 45 days and specific attention is given to each astronaut s overall condition, testing results, medical status, and assigned duties after their mission. Conclusion: Astronauts will experience noticeable deficits in their physical condition after living in microgravity for an extended length of time. After completing postflight reconditioning, it is shown that astronauts have regained, and in most cases improved upon, their preflight baseline condition.

Prevalence and Losses in Quality-Adjusted Life Years of Child Health Conditions: A Burden of Disease Analysis.

PubMed

Craig, Benjamin M; Hartman, John D; Owens, Michelle A; Brown, Derek S

2016-04-01

To estimate the prevalence and losses in quality-adjusted life years (QALYs) associated with 20 child health conditions. Using data from the 2009-2010 National Survey of Children with Special Health Care Needs, preference weights were applied to 14 functional difficulties to summarize the quality of life burden of 20 health conditions. Among the 14 functional difficulties, "a little trouble with breathing" had the highest prevalence (37.1 %), but amounted to a loss of just 0.16 QALYs from the perspective of US adults. Though less prevalent, "a lot of behavioral problems" and "chronic pain" were associated with the greatest losses (1.86 and 3.43 QALYs). Among the 20 conditions, allergies and asthma were the most prevalent but were associated with the least burden. Muscular dystrophy and cerebral palsy were among the least prevalent and most burdensome. Furthermore, a scatterplot shows the association between condition prevalence and burden. In child health, condition prevalence is negatively associated with quality of life burden from the perspective of US adults. Both should be considered carefully when evaluating the appropriate role for public health prevention and interventions.

Changes in Regional Adiposity and Cardio-Metabolic Function Following a Weight Loss Program with Sibutramine in Obese Men with Obstructive Sleep Apnea

PubMed Central

Phillips, Craig L.; Yee, Brendon J.; Trenell, Mike I.; Magnussen, John S.; Wang, David; Banerjee, Dev; Berend, Norbert; Grunstein, Ronald R.

2009-01-01

Background: Although obstructive sleep apnea (OSA) is strongly linked with obesity, both conditions have been associated with increased cardiovascular risk including glucose intolerance, dyslipidemia, and hypertension independent of one another. Weight loss is known to improve both cardiovascular risk and OSA severity. The aim of this study was to evaluate cardiovascular and metabolic changes, including compartment-specific fat loss in obese OSA subjects undergoing a weight loss program. Design: Observational study. Participants: 93 men with moderate-severe OSA. Interventions: 6-month open-label weight loss trial combining sibutramine (a serotonin and noradrenaline reuptake inhibitor) with a 600-kcal deficit diet and exercise. Measurements and Results: At baseline and following 6 months of weight loss, OSA was assessed together with CT-quantified intra-abdominal and liver fat and markers of metabolic and cardiovascular function. At 6 months, weight loss and improvements in OSA were accompanied by improved insulin resistance (HOMA), increased HDL cholesterol, and reduced total cholesterol/HDL ratio. There were also reductions in measures of visceral and subcutaneous abdominal fat and liver fat. Reductions in liver fat and sleep time spent below 90% oxyhemoglobin saturation partly explained the improvement in HOMA (R2 = 0.18). In contrast, arterial stiffness (aortic augmentation index), heart rate, blood pressure, and total cholesterol did not change. Conclusions: Weight loss with sibutramine was associated with improvements in metabolic and body composition risk factors but not blood pressure or arterial stiffness. Improved insulin resistance was partly associated with reductions in liver fat and hypoxemia associated with sleep apnea. Citation: Phillips CL; Yee BJ; Trenell MI; Magnussen JS; Wang D; Banerjee D; Berend N; Grunstein RR. Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea. J Clin Sleep Med 2009;5(5):416-421. PMID:19961024

Interactive effects of climate change and biodiversity loss on ecosystem functioning.

PubMed

Pires, Aliny P F; Srivastava, Diane S; Marino, Nicholas A C; MacDonald, A Andrew M; Figueiredo-Barros, Marcos Paulo; Farjalla, Vinicius F

2018-05-01

Climate change and biodiversity loss are expected to simultaneously affect ecosystems, however research on how each driver mediates the effect of the other has been limited in scope. The multiple stressor framework emphasizes non-additive effects, but biodiversity may also buffer the effects of climate change, and climate change may alter which mechanisms underlie biodiversity-function relationships. Here, we performed an experiment using tank bromeliad ecosystems to test the various ways that rainfall changes and litter diversity may jointly determine ecological processes. Litter diversity and rainfall changes interactively affected multiple functions, but how depends on the process measured. High litter diversity buffered the effects of altered rainfall on detritivore communities, evidence of insurance against impacts of climate change. Altered rainfall affected the mechanisms by which litter diversity influenced decomposition, reducing the importance of complementary attributes of species (complementarity effects), and resulting in an increasing dependence on the maintenance of specific species (dominance effects). Finally, altered rainfall conditions prevented litter diversity from fueling methanogenesis, because such changes in rainfall reduced microbial activity by 58%. Together, these results demonstrate that the effects of climate change and biodiversity loss on ecosystems cannot be understood in isolation and interactions between these stressors can be multifaceted. © 2018 by the Ecological Society of America.

Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads

PubMed Central

Lin, Zhimiao; Zhao, Jiahui; Nitoiu, Daniela; Scott, Claire A.; Plagnol, Vincent; Smith, Frances J.D.; Wilson, Neil J.; Cole, Christian; Schwartz, Mary E.; McLean, W.H. Irwin; Wang, Huijun; Feng, Cheng; Duo, Lina; Zhou, Eray Yihui; Ren, Yali; Dai, Lanlan; Chen, Yulan; Zhang, Jianguo; Xu, Xun; O’Toole, Edel A.; Kelsell, David P.; Yang, Yong

2015-01-01

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST. PMID:25683118

Bromodomain proteins GTE9 and GTE11 are essential for specific BT2-mediated sugar and ABA responses in Arabidopsis thaliana.

PubMed

Misra, Anjali; McKnight, Thomas D; Mandadi, Kranthi K

2018-03-01

Global Transcription Factor Group E proteins GTE9 and GTE11 interact with BT2 to mediate ABA and sugar responses in Arabidopsis thaliana. BT2 is a BTB-domain protein that regulates responses to various hormone, stress and metabolic conditions in Arabidopsis thaliana. Loss of BT2 results in plants that are hypersensitive to inhibition of germination by abscisic acid (ABA) and sugars. Conversely, overexpression of BT2 results in resistance to ABA and sugars. Here, we report the roles of BT2-interacting partners GTE9 and GTE11, bromodomain and extraterminal-domain proteins of Global Transcription Factor Group E, in BT2-mediated responses to sugars and hormones. Loss-of-function mutants, gte9-1 and gte11-1, mimicked the bt2-1-null mutant responses; germination of all three mutants was hypersensitive to inhibition by glucose and ABA. Loss of either GTE9 or GTE11 in a BT2 over-expressing line blocked resistance to sugars and ABA, indicating that both GTE9 and GTE11 were required for BT2 function. Co-immunoprecipitation of BT2 and GTE9 suggested that these proteins physically interact in vivo, and presumably function together to mediate responses to ABA and sugar signals.

A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome

PubMed Central

Samaco, Rodney C.; Fryer, John D.; Ren, Jun; Fyffe, Sharyl; Chao, Hsiao-Tuan; Sun, Yaling; Greer, John J.; Zoghbi, Huda Y.; Neul, Jeffrey L.

2008-01-01

Rett Syndrome, an X-linked dominant neurodevelopmental disorder characterized by regression of language and hand use, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2). Loss of function mutations in MECP2 are also found in other neurodevelopmental disorders such as autism, Angelman-like syndrome and non-specific mental retardation. Furthermore, duplication of the MECP2 genomic region results in mental retardation with speech and social problems. The common features of human neurodevelopmental disorders caused by the loss or increase of MeCP2 function suggest that even modest alterations of MeCP2 protein levels result in neurodevelopmental problems. To determine whether a small reduction in MeCP2 level has phenotypic consequences, we characterized a conditional mouse allele of Mecp2 that expresses 50% of the wild-type level of MeCP2. Upon careful behavioral analysis, mice that harbor this allele display a spectrum of abnormalities such as learning and motor deficits, decreased anxiety, altered social behavior and nest building, decreased pain recognition and disrupted breathing patterns. These results indicate that precise control of MeCP2 is critical for normal behavior and predict that human neurodevelopmental disorders will result from a subtle reduction in MeCP2 expression. PMID:18321864

The quality of life impact of peripheral versus central vision loss with a focus on glaucoma versus age-related macular degeneration

PubMed Central

Evans, Keith; Law, Simon K; Walt, John; Buchholz, Patricia; Hansen, Jan

2009-01-01

Purpose It is well accepted that conditions that cause central vision loss (CVL) have a negative impact on functional ability and quality of life (QoL), but the impact of diseases that cause peripheral vision loss (PVL) is less well understood. Focusing on glaucoma and age-related macular degeneration (ARMD), the effects of CVL and PVL on QoL were compared. Methods A systematic literature review of publications reporting QoL in patients with CVL or PVL identified 87 publications using four generic (Short-Form Health Survey-36 and -12, EuroQoL EQ-5D and Sickness Impact Profile) and five vision-specific (National Eye Institute Visual Function Questionnaire-51, -39, and -25, Impact of Vision Impairment and Visual Function-14) QoL instruments; 33 and 15 publications reported QoL in ARMD and glaucoma, respectively. Results QoL was impaired to a similar extent by diseases associated with PVL and CVL, but different domains were affected. In contrast to ARMD, mental aspects appeared to be affected more than physical aspects in patients with glaucoma. Conclusions The differential impact upon QoL might be a function of the pathology of the diseases, for example potential for blindness and better ability to perform physical tasks due to retention of central vision may explain these observations in glaucoma. PMID:19684867

Molecular etiopathology of naturally occurring reproductive diseases in female goats

PubMed Central

Beena, V.; Pawaiya, R. V. S.; Gururaj, K.; Singh, D. D.; Mishra, A. K.; Gangwar, N. K.; Gupta, V. K.; Singh, R.; Sharma, A. K.; Karikalan, M.; Kumar, Ashok

2017-01-01

Aim: The aim of the present study was to investigate the molecular etiopathology of occurrence of reproductive diseases in female goats. Reproductive diseases in goats account for major economic losses to goat farmers in terms of valuable loss of offspring and animal productivity. Materials and Methods: A total of 660 female genitalia were examined for pathological conditions (macroscopic and microscopic lesions). The etiopathological study was carried out for the presence of pathogenic organisms such as Brucella, Chlamydia, and Campylobacter in the uterus and ovary. Based on the microscopic lesions, suspected samples were subjected to diagnostic polymerase chain reaction (PCR) for various etiological agents employing 16srRNA genus specific primers for Campylobacter and Chlamydophila and OMP31 gene-based PCR for Brucella melitensis and nested PCR using ITS-1 gene primers for Toxoplasma gondii. For Brucella suspected samples, immunohistochemistry (IHC) was also performed. Results: In studied female genitalia, 108 (16.30%) showed gross abnormalities with overall 23.32% occurrence of pathological conditions (macroscopic and microscopic lesions). Pathological involvement of the uterus was the highest 68 (62.96%), followed by the ovaries 27 (25%) and other organs. Major uterine condition observed was endometritis (5.60%). In uterine infections, 35 (5.30%) samples were found positive for Campylobacter spp., 12 (1.81%) samples for B. melitensis, and 3 (0.45%) samples were positive for Chlamydophila spp. Among the samples positive for B. melitensis by PCR, 3 were found positive by IHC also. Corynebacterium ovis was detected by PCR using specific primers in a case of hydrosalpinx. It was concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. Conclusion: The present study concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. PMID:28919691

40 CFR 266.240 - How could you lose the conditional exemption for your LLMW and what action must you take?

Code of Federal Regulations, 2011 CFR

2011-07-01

... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF SPECIFIC HAZARDOUS WASTES AND SPECIFIC TYPES OF HAZARDOUS WASTE MANAGEMENT FACILITIES Conditional Exemption for Low-Level Mixed Waste Storage, Treatment, Transportation and Disposal. Loss of Conditional Exemption § 266...

40 CFR 266.240 - How could you lose the conditional exemption for your LLMW and what action must you take?

Code of Federal Regulations, 2014 CFR

2014-07-01

... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF SPECIFIC HAZARDOUS WASTES AND SPECIFIC TYPES OF HAZARDOUS WASTE MANAGEMENT FACILITIES Conditional Exemption for Low-Level Mixed Waste Storage, Treatment, Transportation and Disposal Loss of Conditional Exemption § 266...

40 CFR 266.240 - How could you lose the conditional exemption for your LLMW and what action must you take?

Code of Federal Regulations, 2010 CFR

2010-07-01

... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF SPECIFIC HAZARDOUS WASTES AND SPECIFIC TYPES OF HAZARDOUS WASTE MANAGEMENT FACILITIES Conditional Exemption for Low-Level Mixed Waste Storage, Treatment, Transportation and Disposal. Loss of Conditional Exemption § 266...

40 CFR 266.240 - How could you lose the conditional exemption for your LLMW and what action must you take?

Code of Federal Regulations, 2012 CFR

2012-07-01

... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF SPECIFIC HAZARDOUS WASTES AND SPECIFIC TYPES OF HAZARDOUS WASTE MANAGEMENT FACILITIES Conditional Exemption for Low-Level Mixed Waste Storage, Treatment, Transportation and Disposal Loss of Conditional Exemption § 266...

Measuring the relative resilience of subarctic lakes to global change: redundancies of functions within and across temporal scales

USGS Publications Warehouse

Angeler, David G.; Allen, Craig R.; Johnson, Richard K.

2013-01-01

1. Ecosystems at high altitudes and latitudes are expected to be particularly vulnerable to the effects of global change. We assessed the responses of littoral invertebrate communities to changing abiotic conditions in subarctic Swedish lakes with long-term data (1988–2010) and compared the responses of subarctic lakes with those of more southern, hemiboreal lakes. 2. We used a complex systems approach, based on multivariate time-series modelling, and identified dominant and distinct temporal frequencies in the data; that is, we tracked community change at distinct temporal scales. We determined the distribution of functional feeding groups of invertebrates within and across temporal scales. Within and cross-scale distributions of functions have been considered to confer resilience to ecosystems, despite changing environmental conditions. 3. Two patterns of temporal change within the invertebrate communities were identified that were consistent across the lakes. The first pattern was one of monotonic change associated with changing abiotic lake conditions. The second was one of showing fluctuation patterns largely unrelated to gradual environmental change. Thus, two dominant and distinct temporal frequencies (temporal scales) were present in all lakes analysed. 4. Although the contribution of individual feeding groups varied between subarctic and hemiboreal lakes, they shared overall similar functional attributes (richness, evenness, diversity) and redundancies of functions within and between the observed temporal scales. This highlights similar resilience characteristics in subarctic and hemiboreal lakes. 5. Synthesis and applications. The effects of global change can be particularly strong at a single scale in ecosystems. Over time, this can cause monotonic change in communities and eventually lead to a loss of important ecosystem services upon reaching a critical threshold. Dynamics at other spatial or temporal scales can be unrelated to environmental change. The relative ‘intactness’ of these scales that are unaffected by global change and the persistence of functions at those scales may safeguard the whole system from the potential loss of functions at the scale at which global change impacts can be substantial. Thus, an understanding of scale-specific processes provides managers with a realistic assessment of vulnerabilities and the relative resilience of ecosystems to environmental change. Explicit consideration of ‘intact’ and ‘affected’ scales in analyses of global change impacts provides opportunities to tailor more specific management plans.

Attitudes towards and perceptions of visual loss and its causes among Hong Kong Chinese adults.

PubMed

Lau, Joseph Tak Fai; Lee, Vincent; Fan, Dorothy; Lau, Mason; Michon, John

2004-06-01

As part of a study of visual function among Hong Kong Chinese adults, their attitudes and perceptions related to visual loss were examined. These included fear of visual loss, negative functional impacts of visual loss, the relationship between ageing and visual loss and help-seeking behaviours related to visual loss. Demographic factors associated with these variables were also studied. The study population were people aged 40 and above randomly selected from the Shatin district of Hong Kong. The participants underwent eye examinations that included visual acuity, intraocular pressure measurement, visual field, slit-lamp biomicroscopy and ophthalmoscopy. The primary cause of visual disability was recorded. The participants were also asked about their attitudes and perceptions regarding visual loss using a structured questionnaire. The prevalence of bilateral visual disability was 2.2% among adults aged 40 or above and 6.4% among adults aged 60 or above. Nearly 36% of the participants selected blindness as the most feared disabling medical condition, which was substantially higher than conditions such as dementia, loss of limbs, deafness or aphasia. Inability to take care of oneself (21.0%), inconvenience related to mobility (20.2%) and inability to work (14.8%) were the three most commonly mentioned 'worst impact' effects of visual loss. Fully 68% of the participants believed that loss of vision is related to ageing. A majority of participants would seek help and advice from family members in case of visual loss. Visual function is perceived to be very important by Hong Kong Chinese adults. The fear of visual loss is widespread and particularly affects self-care and functional abilities. Visual loss is commonly seen as related to ageing. Attitudes and perceptions in this population may be modified by educational and outreach efforts in order to take advantage of preventive measures.

Tooth loss patterns in older adults with special needs: a Minnesota cohort

PubMed Central

Chen, Xi; Clark, Jennifer J

2011-01-01

This study was conducted to detail tooth loss patterns in older adults with special needs. A total of 491 elderly subjects with special needs were retrospectively selected and followed during 10/1999-12/2006. Medical, dental, cognitive, and functional assessments were abstracted from dental records and used to predict risk of tooth loss. Tooth loss events were recorded for subjects during follow-up. Chi-squared tests were used to study the association between tooth loss and the selected risk factors. Logistic, poisson, and negative binomial regressions were developed to study tooth loss patterns. Overall, 27% of the subjects lost at least one tooth during follow-up. Fourteen subjects had tooth loss events per 100 person-years. Tooth loss pattern did not differ significantly among different special-needs subgroups (i.e. community-dwelling vs. long-term care, physically disabled vs. functionally independent). Special-needs subjects with three or more active dental conditions at arrival had more than twice the risk of losing teeth than those without any existing conditions. After adjusting other factors, the number of carious teeth or retained roots at arrival was a significant predictor of tooth loss for older adults with special needs (P=0.001). These findings indicate that appropriately managing active caries and associated conditions is important to prevent tooth loss for older adults with special needs. PMID:21449213

Preseason Functional Movement Screen Predicts Risk of Time-Loss Injury in Experienced Male Rugby Union Athletes.

PubMed

Duke, Sean R; Martin, Steve E; Gaul, Catherine A

2017-10-01

The purpose of this study was to determine the relationship between Functional Movement Screen (FMS) score and the risk of time-loss injury in experienced male rugby union athletes. A secondary purpose was to determine the relationship between FMS-determined asymmetries and the risk of time-loss injury in these athletes. Functional Movement Screen scores were collected from male rugby union athletes (n = 73) during preseason and half-way through one 8-month season. Time-loss injury data were collected throughout the full season. A receiver-operator characteristic curve was created for each half of the season to identify FMS composite and asymmetry cut-off scores associated with increased likelihood of injury and determined odds ratios, sensitivity, and specificity in evaluating FMS as a predictor of injury risk. Odds ratio analyses revealed that when compared with those scoring >14, athletes with an FMS ≤14 were 10.42 times more likely (95% confidence interval [CI]: 1.28-84.75, p = 0.007) to have sustained injury in the first half of the season and 4.97 times (95% CI: 1.02-24.19, p = 0.029) more likely in the second half of the season. The presence of asymmetries was not associated with increased likelihood of injury. Experienced male rugby union athletes with FMS composite scores ≤14 are significantly more likely to sustain time-loss injury in a competitive season than those scoring >14. The quality of fundamental movement, as assessed by the FMS, is predictive of time-loss injury risk in experienced rugby union athletes and should be considered an important preseason assessment tool used by strength and conditioning and medical professionals in this sport with inherently high injury rates.

Performance of bolted closure joint elastomers under cask aging conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verst, C.; Sindelar, R.; Skidmore, E.

The bolted closure joint of a bare spent fuel cask is susceptible to age-related degradation and potential loss of confinement function under long-term storage conditions. Elastomeric seals, a component of the joint typically used to facilitate leak testing of the primary seal that includes the metallic seal and bolting, is susceptible to degradation over time by several mechanisms, principally via thermo-oxidation, stress-relaxation, and radiolytic degradation under time and temperature condition. Irradiation and thermal exposure testing and evaluation of an ethylene-propylene diene monomer (EPDM) elastomeric seal material similar to that used in the CASTOR® V/21 cask for a matrix of temperaturemore » and radiation exposure conditions relevant to the cask extended storage conditions, and development of semiempirical predictive models for loss of sealing force is in progress. A special insert was developed to allow Compressive Stress Relaxation (CSR) measurements before and after the irradiation and/or thermal exposure without unloading the elastomer. A condition of the loss of sealing force for the onset of leakage was suggested. The experimentation and modeling being performed could enable acquisition of extensive coupled aging data as well as an estimation of the timeframe when loss of sealing function under aging (temperature/radiation) conditions may occur.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allison, Steven D.

The role of specific micro-organisms in the carbon cycle, and their responses to environmental change, are unknown in most ecosystems. This knowledge gap limits scientists’ ability to predict how important ecosystem processes, like soil carbon storage and loss, will change with climate and other environmental factors. The investigators addressed this knowledge gap by transplanting microbial communities from different environments into new environments and measuring the response of community composition and carbon cycling over time. Using state-of-the-art sequencing techniques, computational tools, and nanotechnology, the investigators showed that microbial communities on decomposing plant material shift dramatically with natural and experimentally-imposed drought. Microbialmore » communities also shifted in response to added nitrogen, but the effects were smaller. These changes had implications for carbon cycling, with lower rates of carbon loss under drought conditions, and changes in the efficiency of decomposition with nitrogen addition. Even when transplanted into the same conditions, microbial communities from different environments remained distinct in composition and functioning for up to one year. Changes in functioning were related to differences in enzyme gene content across different microbial groups. Computational approaches developed for this project allowed the conclusions to be tested more broadly in other ecosystems, and new computer models will facilitate the prediction of microbial traits and functioning across environments. The data and models resulting from this project benefit the public by improving the ability to predict how microbial communities and carbon cycling functions respond to climate change, nutrient enrichment, and other large-scale environmental changes.« less

Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia.

PubMed

Fielding, Roger A; Vellas, Bruno; Evans, William J; Bhasin, Shalender; Morley, John E; Newman, Anne B; Abellan van Kan, Gabor; Andrieu, Sandrine; Bauer, Juergen; Breuille, Denis; Cederholm, Tommy; Chandler, Julie; De Meynard, Capucine; Donini, Lorenzo; Harris, Tamara; Kannt, Aimo; Keime Guibert, Florence; Onder, Graziano; Papanicolaou, Dimitris; Rolland, Yves; Rooks, Daniel; Sieber, Cornel; Souhami, Elisabeth; Verlaan, Sjors; Zamboni, Mauro

2011-05-01

Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

A validated model to predict microalgae growth in outdoor pond cultures subjected to fluctuating light intensities and water temperatures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huesemann, Michael H.; Crowe, Braden J.; Waller, Peter

Here, a microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in outdoor ponds subjected to fluctuating light intensities and water temperatures. Growth is modeled by first estimating the light attenuation by biomass according to a scatter-corrected Beer-Lambert Law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model requires the following experimentally determined strain-specific input parameters: specific growth rate as a function of light intensity and temperature, biomass loss rate in the dark as amore » function of temperature and average light intensity during the preceding light period, and the scatter-corrected biomass light absorption coefficient. The model was successful in predicting the growth performance and biomass productivity of three different microalgae species (Chlorella sorokiniana, Nannochloropsis salina, and Picochlorum sp.) in raceway pond cultures (batch and semi-continuous) subjected to diurnal sunlight intensity and water temperature variations. Model predictions were moderately sensitive to minor deviations in input parameters. To increase the predictive power of this and other microalgae biomass growth models, a better understanding of the effects of mixing-induced rapid light dark cycles on photo-inhibition and short-term biomass losses due to dark respiration in the aphotic zone of the pond is needed.« less

A validated model to predict microalgae growth in outdoor pond cultures subjected to fluctuating light intensities and water temperatures

DOE PAGES

Huesemann, Michael H.; Crowe, Braden J.; Waller, Peter; ...

2015-12-11

Here, a microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in outdoor ponds subjected to fluctuating light intensities and water temperatures. Growth is modeled by first estimating the light attenuation by biomass according to a scatter-corrected Beer-Lambert Law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model requires the following experimentally determined strain-specific input parameters: specific growth rate as a function of light intensity and temperature, biomass loss rate in the dark as amore » function of temperature and average light intensity during the preceding light period, and the scatter-corrected biomass light absorption coefficient. The model was successful in predicting the growth performance and biomass productivity of three different microalgae species (Chlorella sorokiniana, Nannochloropsis salina, and Picochlorum sp.) in raceway pond cultures (batch and semi-continuous) subjected to diurnal sunlight intensity and water temperature variations. Model predictions were moderately sensitive to minor deviations in input parameters. To increase the predictive power of this and other microalgae biomass growth models, a better understanding of the effects of mixing-induced rapid light dark cycles on photo-inhibition and short-term biomass losses due to dark respiration in the aphotic zone of the pond is needed.« less

Role of Protein Carbonylation in Skeletal Muscle Mass Loss Associated with Chronic Conditions

PubMed Central

Barreiro, Esther

2016-01-01

Muscle dysfunction, characterized by a reductive remodeling of muscle fibers, is a common systemic manifestation in highly prevalent conditions such as chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), cancer cachexia, and critically ill patients. Skeletal muscle dysfunction and impaired muscle mass may predict morbidity and mortality in patients with chronic diseases, regardless of the underlying condition. High levels of oxidants may alter function and structure of key cellular molecules such as proteins, DNA, and lipids, leading to cellular injury and death. Protein oxidation including protein carbonylation was demonstrated to modify enzyme activity and DNA binding of transcription factors, while also rendering proteins more prone to proteolytic degradation. Given the relevance of protein oxidation in the pathophysiology of many chronic conditions and their comorbidities, the current review focuses on the analysis of different studies in which the biological and clinical significance of the modifications induced by reactive carbonyls on proteins have been explored so far in skeletal muscles of patients and animal models of chronic conditions such as COPD, disuse muscle atrophy, cancer cachexia, sepsis, and physiological aging. Future research will elucidate the specific impact and sites of reactive carbonyls on muscle protein content and function in human conditions. PMID:28248228

Pbx3 is required for normal locomotion and dorsal horn development.

PubMed

Rottkamp, Catherine A; Lobur, Katherine J; Wladyka, Cynthia L; Lucky, Amy K; O'Gorman, Stephen

2008-02-01

The transcription cofactor Pbx3 is critical for the function of hindbrain circuits controlling respiration in mammals, but the perinatal lethality caused by constitutively null mutations has hampered investigation of other roles it may play in neural development and function. Here we report that the conditional loss of Pbx3 function in most tissues caudal to the hindbrain resulted in progressive deficits of posture, locomotion, and sensation that became apparent during adolescence. In adult mutants, the size of the dorsal horn of the spinal cord and the numbers of calbindin-, PKC-gamma, and calretinin-expressing neurons in laminae I-III were markedly reduced, but the ventral cord and peripheral nervous system appeared normal. In the embryonic dorsal horn, Pbx3 expression was restricted to a subset of glutamatergic neurons, but its absence did not affect the initial balance of excitatory and inhibitory interneuron phenotypes. By embryonic day 15 a subset of Meis(+) glutamatergic neurons assumed abnormally superficial positions and the number of calbindin(+) neurons was increased three-fold in the mutants. Loss of Pbx3 function thus leads to the incorrect specification of some glutamatergic neurons in the dorsal horn and alters the integration of peripheral sensation into the spinal circuitry regulating locomotion.

Overexpression of the rice AKT1 potassium channel affects potassium nutrition and rice drought tolerance

PubMed Central

Ahmad, Izhar; Mian, Afaq; Maathuis, Frans J. M.

2016-01-01

Potassium (K+) is the most important cationic nutrient for all living organisms and has roles in most aspects of plant physiology. To assess the impact of one of the main K+ uptake components, the K+ inward rectifying channel AKT1, we characterized both loss of function and overexpression of OsAKT1 in rice. In many conditions, AKT1 expression correlated with K+ uptake and tissue K+ levels. No salinity-related growth phenotype was observed for either loss or gain of function mutants. However, a correlation between AKT1 expression and root Na+ when the external Na/K ratio was high suggests that there may be a role for AKT1 in Na+ uptake in such conditions. In contrast to findings with Arabidopsis thaliana, we did not detect any change in growth of AKT1 loss of function mutants in the presence of NH4 +. Nevertheless, NH4 +-dependent inhibition was detected during K+ uptake assays in loss of function and wild type plants, depending on pre-growth conditions. The most prominent result of OsAKT1 overexpression was a reduction in sensitivity to osmotic/drought stress in transgenic plants: the data suggest that AKT1 overexpression improved rice osmotic and drought stress tolerance by increasing tissue levels of K+, especially in the root. PMID:26969743

Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.

PubMed

Jakobsson, Lars; van Meeteren, Laurens A

2013-05-15

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor β (TGF-β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-β family in the mouse. Copyright © 2013 Elsevier Inc. All rights reserved.

The Generation of Dehydroalanine Residues in Protonated Polypeptides: Ion/Ion Reactions for Introducing Selective Cleavages

NASA Astrophysics Data System (ADS)

Peng, Zhou; Bu, Jiexun; McLuckey, Scott A.

2017-09-01

We examine a gas-phase approach for converting a subset of amino acid residues in polypeptide cations to dehydroalanine (Dha). Subsequent activation of the modified polypeptide ions gives rise to specific cleavage N-terminal to the Dha residue. This process allows for the incorporation of selective cleavages in the structural characterization of polypeptide ions. An ion/ion reaction within the mass spectrometer between a multiply protonated polypeptide and the sulfate radical anion introduces a radical site into the multiply protonated polypeptide reactant. Subsequent collisional activation of the polypeptide radical cation gives rise to radical side chain loss from one of several particular amino acid side chains (e.g., leucine, asparagine, lysine, glutamine, and glutamic acid) to yield a Dha residue. The Dha residues facilitate preferential backbone cleavages to produce signature c- and z-ions, demonstrated with cations derived from melittin, mechano growth factor (MGF), and ubiquitin. The efficiencies for radical side chain loss and for subsequent generation of specific c- and z-ions have been examined as functions of precursor ion charge state and activation conditions using cations of ubiquitin as a model for a small protein. It is noted that these efficiencies are not strongly dependent on ion trap collisional activation conditions but are sensitive to precursor ion charge state. Moderate to low charge states show the greatest overall yields for the specific Dha cleavages, whereas small molecule losses (e.g., water/ammonia) dominate at the lowest charge states and proton catalyzed amide bond cleavages that give rise to b- and y-ions tend to dominate at high charge states. [Figure not available: see fulltext.

Proprioception: where are we now? A commentary on clinical assessment, changes across the life course, functional implications and future interventions.

PubMed

Suetterlin, Karen Joan; Sayer, Avan Aihie

2014-05-01

Proprioception, the sense of where one is in space, is essential for effective interaction with the environment. A lack of or reduction in proprioceptive acuity has been directly correlated with falls and with reduced functional independence in older people. Proprioceptive losses have also been shown to negatively correlate with functional recovery post stroke and play a significant role in other conditions such as Parkinson's disease. However, despite its central importance to many geriatric syndromes, the clinical assessment of proprioception has remained remarkably static. We look at approaches to the clinical assessment of proprioception, changes in proprioception across the life course, functional implications of proprioception in health and disease and the potential for targeted interventions in the future such as joint taping, and proprioception-specific rehabilitation and footwear.

Dnmt1 regulates the myogenic lineage specification of muscle stem cells.

PubMed

Liu, Renjing; Kim, Kun-Yong; Jung, Yong-Wook; Park, In-Hyun

2016-10-18

DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle. These mice were born runted, with smaller body weights, and reduced ability to form myotubes in vitro. We show that expression of Id-1, a negative regulator of myogenesis, is enhanced in Dnmt1-deficient cultures, leading to enhanced transdifferentiation of myoblasts toward the osteogenic lineage. Thus, these studies demonstrate that Dnmt1 influences cellular identity and determines lineage fidelity.

Dnmt1 regulates the myogenic lineage specification of muscle stem cells

PubMed Central

Liu, Renjing; Kim, Kun-Yong; Jung, Yong-Wook; Park, In-Hyun

2016-01-01

DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle. These mice were born runted, with smaller body weights, and reduced ability to form myotubes in vitro. We show that expression of Id-1, a negative regulator of myogenesis, is enhanced in Dnmt1-deficient cultures, leading to enhanced transdifferentiation of myoblasts toward the osteogenic lineage. Thus, these studies demonstrate that Dnmt1 influences cellular identity and determines lineage fidelity. PMID:27752090

Identifying the perfect absorption of metamaterial absorbers

NASA Astrophysics Data System (ADS)

Duan, G.; Schalch, J.; Zhao, X.; Zhang, J.; Averitt, R. D.; Zhang, X.

2018-01-01

We present a detailed analysis of the conditions that result in unity absorption in metamaterial absorbers to guide the design and optimization of this important class of functional electromagnetic composites. Multilayer absorbers consisting of a metamaterial layer, dielectric spacer, and ground plane are specifically considered. Using interference theory, the dielectric spacer thickness and resonant frequency for unity absorption can be numerically determined from the functional dependence of the relative phase shift of the total reflection. Further, using transmission line theory in combination with interference theory we obtain analytical expressions for the unity absorption resonance frequency and corresponding spacer layer thickness in terms of the bare resonant frequency of the metamaterial layer and metallic and dielectric losses within the absorber structure. These simple expressions reveal a redshift of the unity absorption frequency with increasing loss that, in turn, necessitates an increase in the thickness of the dielectric spacer. The results of our analysis are experimentally confirmed by performing reflection-based terahertz time-domain spectroscopy on fabricated absorber structures covering a range of dielectric spacer thicknesses with careful control of the loss accomplished through water absorption in a semiporous polyimide dielectric spacer. Our findings can be widely applied to guide the design and optimization of the metamaterial absorbers and sensors.

Is wetland mitigation successful in Southern California?

NASA Astrophysics Data System (ADS)

Cummings, D. L.; Rademacher, L. K.

2004-12-01

Wetlands perform many vital functions within their landscape position; they provide unique habitats for a variety of flora and fauna and they act as treatment systems for upstream natural and anthropogenic waste. California has lost an estimated 91% of its wetlands. Despite the 1989 "No Net Loss" policy and mitigation requirements by the regulatory agencies, the implemented mitigation may not be offsetting wetlands losses. The "No Net Loss" policy is likely failing for numerous reasons related to processes in the wetlands themselves and the policies governing their recovery. Of particular interest is whether these mitigation sites are performing essential wetlands functions. Specific questions include: 1) Are hydric soil conditions forming in mitigation sites; and, 2) are the water quality-related chemical transformations that occur in natural wetlands observed in mitigation sites. This study focuses on success (or lack of success) in wetlands mitigation sites in Southern California. Soil and water quality investigations were conducted in wetland mitigation sites deemed to be successful by vegetation standards. Observations of the Standard National Resource Conservation Service field indicators of reducing conditions were made to determine whether hydric soil conditions have developed in the five or more years since the implementation of mitigation plans. In addition, water quality measurements were performed at the inlet and outlet of these mitigation sites to determine whether these sites perform similar water quality transformations to natural wetlands within the same ecosystem. Water quality measurements included nutrient, trace metal, and carbon species measurements. A wetland location with minimal anthropogenic changes and similar hydrologic and vegetative features was used as a control site. All sites selected for study are within a similar ecosystem, in the interior San Diego and western Riverside Counties, in Southern California.

Temporal dynamics of CO 2 and CH 4 loss potentials in response to rapid hydrological shifts in tidal freshwater wetland soils

DOE Office of Scientific and Technical Information (OSTI.GOV)

RoyChowdhury, Taniya; Bramer, Lisa; Hoyt, David W.

tEarth System Models predict climate extremes that will impact regional and global hydrology. Aquatic-terrestrial transition zones like wetlands are subjected to the immediate consequence of climate change with shifts in the magnitude and dynamics of hydrologic flow. Such fluctuating hydrology can alterthe nature and rate of biogeochemical transformations and significantly impact the carbon balance ofthe ecosystem. We tested the impacts of fluctuating hydrology and, specifically, the role of antecedentmoisture conditions in determining the dominant carbon loss mechanisms in soils sampled from a tidalfreshwater wetland system in the lower Columbia River, WA, USA. Our objective was to understand shiftsin biogeochemical processesmore » in response to changing soil moisture, based on soil respiration and methaneproduction rates, and to elucidate such responses based on the observed electron acceptor and metaboliteprofiles under laboratory conditions. Metabolomics and biogeochemical process rates provided evidencethat soil redox was the principal factor driving metabolic function. Fluctuating redox conditions alteredterminal electron acceptor and donor availability and recovery strengths of their concentrations in soilsuch that a disproportionate release of carbon dioxide stemmed from alternative anaerobic degradationprocesses like sulfate and iron reduction compared to carbon loss due to methanogenesis. Our resultsshow that extended and short-term saturation created conditions conducive to increasing metaboliteavailability for anaerobic decomposition processes, with a significant lag in methanogenesis. In contrast,extended drying caused a cellular-level stress response and rapid recycling of alternate electron acceptors.« less

Temporal dynamics of CO2and CH4 loss potentials in response to rapid hydrological shifts in tidal freshwater wetland soils

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roy Chowdhury, Taniya; Bramer, Lisa M.; Hoyt, Davi

2018-04-15

tEarth System Models predict climate extremes that will impact regional and global hydrology. Aquatic-terrestrial transition zones like wetlands are subjected to the immediate consequence of climate change with shifts in the magnitude and dynamics of hydrologic flow. Such fluctuating hydrology can alterthe nature and rate of biogeochemical transformations and significantly impact the carbon balance ofthe ecosystem. We tested the impacts of fluctuating hydrology and, specifically, the role of antecedentmoisture conditions in determining the dominant carbon loss mechanisms in soils sampled from a tidalfreshwater wetland system in the lower Columbia River, WA, USA. Our objective was to understand shiftsin biogeochemical processesmore » in response to changing soil moisture, based on soil respiration and methaneproduction rates, and to elucidate such responses based on the observed electron acceptor and metaboliteprofiles under laboratory conditions. Metabolomics and biogeochemical process rates provided evidencethat soil redox was the principal factor driving metabolic function. Fluctuating redox conditions alteredterminal electron acceptor and donor availability and recovery strengths of their concentrations in soilsuch that a disproportionate release of carbon dioxide stemmed from alternative anaerobic degradationprocesses like sulfate and iron reduction compared to carbon loss due to methanogenesis. Our resultsshow that extended and short-term saturation created conditions conducive to increasing metaboliteavailability for anaerobic decomposition processes, with a significant lag in methanogenesis. In contrast,extended drying caused a cellular-level stress response and rapid recycling of alternate electron acceptors.« less

A transgenic resource for conditional competitive inhibition of conserved Drosophila microRNAs

PubMed Central

Fulga, Tudor A.; McNeill, Elizabeth M.; Binari, Richard; Yelick, Julia; Blanche, Alexandra; Booker, Matthew; Steinkraus, Bruno R.; Schnall-Levin, Michael; Zhao, Yong; DeLuca, Todd; Bejarano, Fernando; Han, Zhe; Lai, Eric C.; Wall, Dennis P.; Perrimon, Norbert; Van Vactor, David

2015-01-01

Although the impact of microRNAs (miRNAs) in development and disease is well established, understanding the function of individual miRNAs remains challenging. Development of competitive inhibitor molecules such as miRNA sponges has allowed the community to address individual miRNA function in vivo. However, the application of these loss-of-function strategies has been limited. Here we offer a comprehensive library of 141 conditional miRNA sponges targeting well-conserved miRNAs in Drosophila. Ubiquitous miRNA sponge delivery and consequent systemic miRNA inhibition uncovers a relatively small number of miRNA families underlying viability and gross morphogenesis, with false discovery rates in the 4–8% range. In contrast, tissue-specific silencing of muscle-enriched miRNAs reveals a surprisingly large number of novel miRNA contributions to the maintenance of adult indirect flight muscle structure and function. A strong correlation between miRNA abundance and physiological relevance is not observed, underscoring the importance of unbiased screens when assessing the contributions of miRNAs to complex biological processes. PMID:26081261

Coping with heat stress during match-play tennis: does an individualised hydration regimen enhance performance and recovery?

PubMed

Périard, Julien D; Racinais, Sebastien; Knez, Wade L; Herrera, Christopher P; Christian, Ryan J; Girard, Olivier

2014-04-01

To determine whether an individualised hydration regimen reduces thermal, physiological and perceptual strain during match-play tennis in the heat, and minimises alterations in neuromuscular function and physical performance postmatch and into recovery. 10 men undertook two matches for an effective playing time (ball in play) of 20 min (∼113 min) in ∼37°C and ∼33% RH conditions. Participants consumed fluids ad libitum during the first match (HOT) and followed a hydration regimen (HYD) in the second match based on undertaking play euhydrated, standardising sodium intake and minimising body mass losses. HYD improved prematch urine specific gravity (1.013±0.006 vs 1.021±0.009 g/mL; p<0.05). Body mass losses (∼0.3%), fluid intake (∼2 L/h) and sweat rates (∼1.6 L/h) were similar between conditions. Core temperature was higher during the first 10 min of effective play in HOT (p<0.05), but increased similarly (∼39.3°C) on match completion. Heart rate was higher (∼11 bpm) throughout HOT (p<0.001). Thermal sensation was higher during the first 7.5 min of effective play in HOT (p<0.05). Postmatch knee extensor and plantar flexor strength losses, along with reductions in 15 m sprint time and repeated-sprint ability (p<0.05), were similar in both conditions, and were restored within 24 h. Both the hydration regimen and ad libitum fluid consumption allowed for minimal body mass losses (<1%). However, undertaking match-play in a euhydrated state attenuated thermal, physiological and perceptual strain. Maximal voluntary strength in the lower limbs and repeated-sprint ability deteriorated similarly in both conditions, but were restored within 24 h.

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

PubMed Central

Tomassy, Giulio Srubek; De Leonibus, Elvira; Jabaudon, Denis; Lodato, Simona; Alfano, Christian; Mele, Andrea; Macklis, Jeffrey D.; Studer, Michèle

2010-01-01

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. PMID:20133588

The Communicative Function of Sad Facial Expressions.

PubMed

Reed, Lawrence Ian; DeScioli, Peter

2017-01-01

What are the communicative functions of sad facial expressions? Research shows that people feel sadness in response to losses but it's unclear whether sad expressions function to communicate losses to others and if so, what makes these signals credible. Here we use economic games to test the hypothesis that sad expressions lend credibility to claims of loss. Participants play the role of either a proposer or recipient in a game with a fictional backstory and real monetary payoffs. The proposers view a (fictional) video of the recipient's character displaying either a neutral or sad expression paired with a claim of loss. The proposer then decided how much money to give to the recipient. In three experiments, we test alternative theories by using situations in which the recipient's losses were uncertain (Experiment 1), the recipient's losses were certain (Experiment 2), or the recipient claims failed gains rather than losses (Experiment 3). Overall, we find that participants gave more money to recipients who displayed sad expressions compared to neutral expressions, but only under conditions of uncertain loss. This finding supports the hypothesis that sad expressions function to increase the credibility of claims of loss.

A Conditional Knockout Mouse Model Reveals a Critical Role of PKD1 in Osteoblast Differentiation and Bone Development

PubMed Central

Li, Shao; Xu, Wanfu; Xing, Zhe; Qian, Jiabi; Chen, Liping; Gu, Ruonan; Guo, Wenjing; Lai, Xiaoju; Zhao, Wanlu; Li, Songyu; Wang, Yaodong; Wang, Q. Jane; Deng, Fan

2017-01-01

The protein kinase D family of serine/threonine kinases, particularly PKD1, has been implicated in the regulation of a complex array of fundamental biological processes. However, its function and mechanism underlying PKD1-mediated the bone development and osteoblast differentiation are not fully understood. Here we demonstrate that loss of PKD1 function led to impaired bone development and osteoblast differentiation through STAT3 and p38 MAPK signaling using in vitro and in vivo bone-specific conditional PKD1-knockout (PKD1-KO) mice models. These mice developed markedly craniofacial dysplasia, scapula dysplasia, long bone length shortage and body weight decrease compared with wild-type littermates. Moreover, deletion of PKD1 in vivo reduced trabecular development and activity of osteoblast development, confirmed by Micro-CT and histological staining as well as expression of osteoblastic marker (OPN, Runx2 and OSX). Mechanistically, loss of PKD1 mediated the downregulation of osteoblast markers and impaired osteoblast differentiation through STAT3 and p38 MAPK signaling pathways. Taken together, these results demonstrated that PKD1 contributes to the osteoblast differentiation and bone development via elevation of osteoblast markers through activation of STAT3 and p38 MAPK signaling pathways. PMID:28084409

Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis.

PubMed

MacKenzie-Graham, Allan; Kurth, Florian; Itoh, Yuichiro; Wang, He-Jing; Montag, Michael J; Elashoff, Robert; Voskuhl, Rhonda R

2016-08-01

Multiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown. To understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS. In this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014. Voxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores). Among the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations. These biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

Child loss and psychosis onset: evidence for traumatic experience as an etiological factor in psychosis.

PubMed

Devylder, Jordan E; Wang, Julia S-H; Oh, Hans Y; Lukens, Ellen P

2013-01-30

Previous research suggests that trauma may contribute to psychosis onset. In this study, we examine the effect of parental loss of a child on the onset of psychotic experience using data from the National Comorbidity Survey Replication, hypothesizing that child loss will precede the onset of psychosis and will be associated with a later age of onset. We likewise tested this association for six other psychiatric conditions to demonstrate specificity for psychosis. Individuals with a psychotic disorder who had lost a child had a significantly later age of onset, particularly in males, even when controlling for demographic variables and co-occurring substance abuse and psychiatric disorders. Psychosis onset frequently occurred within a year of child loss. No associations were found between child loss and onset of other psychiatric conditions, supporting specificity of the effect on psychosis. The presented findings implicate child loss as an etiological factor in the onset of psychosis, providing converging evidence with previous studies demonstrating associations between more widely studied trauma exposures (abuse, neglect, and assault) and psychosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Caenorhabditis elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

PubMed Central

Ezak , Meredith J.; Hong , Elizabeth; Chaparro-Garcia , Angela; Ferkey , Denise M.

2010-01-01

Olfaction and some forms of taste (including bitter) are mediated by G protein-coupled signal transduction pathways. Olfactory and gustatory ligands bind to chemosensory G protein-coupled receptors (GPCRs) in specialized sensory cells to activate intracellular signal transduction cascades. G protein-coupled receptor kinases (GRKs) are negative regulators of signaling that specifically phosphorylate activated GPCRs to terminate signaling. Although loss of GRK function usually results in enhanced cellular signaling, Caenorhabditis elegans lacking GRK-2 function are not hypersensitive to chemosensory stimuli. Instead, grk-2 mutant animals do not chemotax toward attractive olfactory stimuli or avoid aversive tastes and smells. We show here that loss-of-function mutations in the transient receptor potential vanilloid (TRPV) channels OSM-9 and OCR-2 selectively restore grk-2 behavioral avoidance of bitter tastants, revealing modality-specific mechanisms for TRPV channel function in the regulation of C. elegans chemosensation. Additionally, a single amino acid point mutation in OCR-2 that disrupts TRPV channel-mediated gene expression, but does not decrease channel function in chemosensory primary signal transduction, also restores grk-2 bitter taste avoidance. Thus, loss of GRK-2 function may lead to changes in gene expression, via OSM-9/OCR-2, to selectively alter the levels of signaling components that transduce or regulate bitter taste responses. Our results suggest a novel mechanism and multiple modality-specific pathways that sensory cells employ in response to aberrant signal transduction. PMID:20176974

Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads.

PubMed

Lin, Zhimiao; Zhao, Jiahui; Nitoiu, Daniela; Scott, Claire A; Plagnol, Vincent; Smith, Frances J D; Wilson, Neil J; Cole, Christian; Schwartz, Mary E; McLean, W H Irwin; Wang, Huijun; Feng, Cheng; Duo, Lina; Zhou, Eray Yihui; Ren, Yali; Dai, Lanlan; Chen, Yulan; Zhang, Jianguo; Xu, Xun; O'Toole, Edel A; Kelsell, David P; Yang, Yong

2015-03-05

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Neuromuscular adaptation to actual and simulated weightlessness

NASA Technical Reports Server (NTRS)

Edgerton, V. R.; Roy, R. R.

1994-01-01

The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

Inferring Gene Family Histories in Yeast Identifies Lineage Specific Expansions

PubMed Central

Ames, Ryan M.; Money, Daniel; Lovell, Simon C.

2014-01-01

The complement of genes found in the genome is a balance between gene gain and gene loss. Knowledge of the specific genes that are gained and lost over evolutionary time allows an understanding of the evolution of biological functions. Here we use new evolutionary models to infer gene family histories across complete yeast genomes; these models allow us to estimate the relative genome-wide rates of gene birth, death, innovation and extinction (loss of an entire family) for the first time. We show that the rates of gene family evolution vary both between gene families and between species. We are also able to identify those families that have experienced rapid lineage specific expansion/contraction and show that these families are enriched for specific functions. Moreover, we find that families with specific functions are repeatedly expanded in multiple species, suggesting the presence of common adaptations and that these family expansions/contractions are not random. Additionally, we identify potential specialisations, unique to specific species, in the functions of lineage specific expanded families. These results suggest that an important mechanism in the evolution of genome content is the presence of lineage-specific gene family changes. PMID:24921666

Glial-Specific Functions of Microcephaly Protein WDR62 and Interaction with the Mitotic Kinase AURKA Are Essential for Drosophila Brain Growth.

PubMed

Lim, Nicholas R; Shohayeb, Belal; Zaytseva, Olga; Mitchell, Naomi; Millard, S Sean; Ng, Dominic C H; Quinn, Leonie M

2017-07-11

The second most commonly mutated gene in primary microcephaly (MCPH) patients is wd40-repeat protein 62 (wdr62), but the relative contribution of WDR62 function to the growth of major brain lineages is unknown. Here, we use Drosophila models to dissect lineage-specific WDR62 function(s). Interestingly, although neural stem cell (neuroblast)-specific depletion of WDR62 significantly decreased neuroblast number, brain size was unchanged. In contrast, glial lineage-specific WDR62 depletion significantly decreased brain volume. Moreover, loss of function in glia not only decreased the glial population but also non-autonomously caused neuroblast loss. We further demonstrated that WDR62 controls brain growth through lineage-specific interactions with master mitotic signaling kinase, AURKA. Depletion of AURKA in neuroblasts drives brain overgrowth, which was suppressed by WDR62 co-depletion. In contrast, glial-specific depletion of AURKA significantly decreased brain volume, which was further decreased by WDR62 co-depletion. Thus, dissecting relative contributions of MCPH factors to individual neural lineages will be critical for understanding complex diseases such as microcephaly. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Effect of a Long-Term Intensive Lifestyle Intervention on Cognitive Function: Action for Health in Diabetes Study.

PubMed

Rapp, Stephen R; Luchsinger, Jose A; Baker, Laura D; Blackburn, George L; Hazuda, Helen P; Demos-McDermott, Kathryn E; Jeffery, Robert W; Keller, Jeffrey N; McCaffery, Jeanne M; Pajewski, Nicholas M; Evans, Mary; Wadden, Thomas A; Arnold, Steven E; Espeland, Mark A

2017-05-01

To assess whether randomization to 10 years of lifestyle intervention to induce and maintain weight loss improves cognitive function. Randomized controlled clinical trial. Data obtained as part of the Action for Health in Diabetes (Look AHEAD) trial (NCT00017953) and Look AHEAD Continuation study (U01 DK057136-15). Overweight and obese individuals with type 2 diabetes mellitus aged 45 to 76 (N = 3,751). Intensive lifestyle intervention (ILI) for weight loss through reduced caloric intake and increased physical activity compared with a control condition of diabetes support and education (DSE). Certified examiners who were masked to intervention assignment administered a standard battery of cognitive function tests (Modified Mini-Mental State Examination, Rey Auditory Verbal Learning Test, Digit Symbol Coding, Trail-Making Test, Modified Stroop Color-Word Test) to participants 10 to 13 years after enrollment. Assignment to lifestyle intervention was not associated with significantly different overall (P = .10) or domain-specific (all P > .10) cognitive function than assignment to diabetes support and education. Results were fairly consistent across prespecified groups, but there was some evidence of trends for differential intervention effects showing modest harm in ILI in participants with greater body mass index and in individuals with a history of cardiovascular disease. Cognitive function was not associated with changes in weight or fitness (all P > .05). A long-term behavioral weight loss intervention for overweight and obese adults with diabetes mellitus was not associated with cognitive benefit. Trial Registration clinicaltrials.gov Identifier: NCT00017953. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Assessing the Response of Nematode Communities to Climate Change-Driven Warming: A Microcosm Experiment.

PubMed

Gingold, Ruth; Moens, Tom; Rocha-Olivares, Axayácatl

2013-01-01

Biodiversity has diminished over the past decades with climate change being among the main responsible factors. One consequence of climate change is the increase in sea surface temperature, which, together with long exposure periods in intertidal areas, may exceed the tolerance level of benthic organisms. Benthic communities may suffer structural changes due to the loss of species or functional groups, putting ecological services at risk. In sandy beaches, free-living marine nematodes usually are the most abundant and diverse group of intertidal meiofauna, playing an important role in the benthic food web. While apparently many functionally similar nematode species co-exist temporally and spatially, experimental results on selected bacterivore species suggest no functional overlap, but rather an idiosyncratic contribution to ecosystem functioning. However, we hypothesize that functional redundancy is more likely to observe when taking into account the entire diversity of natural assemblages. We conducted a microcosm experiment with two natural communities to assess their stress response to elevated temperature. The two communities differed in diversity (high [HD] vs. low [LD]) and environmental origin (harsh vs. moderate conditions). We assessed their stress resistance to the experimental treatment in terms of species and diversity changes, and their function in terms of abundance, biomass, and trophic diversity. According to the Insurance Hypothesis, we hypothesized that the HD community would cope better with the stressful treatment due to species functional overlap, whereas the LD community functioning would benefit from species better adapted to harsh conditions. Our results indicate no evidence of functional redundancy in the studied nematofaunal communities. The species loss was more prominent and size specific in the HD; large predators and omnivores were lost, which may have important consequences for the benthic food web. Yet, we found evidence for alternative diversity-ecosystem functioning relationships, such as the Rivets and the Idiosyncrasy Model.

The thyrotropin receptor mutation database: update 2003.

PubMed

Führer, Dagmar; Lachmund, Peter; Nebel, Istvan-Tibor; Paschke, Ralf

2003-12-01

In 1999 we have created a TSHR mutation database compiling TSHR mutations with their basic characteristics and associated clinical conditions (www.uni-leipzig.de/innere/tshr). Since then, more than 2887 users from 36 countries have logged into the TSHR mutation database and have contributed several valuable suggestions for further improvement of the database. We now present an updated and extended version of the TSHR database to which several novel features have been introduced: 1. detailed functional characteristics on all 65 mutations (43 activating and 22 inactivating mutations) reported to date, 2. 40 pedigrees with detailed information on molecular aspects, clinical courses and treatment options in patients with gain-of-function and loss-of-function germline TSHR mutations, 3. a first compilation of site-directed mutagenesis studies, 4. references with Medline links, 5. a user friendly search tool for specific database searches, user-specific database output and 6. an administrator tool for the submission of novel TSHR mutations. The TSHR mutation database is installed as one of the locus specific HUGO mutation databases. It is listed under index TSHR 603372 (http://ariel.ucs.unimelb.edu.au/~cotton/glsdbq.htm) and can be accessed via www.uni-leipzig.de/innere/tshr.

Daily stressors, war experiences, and mental health in Afghanistan.

PubMed

Miller, Kenneth E; Omidian, Patricia; Rasmussen, Andrew; Yaqubi, Aziz; Daudzai, Haqmal

2008-12-01

Working in Afghanistan's capital city of Kabul, the authors assessed the relative contribution of daily stressors and war-related experiences of violence and loss to levels of depression, PTSD, impaired functioning, and a culturally specific measure of general psychological distress. For women, daily stressors were a better predictor than war experiences of all mental health outcomes except for PTSD; for men, daily stressors were a better predictor of depression and functional impairment, while war experiences and daily stressors were similarly predictive of general distress. For men, daily stressors moderated the relationship between war experiences and PTSD, which was significant only under conditions of low daily stress. The study's implications for research and intervention in conflict and post-conflict settings are considered.

Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa.

PubMed

Petit, Lolita; Ma, Shan; Cipi, Joris; Cheng, Shun-Yun; Zieger, Marina; Hay, Nissim; Punzo, Claudio

2018-05-29

Aerobic glycolysis accounts for ∼80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A comparison of average wages with age-specific wages for assessing indirect productivity losses: analytic simplicity versus analytic precision.

PubMed

Connolly, Mark P; Tashjian, Cole; Kotsopoulos, Nikolaos; Bhatt, Aomesh; Postma, Maarten J

2017-07-01

Numerous approaches are used to estimate indirect productivity losses using various wage estimates applied to poor health in working aged adults. Considering the different wage estimation approaches observed in the published literature, we sought to assess variation in productivity loss estimates when using average wages compared with age-specific wages. Published estimates for average and age-specific wages for combined male/female wages were obtained from the UK Office of National Statistics. A polynomial interpolation was used to convert 5-year age-banded wage data into annual age-specific wages estimates. To compare indirect cost estimates, average wages and age-specific wages were used to project productivity losses at various stages of life based on the human capital approach. Discount rates of 0, 3, and 6 % were applied to projected age-specific and average wage losses. Using average wages was found to overestimate lifetime wages in conditions afflicting those aged 1-27 and 57-67, while underestimating lifetime wages in those aged 27-57. The difference was most significant for children where average wage overestimated wages by 15 % and for 40-year-olds where it underestimated wages by 14 %. Large differences in projecting productivity losses exist when using the average wage applied over a lifetime. Specifically, use of average wages overestimates productivity losses between 8 and 15 % for childhood illnesses. Furthermore, during prime working years, use of average wages will underestimate productivity losses by 14 %. We suggest that to achieve more precise estimates of productivity losses, age-specific wages should become the standard analytic approach.

Dynamic Changes in Yeast Phosphatase Families Allow for Specialization in Phosphate and Thiamine Starvation.

PubMed

Nahas, John V; Iosue, Christine L; Shaik, Noor F; Selhorst, Kathleen; He, Bin Z; Wykoff, Dennis D

2018-05-10

Convergent evolution is often due to selective pressures generating a similar phenotype. We observe relatively recent duplications in a spectrum of Saccharomycetaceae yeast species resulting in multiple phosphatases that are regulated by different nutrient conditions - thiamine and phosphate starvation. This specialization is both transcriptional and at the level of phosphatase substrate specificity. In Candida glabrata , loss of the ancestral phosphatase family was compensated by the co-option of a different histidine phosphatase family with three paralogs. Using RNA-seq and functional assays, we identify one of these paralogs, CgPMU3 , as a thiamine phosphatase. We further determine that the 81% identical paralog CgPMU2 does not encode thiamine phosphatase activity; however, both are capable of cleaving the phosphatase substrate, 1-napthyl-phosphate. We functionally demonstrate that members of this family evolved novel enzymatic functions for phosphate and thiamine starvation, and are regulated transcriptionally by either nutrient condition, and observe similar trends in other yeast species. This independent, parallel evolution involving two different families of histidine phosphatases suggests that there were likely similar selective pressures on multiple yeast species to recycle thiamine and phosphate. In this work, we focused on duplication and specialization, but there is also repeated loss of phosphatases, indicating that the expansion and contraction of the phosphatase family is dynamic in many Ascomycetes. The dynamic evolution of the phosphatase gene families is perhaps just one example of how gene duplication, co-option, and transcriptional and functional specialization together allow species to adapt to their environment with existing genetic resources. Copyright © 2018, G3: Genes, Genomes, Genetics.

Establishment of Functional Acinar-like Cultures from Human Salivary Glands

PubMed Central

Jang, S.I.; Ong, H.L.; Gallo, A.; Liu, X.; Illei, G.

2015-01-01

Disorders of human salivary glands resulting from therapeutic radiation treatment for head and neck cancers or from the autoimmune disease Sjögren syndrome (SS) frequently result in the reduction or complete loss of saliva secretion. Such irreversible dysfunction of the salivary glands is due to the impairment of acinar cells, the major glandular cells of protein, salt secretion, and fluid movement. Availability of primary epithelial cells from human salivary gland tissue is critical for studying the underlying mechanisms of these irreversible disorders. We applied 2 culture system techniques on human minor salivary gland epithelial cells (phmSG) and optimized the growth conditions to achieve the maintenance of phmSG in an acinar-like phenotype. These phmSG cells exhibited progenitor cell markers (keratin 5 and nanog) as well as acinar-specific markers—namely, α-amylase, cystatin C, TMEM16A, and NKCC1. Importantly, with an increase of the calcium concentration in the growth medium, these phmSG cells were further promoted to acinar-like cells in vitro, as indicated by an increase in AQP5 expression. In addition, these phmSG cells also demonstrated functional calcium mobilization, formation of epithelial monolayer with high transepithelial electrical resistance (TER), and polarized secretion of α-amylase secretion after β-adrenergic receptor stimulation. Taken together, suitable growth conditions have been established to isolate and support culture of acinar-like cells from the human salivary gland. These primary epithelial cells can be useful for study of molecular mechanisms involved in regulating the function of acinar cells and in the loss of salivary gland function in patients. PMID:25416669

Repressor of Estrogen Receptor Activity (REA) Is Essential for Mammary Gland Morphogenesis and Functional Activities: Studies in Conditional Knockout Mice

PubMed Central

Park, Sunghee; Zhao, Yuechao; Yoon, Sangyeon; Xu, Jianming; Liao, Lan; Lydon, John; DeMayo, Franco; O'Malley, Bert W.

2011-01-01

Estrogen receptor (ER) is a key regulator of mammary gland development and is also implicated in breast tumorigenesis. Because ER-mediated activities depend critically on coregulator partner proteins, we have investigated the consequences of reduction or loss of function of the coregulator repressor of ER activity (REA) by conditionally deleting one allele or both alleles of the REA gene at different stages of mammary gland development. Notably, we find that heterozygosity and nullizygosity for REA result in very different mammary phenotypes and that REA has essential roles in the distinct morphogenesis and functions of the mammary gland at different stages of development, pregnancy, and lactation. During puberty, mice homozygous null for REA in the mammary gland (REAf/f PRcre/+) showed severely impaired mammary ductal elongation and morphogenesis, whereas mice heterozygous for REA (REAf/+ PRcre/+) displayed accelerated mammary ductal elongation, increased numbers of terminal end buds, and up-regulation of amphiregulin, the major paracrine mediator of estrogen-induced ductal morphogenesis. During pregnancy and lactation, mice with homozygous REA gene deletion in mammary epithelium (REAf/f whey acidic protein-Cre) showed a loss of lobuloalveolar structures and increased apoptosis of mammary alveolar epithelium, leading to impaired milk production and significant reduction in growth of their offspring, whereas body weights of the offspring nursed by females heterozygous for REA were slightly greater than those of control mice. Our findings reveal that REA is essential for mammary gland development and has a gene dosage-dependent role in the regulation of stage-specific physiological functions of the mammary gland. PMID:21862609

Mapping DNA damage-dependent genetic interactions in yeast via party mating and barcode fusion genetics.

PubMed

Díaz-Mejía, J Javier; Celaj, Albi; Mellor, Joseph C; Coté, Atina; Balint, Attila; Ho, Brandon; Bansal, Pritpal; Shaeri, Fatemeh; Gebbia, Marinella; Weile, Jochen; Verby, Marta; Karkhanina, Anna; Zhang, YiFan; Wong, Cassandra; Rich, Justin; Prendergast, D'Arcy; Gupta, Gaurav; Öztürk, Sedide; Durocher, Daniel; Brown, Grant W; Roth, Frederick P

2018-05-28

Condition-dependent genetic interactions can reveal functional relationships between genes that are not evident under standard culture conditions. State-of-the-art yeast genetic interaction mapping, which relies on robotic manipulation of arrays of double-mutant strains, does not scale readily to multi-condition studies. Here, we describe barcode fusion genetics to map genetic interactions (BFG-GI), by which double-mutant strains generated via en masse "party" mating can also be monitored en masse for growth to detect genetic interactions. By using site-specific recombination to fuse two DNA barcodes, each representing a specific gene deletion, BFG-GI enables multiplexed quantitative tracking of double mutants via next-generation sequencing. We applied BFG-GI to a matrix of DNA repair genes under nine different conditions, including methyl methanesulfonate (MMS), 4-nitroquinoline 1-oxide (4NQO), bleomycin, zeocin, and three other DNA-damaging environments. BFG-GI recapitulated known genetic interactions and yielded new condition-dependent genetic interactions. We validated and further explored a subnetwork of condition-dependent genetic interactions involving MAG1 , SLX4, and genes encoding the Shu complex, and inferred that loss of the Shu complex leads to an increase in the activation of the checkpoint protein kinase Rad53. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Uncertainty in sample estimates and the implicit loss function for soil information.

NASA Astrophysics Data System (ADS)

Lark, Murray

2015-04-01

One significant challenge in the communication of uncertain information is how to enable the sponsors of sampling exercises to make a rational choice of sample size. One way to do this is to compute the value of additional information given the loss function for errors. The loss function expresses the costs that result from decisions made using erroneous information. In certain circumstances, such as remediation of contaminated land prior to development, loss functions can be computed and used to guide rational decision making on the amount of resource to spend on sampling to collect soil information. In many circumstances the loss function cannot be obtained prior to decision making. This may be the case when multiple decisions may be based on the soil information and the costs of errors are hard to predict. The implicit loss function is proposed as a tool to aid decision making in these circumstances. Conditional on a logistical model which expresses costs of soil sampling as a function of effort, and statistical information from which the error of estimates can be modelled as a function of effort, the implicit loss function is the loss function which makes a particular decision on effort rational. In this presentation the loss function is defined and computed for a number of arbitrary decisions on sampling effort for a hypothetical soil monitoring problem. This is based on a logistical model of sampling cost parameterized from a recent geochemical survey of soil in Donegal, Ireland and on statistical parameters estimated with the aid of a process model for change in soil organic carbon. It is shown how the implicit loss function might provide a basis for reflection on a particular choice of sample size by comparing it with the values attributed to soil properties and functions. Scope for further research to develop and apply the implicit loss function to help decision making by policy makers and regulators is then discussed.

Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection

PubMed Central

Salinas, Eduardo; Sifford, Jeffrey M.; Oldenburg, Darby G.

2018-01-01

Gammaherpesvirus (GHV) pathogenesis is a complex process that involves productive viral replication, dissemination to tissues that harbor lifelong latent infection, and reactivation from latency back into a productive replication cycle. Traditional loss-of-function mutagenesis approaches in mice using murine gammaherpesvirus 68 (MHV68), a model that allows for examination of GHV pathogenesis in vivo, have been invaluable for defining requirements for specific viral gene products in GHV infection. But these approaches are insufficient to fully reveal how viral gene products contribute when the encoded protein facilitates multiple processes in the infectious cycle and when these functions vary over time and from one host tissue to another. To address this complexity, we developed an MHV68 genetic platform that enables cell-type-specific and inducible viral gene deletion in vivo. We employed this system to re-evaluate functions of the MHV68 latency-associated nuclear antigen (mLANA), a protein with roles in both viral replication and latency. Cre-mediated deletion in mice of loxP-flanked ORF73 demonstrated the necessity of mLANA in B cells for MHV68 latency establishment. Impaired latency during the transition from draining lymph nodes to blood following mLANA deletion also was observed, supporting the hypothesis that B cells are a major conduit for viral dissemination. Ablation of mLANA in infected germinal center (GC) B cells severely impaired viral latency, indicating the importance of viral passage through the GC for latency establishment. Finally, induced ablation of mLANA during latency resulted in complete loss of affected viral genomes, indicating that mLANA is critically important for maintenance of viral genomes during stable latency. Collectively, these experiments provide new insights into LANA homolog functions in GHV colonization of the host and highlight the potential of a new MHV68 genetic platform to foster a more complete understanding of viral gene functions at discrete stages of GHV pathogenesis. PMID:29364981

Age-Related Hearing Loss: Quality of Care for Quality of Life

ERIC Educational Resources Information Center

Li-Korotky, Ha-Sheng

2012-01-01

Age-related hearing loss (ARHL), known as presbycusis, is characterized by progressive deterioration of auditory sensitivity, loss of the auditory sensory cells, and central processing functions associated with the aging process. ARHL is the third most prevalent chronic condition in older Americans, after hypertension and arthritis, and is a…

Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning.

PubMed

Kinoshita, Ken-ichi; Tada, Yayoi; Muroi, Yoshikage; Unno, Toshihiro; Ishii, Toshiaki

2015-09-15

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1mA/2s duration, once, or an intense unconditioned stimulus: 2mA/2s duration, twice), and 24h later, mice were re-exposed to the training context for 3min to determine reconsolidation or 30min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning. Copyright © 2015 Elsevier Inc. All rights reserved.

Final Report for DE-FG02-04ER15626: P-type ATPases in Plants – Role of Lipid Flippases in Membrane Biogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harper, Jeffrey F.

The long-range goal of the research is to understand the structure and biological functions of different P-type ATPases (ion pumps) in plant cells, and to use that knowledge to enhance the production of bioenergy from plants, or plant-research inspired technologies. Ptype ATPases include ion pumps that specifically transport H +, Ca 2+, Zn 2+, Cu 2+, K +, or Na +, as well as at least one unusual subfamily that appears to function as lipid flippases, flipping specific lipids from one side of a membrane bilayer to the other. As a group, P-type ATPases are thought to consume more thanmore » 1/3 of the cellular ATP in typical eukaryotic cells. Recent research in the Harper lab focused on understanding the biochemical and biological functions of P-type ATPases that flip lipids. These flippases belong to the P4 subfamily of P-type ATPases. The activity of lipid flippases is thought to induce membrane curvature and/or create an asymmetry in which certain lipid head groups are preferential exposed to one surface or the other. In Arabidopsis thaliana there are 12 members of this family referred to as Aminophospholipid ATPase (ALA) 1 to ALA12. Using genetic knockouts, the Harper lab has established that this unusual subfamily of P-type ATPases are critical for plants to cope with even modest changes in temperature (e.g., down to 15°C, or up to 30°C). In addition, members of one subclade are critical for cell expansion, and loss of function mutants result in severe dwarfism. Other members of this same sub-clade are critical for pollen tube growth, and loss of function mutants are sterile under conditions of hot days and cold nights. While the cellular processes that depend on lipid flippases are still unclear, the genetic analysis of loss of function mutants clearly show they are of fundamental importance to plant growth and response to the environment.« less

Combining the auxin-inducible degradation system with CRISPR/Cas9-based genome editing for the conditional depletion of endogenous Drosophila melanogaster proteins.

PubMed

Bence, Melinda; Jankovics, Ferenc; Lukácsovich, Tamás; Erdélyi, Miklós

2017-04-01

Inducible protein degradation techniques have considerable advantages over classical genetic approaches, which generate loss-of-function phenotypes at the gene or mRNA level. The plant-derived auxin-inducible degradation system (AID) is a promising technique which enables the degradation of target proteins tagged with the AID motif in nonplant cells. Here, we present a detailed characterization of this method employed during the adult oogenesis of Drosophila. Furthermore, with the help of CRISPR/Cas9-based genome editing, we improve the utility of the AID system in the conditional elimination of endogenously expressed proteins. We demonstrate that the AID system induces efficient and reversible protein depletion of maternally provided proteins both in the ovary and the early embryo. Moreover, the AID system provides a fine spatiotemporal control of protein degradation and allows for the generation of different levels of protein knockdown in a well-regulated manner. These features of the AID system enable the unraveling of the discrete phenotypes of genes with highly complex functions. We utilized this system to generate a conditional loss-of-function allele which allows for the specific degradation of the Vasa protein without affecting its alternative splice variant (solo) and the vasa intronic gene (vig). With the help of this special allele, we demonstrate that dramatic decrease of Vasa protein in the vitellarium does not influence the completion of oogenesis as well as the establishment of proper anteroposterior and dorsoventral polarity in the developing oocyte. Our study suggests that both the localization and the translation of gurken mRNA in the vitellarium is independent from Vasa. © 2017 Federation of European Biochemical Societies.

Neural Alterations in Acquired Age-Related Hearing Loss

PubMed Central

Mudar, Raksha A.; Husain, Fatima T.

2016-01-01

Hearing loss is one of the most prevalent chronic health conditions in older adults. Growing evidence suggests that hearing loss is associated with reduced cognitive functioning and incident dementia. In this mini-review, we briefly examine literature on anatomical and functional alterations in the brains of adults with acquired age-associated hearing loss, which may underlie the cognitive consequences observed in this population, focusing on studies that have used structural and functional magnetic resonance imaging, diffusion tensor imaging, and event-related electroencephalography. We discuss structural and functional alterations observed in the temporal and frontal cortices and the limbic system. These neural alterations are discussed in the context of common cause, information-degradation, and sensory-deprivation hypotheses, and we suggest possible rehabilitation strategies. Although, we are beginning to learn more about changes in neural architecture and functionality related to age-associated hearing loss, much work remains to be done. Understanding the neural alterations will provide objective markers for early identification of neural consequences of age-associated hearing loss and for evaluating benefits of intervention approaches. PMID:27313556

Adjoint optimization of natural convection problems: differentially heated cavity

NASA Astrophysics Data System (ADS)

Saglietti, Clio; Schlatter, Philipp; Monokrousos, Antonios; Henningson, Dan S.

2017-12-01

Optimization of natural convection-driven flows may provide significant improvements to the performance of cooling devices, but a theoretical investigation of such flows has been rarely done. The present paper illustrates an efficient gradient-based optimization method for analyzing such systems. We consider numerically the natural convection-driven flow in a differentially heated cavity with three Prandtl numbers (Pr=0.15{-}7) at super-critical conditions. All results and implementations were done with the spectral element code Nek5000. The flow is analyzed using linear direct and adjoint computations about a nonlinear base flow, extracting in particular optimal initial conditions using power iteration and the solution of the full adjoint direct eigenproblem. The cost function for both temperature and velocity is based on the kinetic energy and the concept of entransy, which yields a quadratic functional. Results are presented as a function of Prandtl number, time horizons and weights between kinetic energy and entransy. In particular, it is shown that the maximum transient growth is achieved at time horizons on the order of 5 time units for all cases, whereas for larger time horizons the adjoint mode is recovered as optimal initial condition. For smaller time horizons, the influence of the weights leads either to a concentric temperature distribution or to an initial condition pattern that opposes the mean shear and grows according to the Orr mechanism. For specific cases, it could also been shown that the computation of optimal initial conditions leads to a degenerate problem, with a potential loss of symmetry. In these situations, it turns out that any initial condition lying in a specific span of the eigenfunctions will yield exactly the same transient amplification. As a consequence, the power iteration converges very slowly and fails to extract all possible optimal initial conditions. According to the authors' knowledge, this behavior is illustrated here for the first time.

Temporal dynamics of CO 2 and CH 4 loss potentials in response to rapid hydrological shifts in tidal freshwater wetland soils

DOE Office of Scientific and Technical Information (OSTI.GOV)

RoyChowdhury, Taniya; Bramer, Lisa; Hoyt, David W.

Earth System Models predict climate extremes that will impact regional and global hydrology. Aquatic-terrestrial transition zones like wetlands are subjected to the immediate consequence of climate change with shifts in the magnitude and dynamics of hydrologic flow. Such fluctuating hydrology can alter the nature and rate of biogeochemical transformations and significantly impact the carbon balance of the ecosystem. We tested the impacts of fluctuating hydrology and, specifically, the role of antecedent moisture conditions in determining the dominant carbon loss mechanisms in soils sampled from a tidal freshwater wetland system in the lower Columbia River, WA, USA. The objective was tomore » understand shifts in biogeochemical processes in response to changing soil moisture, based on soil respiration and methane production rates, and to elucidate such responses based on the observed electron acceptor and metabolite profiles under laboratory conditions. Metabolomics and biogeochemical process rates provided evidence that soil redox was the principal factor driving metabolic function. Fluctuating redox conditions altered terminal electron acceptor and donor availability and recovery strengths of their concentrations in soil such that a disproportionate release of carbon dioxide stemmed from alternative anaerobic degradation processes like sulfate and iron reduction compared to carbon loss due to methanogenesis. These results show that extended and short-term saturation created conditions conducive to increasing metabolite availability for anaerobic decomposition processes, with a significant lag in methanogenesis. In contrast, extended drying caused a cellular-level stress response and rapid recycling of alternate electron acceptors.« less

Temporal dynamics of CO 2 and CH 4 loss potentials in response to rapid hydrological shifts in tidal freshwater wetland soils

DOE PAGES

RoyChowdhury, Taniya; Bramer, Lisa; Hoyt, David W.; ...

2017-06-27

Earth System Models predict climate extremes that will impact regional and global hydrology. Aquatic-terrestrial transition zones like wetlands are subjected to the immediate consequence of climate change with shifts in the magnitude and dynamics of hydrologic flow. Such fluctuating hydrology can alter the nature and rate of biogeochemical transformations and significantly impact the carbon balance of the ecosystem. We tested the impacts of fluctuating hydrology and, specifically, the role of antecedent moisture conditions in determining the dominant carbon loss mechanisms in soils sampled from a tidal freshwater wetland system in the lower Columbia River, WA, USA. The objective was tomore » understand shifts in biogeochemical processes in response to changing soil moisture, based on soil respiration and methane production rates, and to elucidate such responses based on the observed electron acceptor and metabolite profiles under laboratory conditions. Metabolomics and biogeochemical process rates provided evidence that soil redox was the principal factor driving metabolic function. Fluctuating redox conditions altered terminal electron acceptor and donor availability and recovery strengths of their concentrations in soil such that a disproportionate release of carbon dioxide stemmed from alternative anaerobic degradation processes like sulfate and iron reduction compared to carbon loss due to methanogenesis. These results show that extended and short-term saturation created conditions conducive to increasing metabolite availability for anaerobic decomposition processes, with a significant lag in methanogenesis. In contrast, extended drying caused a cellular-level stress response and rapid recycling of alternate electron acceptors.« less

MorTAL Kombat: the story of defense against TAL effectors through loss-of-susceptibility

PubMed Central

Hutin, Mathilde; Pérez-Quintero, Alvaro L.; Lopez, Camilo; Szurek, Boris

2015-01-01

Many plant-pathogenic xanthomonads rely on Transcription Activator-Like (TAL) effectors to colonize their host. This particular family of type III effectors functions as specific plant transcription factors via a programmable DNA-binding domain. Upon binding to the promoters of plant disease susceptibility genes in a sequence-specific manner, the expression of these host genes is induced. However, plants have evolved specific strategies to counter the action of TAL effectors and confer resistance. One mechanism is to avoid the binding of TAL effectors by mutations of their DNA binding sites, resulting in resistance by loss-of-susceptibility. This article reviews our current knowledge of the susceptibility hubs targeted by Xanthomonas TAL effectors, possible evolutionary scenarios for plants to combat the pathogen with loss-of-function alleles, and how this knowledge can be used overall to develop new pathogen-informed breeding strategies and improve crop resistance. PMID:26236326

Pontin is required for pre-TCR signaling at the β-selection checkpoint in T cell development.

PubMed

Boo, Kyungjin; Baek, Sung Hee; Lee, Ho

2014-04-25

Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Based on high expression in lymphoid tissues, we examined whether Pontin has a T cell-specific function. We generated Pontin(f/f);Lck-Cre mice, in which Pontin can be conditionally deleted in T cells and then explored T cell-specific function of Pontin in vivo. Here, we show that specific abrogation of Pontin expression in T cells almost completely blocked development of αβ T cells at the β-selection checkpoint by inducing cell apoptosis indicating that Pontin is essential for early T cell development. Pontin-deficient thymocytes show a comparable expression level of T cell receptor (TCR)β chain, but have enhanced activation of p53 and Notch signaling compared to wild-type thymocytes. Intriguingly, the developmental block of αβ T cells can be partially rescued by loss of p53. Together, our data demonstrate a novel role of Pontin as a crucial regulator in pre-TCR signaling during T cell development. Copyright © 2014 Elsevier Inc. All rights reserved.

[Loss of appetite in elderly people in the community and its relationship with functional capacity].

PubMed

Serra Prat, Mateu; Fernández, Xavier; Ribó, Laura; Palomera, Elisabet; Papiol, Mònica; Serra, Pere

2008-04-19

The reasons of anorexia of ageing are multiple and not well-known. One of them is loss of appetite. We aimed to know the prevalence of self-reported appetite-loss in the elderly and its relationship with nutritional status, muscle strength and functional capacity. A population based cross-sectional study in which 236 non-institutionalized subjects over 70 years were randomly selected. Hand grip, functional capacity and nutritional status were assessed and a specific questionnaire was administered to assess appetite. Anorexia or loss of appetite was considered when subjects declared none or low usual appetite both in breakfast and lunch time. A 30.0% global prevalence of anorexia was observed (37.1% in females and 17.9% in males; p = 0.001). Loss of appetite was related to higher risk of malnutrition (41% in anorexic vs 27% in non-anorexic; p = 0.039), lower muscular strength and poorer functional capacity. Loss of appetite in the elderly has a high prevalence and must alert about frailty.

Modulation of GH/IGF-1 axis: potential strategies to counteract sarcopenia in older adults.

PubMed

Giovannini, Silvia; Marzetti, Emanuele; Borst, Stephen E; Leeuwenburgh, Christiaan

2008-10-01

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.

β2-Adrenergic Receptor Knockout Mice Exhibit A Diabetic Retinopathy Phenotype

PubMed Central

Jiang, Youde; Zhang, Qiuhua; Liu, Li; Tang, Jie; Kern, Timothy S.; Steinle, Jena J.

2013-01-01

There is considerable evidence from our lab and others for a functional link between β-adrenergic receptor and insulin receptor signaling pathways in retina. Furthermore, we hypothesize that this link may contribute to lesions similar to diabetic retinopathy in that the loss of adrenergic input observed in diabetic retinopathy may disrupt normal anti-apoptotic insulin signaling, leading to retinal cell death. Our studies included assessment of neural retina function (ERG), vascular degeneration, and Müller glial cells (which express only β1 and β2-adrenergic receptor subtypes). In the current study, we produced β2-adrenergic receptor knockout mice to examine this deletion on retinal neurons and vasculature, and to identify specific pathways through which β2-adrenergic receptor modulates insulin signaling. As predicted from our hypothesis, β2-adrenergic receptor knockout mice display certain features similar to diabetic retinopathy. In addition, loss of β2-adrenergic input resulted in an increase in TNFα, a key inhibitor of insulin receptor signaling. Increased TNFα may be associated with insulin-dependent production of the anti-apoptotic factor, Akt. Since the effects occurred in vivo under normal glucose conditions, we postulate that aspects of the diabetic retinopathy phenotype might be triggered by loss of β2-adrenergic receptor signaling. PMID:23894672

NDH expression marks major transitions in plant evolution and reveals coordinate intracellular gene loss.

PubMed

Ruhlman, Tracey A; Chang, Wan-Jung; Chen, Jeremy J W; Huang, Yao-Ting; Chan, Ming-Tsair; Zhang, Jin; Liao, De-Chih; Blazier, John C; Jin, Xiaohua; Shih, Ming-Che; Jansen, Robert K; Lin, Choun-Sea

2015-04-11

Key innovations have facilitated novel niche utilization, such as the movement of the algal predecessors of land plants into terrestrial habitats where drastic fluctuations in light intensity, ultraviolet radiation and water limitation required a number of adaptations. The NDH (NADH dehydrogenase-like) complex of Viridiplantae plastids participates in adapting the photosynthetic response to environmental stress, suggesting its involvement in the transition to terrestrial habitats. Although relatively rare, the loss or pseudogenization of plastid NDH genes is widely distributed across diverse lineages of photoautotrophic seed plants and mutants/transgenics lacking NDH function demonstrate little difference from wild type under non-stressed conditions. This study analyzes large transcriptomic and genomic datasets to evaluate the persistence and loss of NDH expression across plants. Nuclear expression profiles showed accretion of the NDH gene complement at key transitions in land plant evolution, such as the transition to land and at the base of the angiosperm lineage. While detection of transcripts for a selection of non-NDH, photosynthesis related proteins was independent of the state of NDH, coordinate, lineage-specific loss of plastid NDH genes and expression of nuclear-encoded NDH subunits was documented in Pinaceae, gnetophytes, Orchidaceae and Geraniales confirming the independent and complete loss of NDH in these diverse seed plant taxa. The broad phylogenetic distribution of NDH loss and the subtle phenotypes of mutants suggest that the NDH complex is of limited biological significance in contemporary plants. While NDH activity appears dispensable under favorable conditions, there were likely sufficiently frequent episodes of abiotic stress affecting terrestrial habitats to allow the retention of NDH activity. These findings reveal genetic factors influencing plant/environment interactions in a changing climate through 450 million years of land plant evolution.

Evolution of substrate specificity in a retained enzyme driven by gene loss

PubMed Central

Juárez-Vázquez, Ana Lilia; Edirisinghe, Janaka N; Verduzco-Castro, Ernesto A; Michalska, Karolina; Wu, Chenggang; Noda-García, Lianet; Babnigg, Gyorgy; Endres, Michael; Medina-Ruíz, Sofía; Santoyo-Flores, Julián; Carrillo-Tripp, Mauricio; Ton-That, Hung; Joachimiak, Andrzej; Henry, Christopher S; Barona-Gómez, Francisco

2017-01-01

The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Our results show how gene loss can drive the evolution of substrate specificity from retained enzymes. DOI: http://dx.doi.org/10.7554/eLife.22679.001 PMID:28362260

Evolution of Substrate Specificity in A Retained Enzyme Driven by Gene Loss

DOE PAGES

Juarez-Vazquez, Ana L.; Edirisinghe, Janaka N.; Verduzco-Castro, Ernesto A.; ...

2017-03-31

The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. Here, we apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We also observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to amore » monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. These results show how gene loss can drive the evolution of substrate specificity from retained enzymes.« less

Evolution of substrate specificity in a retained enzyme driven by gene loss

DOE PAGES

Juárez-Vázquez, Ana Lilia; Edirisinghe, Janaka N.; Verduzco-Castro, Ernesto A.; ...

2017-03-31

The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence oftrpandhisgenes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficientmore » form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Finally, our results show how gene loss can drive the evolution of substrate specificity from retained enzymes.« less

Evolution of substrate specificity in a retained enzyme driven by gene loss

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juárez-Vázquez, Ana Lilia; Edirisinghe, Janaka N.; Verduzco-Castro, Ernesto A.

The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence oftrpandhisgenes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficientmore » form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Finally, our results show how gene loss can drive the evolution of substrate specificity from retained enzymes.« less

Evolution of Substrate Specificity in A Retained Enzyme Driven by Gene Loss

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juarez-Vazquez, Ana L.; Edirisinghe, Janaka N.; Verduzco-Castro, Ernesto A.

The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. Here, we apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We also observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to amore » monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. These results show how gene loss can drive the evolution of substrate specificity from retained enzymes.« less

Species-Specific Exon Loss in Human Transcriptomes

PubMed Central

Wang, Jinkai; Lu, Zhi-xiang; Tokheim, Collin J.; Miller, Sara E.; Xing, Yi

2015-01-01

Changes in exon–intron structures and splicing patterns represent an important mechanism for the evolution of gene functions and species-specific regulatory networks. Although exon creation is widespread during primate and human evolution and has been studied extensively, much less is known about the scope and potential impact of human-specific exon loss events. Historically, transcriptome data and exon annotations are significantly biased toward humans over nonhuman primates. This ascertainment bias makes it challenging to discover human-specific exon loss events. We carried out a transcriptome-wide search of human-specific exon loss events, by taking advantage of RNA sequencing (RNA-seq) as a powerful and unbiased tool for exon discovery and annotation. Using RNA-seq data of humans, chimpanzees, and other primates, we reconstructed and compared transcript structures across the primate phylogeny. We discovered 33 candidate human-specific exon loss events, among which six exons passed stringent experimental filters for the complete loss of splicing activities in diverse human tissues. These events may result from human-specific deletion of genomic DNA, or small-scale sequence changes that inactivated splicing signals. The impact of human-specific exon loss events is predominantly regulatory. Three of the six events occurred in the 5′ untranslated region (5′-UTR) and affected cis-regulatory elements of mRNA translation. In SLC7A6, a gene encoding an amino acid transporter, luciferase reporter assays suggested that both a human-specific exon loss event and an independent human-specific single nucleotide substitution in the 5′-UTR increased mRNA translational efficiency. Our study provides novel insights into the molecular mechanisms and evolutionary consequences of exon loss during human evolution. PMID:25398629

[The specific microbiological and clinical features of acute otitis media].

PubMed

Gurov, A V; Levina, Yu V; Guseva, A L; Elchueva, Z G; Efimova, S P; Gordienko, M V

The objective of the present study was to elucidate the specific features of the clinical course of acute otitis media as well as the peculiarities of the vestibular function and the microbial paysage associated with this pathological condition under the present-day conditions. The study included 135 patients presenting with acute otitis media (AOM) at different stages of the disease. The discharge obtained from the tympanic cavity of all the patients was examined with the use of polymerase chain reaction in real time, audiological and vestibulogical methods. The distinctive features of acute otitis medium associated with Streptococcus pneumoniae infection were found to be the intense pain syndrome with the symptoms of intoxication, well apparent inflammatory changes in the tympanic membrane as revealed by otoscopy, the increased frequency of sensorineural impairment of hearing, and the characteristic type B tympanometric curve. Typical of AOM associated with Haemophilus influenza infection are the mild pain syndrome, weak changes in the tympanic membrane as revealed by otoscopy, conductive hearing loss, and the type C tympanometric curve.

Thermal modelling of cooling tool cutting when milling by electrical analogy

NASA Astrophysics Data System (ADS)

Benabid, F.; Arrouf, M.; Assas, M.; Benmoussa, H.

2010-06-01

Measurement temperatures by (some devises) are applied immediately after shut-down and may be corrected for the temperature drop that occurs in the interval between shut-down and measurement. This paper presents a new procedure for thermal modelling of the tool cutting used just after machining; when the tool is out off the chip in order to extrapolate the cutting temperature from the temperature measured when the tool is at stand still. A fin approximation is made in enhancing heat loss (by conduction and convection) to air stream is used. In the modelling we introduce an equivalent thermal network to estimate the cutting temperature as a function of specific energy. In another hand, a local modified element lumped conduction equation is used to predict the temperature gradient with time when the tool is being cooled, with initial and boundary conditions. These predictions provide a detailed view of the global heat transfer coefficient as a function of cutting speed because the heat loss for the tool in air stream is an order of magnitude larger than in normal environment. Finally we deduct the cutting temperature by inverse method.

Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alcaraz, Jordi; Xu, Ren; Mori, Hidetoshi

2008-10-20

In the mammary gland, epithelial cells are embedded in a 'soft' environment and become functionally differentiated in culture when exposed to a laminin-rich extracellular matrix gel. Here, we define the processes by which mammary epithelial cells integrate biochemical and mechanical extracellular cues to maintain their differentiated phenotype. We used single cells cultured on top of gels in conditions permissive for {beta}-casein expression using atomic force microscopy to measure the elasticity of the cells and their underlying substrata. We found that maintenance of {beta}-casein expression required both laminin signalling and a 'soft' extracellular matrix, as is the case in normal tissuesmore » in vivo, and biomimetic intracellular elasticity, as is the case in primary mammary epithelial organoids. Conversely, two hallmarks of breast cancer development, stiffening of the extracellular matrix and loss of laminin signalling, led to the loss of {beta}-casein expression and non-biomimetic intracellular elasticity. Our data indicate that tissue-specific gene expression is controlled by both the tissues unique biochemical milieu and mechanical properties, processes involved in maintenance of tissue integrity and protection against tumorigenesis.« less

Do more specific plans help you lose weight? Examining the relationship between plan specificity, weight loss goals, and plan content in the context of a weight management programme.

PubMed

Dombrowski, Stephan U; Endevelt, Ronit; Steinberg, David M; Benyamini, Yael

2016-11-01

The conditions under which planning for behaviour change is most effective are not fully understood. In the context of a weight management programme, we examined the interrelationship between plan specificity, type of behaviour planned (diet vs. exercise), and weight loss goals. Prospective design and content analysis of plans formed by participants of a 10-week weight management programme. Participants (n = 239) formulated two plans, for dietary and exercise behaviours, respectively. Plans were rated for specificity by examining the number of plan components. Weight loss goals were assessed by asking how much weight participants intend to lose. Weight was measured objectively each of the 10 weeks. Changes in body mass index (BMI) over time and the interactions between plan specificity and weight loss goals, for all plans and separately for diet and exercise, were estimated using linear mixed models. Plan specificity was unrelated to weight loss, but interacted with weight loss goals in predicting linear change in BMI (t = -2.48): More specific plans were associated with higher decreases in weight in participants with high weight loss goals. Separate interaction tests for plans formulated for diet and exercise change showed that more specific dietary plans, but not exercise plans, were associated with higher decreases in weight in participants with high weight loss goals (t = -2.21). Within a population that is highly motivated to lose weight, the combination of high weight loss goals and formulating detailed plans for changing dietary behaviours may be most effective in supporting weight loss. Statement of contribution What is already known on this subject? More specific plans are associated with increased performance of health-related behaviours. More motivated individuals form more specific plans. The interrelationship between plan specificity, plan content and behaviour-related goals in relation intervention effectiveness has not been explored to date. What does this study add? The effectiveness of forming specific plans may depend on the strength of behaviour-related goals as well as the behaviour selected for change. More detailed plans, in particular dietary plans, were related to greater weight loss, but only for participants with higher initial weight loss goals. Detailed exercise plans were not associated with weight loss, regardless of initial weight loss goals. © 2016 The British Psychological Society.

Cardiac Cachexia: Perspectives for Prevention and Treatment.

PubMed

Okoshi, Marina Politi; Capalbo, Rafael Verardino; Romeiro, Fernando G; Okoshi, Katashi

2017-01-01

Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

Shifts in Selective Pressures on Snake Phototransduction Genes Associated with Photoreceptor Transmutation and Dim-Light Ancestry.

PubMed

Schott, Ryan K; Van Nynatten, Alexander; Card, Daren C; Castoe, Todd A; S W Chang, Belinda

2018-06-01

The visual systems of snakes are heavily modified relative to other squamates, a condition often thought to reflect their fossorial origins. Further modifications are seen in caenophidian snakes, where evolutionary transitions between rod and cone photoreceptors, termed photoreceptor transmutations, have occurred in many lineages. Little previous work, however, has focused on the molecular evolutionary underpinnings of these morphological changes. To address this, we sequenced seven snake eye transcriptomes and utilized new whole-genome and targeted capture sequencing data. We used these data to analyze gene loss and shifts in selection pressures in phototransduction genes that may be associated with snake evolutionary origins and photoreceptor transmutation. We identified the surprising loss of rhodopsin kinase (GRK1), despite a low degree of gene loss overall and a lack of relaxed selection early during snake evolution. These results provide some of the first evolutionary genomic corroboration for a dim-light ancestor that lacks strong fossorial adaptations. Our results also indicate that snakes with photoreceptor transmutation experienced significantly different selection pressures from other reptiles. Significant positive selection was found primarily in cone-specific genes, but not rod-specific genes, contrary to our expectations. These results reveal potential molecular adaptations associated with photoreceptor transmutation and also highlight unappreciated functional differences between rod- and cone-specific phototransduction proteins. This intriguing example of snake visual system evolution illustrates how the underlying molecular components of a complex system can be reshaped in response to changing selection pressures.

Performance on the Iowa gambling task is related to magnitude of weight loss and salivary cortisol in a diet-induced weight loss intervention in overweight women

USDA-ARS?s Scientific Manuscript database

The overall objective of this study was to examine the relationship between executive function, specifically decision making, and weight loss. We used the Iowa Gambling Task (IGT) to characterize decision making and compared performance on this task to weight loss in obese women (n=29) participatin...

Regenerative and rehabilitative medicine: A necessary synergy for functional recovery from volumetric muscle loss injury

PubMed Central

Greising, Sarah M.; Dearth, Christopher L.; Corona, Benjamin T.

2017-01-01

Volumetric muscle loss (VML) is a complex and heterogeneous problem due to significant traumatic or surgical loss of skeletal muscle tissue. The consequences of VML are substantial functional deficits in joint range of motion and skeletal muscle strength, resulting in life long dysfunction and disability. Traditional physical medicine and rehabilitation paradigms do not address the magnitude of force loss due to VML and related musculoskeletal co-morbidities. Recent advancements in regenerative medicine have set forth encouraging and emerging therapeutic options for VML injuries. There is significant potential that combined rehabilitative and regenerative therapies can restore limb and muscle function following VML injury in a synergistic manner. This review presents the current state of the VML field, spanning clinical and preclinical literature, with particular focus on rehabilitation and regenerative medicine in addition to their synergy. Moving forward, multidisciplinary collaboration between clinical and research fields is encouraged in order to continue to improve the treatment of VML injuries and specifically address the encompassing physiology, pathology, and specific needs of this patient population. PMID:27825146

Limb deficiency and prosthetic management. 2. Aging with limb loss.

PubMed

Flood, Katherine M; Huang, Mark E; Roberts, Toni L; Pasquina, Paul F; Nelson, Virginia S; Bryant, Phillip R

2006-03-01

This self-directed learning module highlights the issues faced by people aging with limb loss. It is part of the study guide on limb deficiency and vascular rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the impact that limb loss has on health and physical function throughout the life span. Case examples are used to illustrate what effect limb loss in childhood or young adulthood has on the incidence and management of new impairments or disease processes commonly associated with aging. To discuss the impact of early-life limb loss on the incidence and management of physiologic and functional changes associated with aging.

Motivation by potential gains and losses affects control processes via different mechanisms in the attentional network.

PubMed

Paschke, Lena M; Walter, Henrik; Steimke, Rosa; Ludwig, Vera U; Gaschler, Robert; Schubert, Torsten; Stelzel, Christine

2015-05-01

Attentional control in demanding cognitive tasks can be improved by manipulating the motivational state. Motivation to obtain gains and motivation to avoid losses both usually result in faster reaction times and stronger activation in relevant brain areas such as the prefrontal cortex, but little is known about differences in the underlying neurocognitive mechanisms of these types of motivation in an attentional control context. In the present functional magnetic resonance imaging (fMRI) study, we tested whether potential gain and loss as motivating incentives lead to overlapping or distinct neural effects in the attentional network, and whether one of these conditions is more effective than the other. A Flanker task with word stimuli as targets and distracters was performed by 115 healthy participants. Using a mixed blocked and event-related design allowed us to investigate transient and sustained motivation-related effects. Participants could either gain money (potential gain) or avoid losing money (potential loss) in different task blocks. Participants showed a congruency effect with increased reaction times for incongruent compared to congruent trials. Potential gain led to generally faster responses compared to the neutral condition and to stronger improvements than potential loss. Potential loss also led to shorter response times compared to the neutral condition, but participants improved mainly during incongruent and not during congruent trials. The event-related fMRI data revealed a main effect of congruency with increased activity in the left inferior frontal gyrus (IFG) and inferior frontal junction area (IFJ), the pre-supplementary motor area (pre-SMA), bilateral insula, intraparietal sulcus (IPS) and visual word form area (VWFA). While potential gain led to increased activity in a cluster of the IFJ and the VWFA only during incongruent trials, potential loss was linked to activity increases in these regions during incongruent and congruent trials. The block analysis revealed greater activity in gain and loss blocks compared to the neutral condition in most of these regions but no differences in the direct comparison of gain and loss blocks. These findings show that potential monetary gain and loss rely on different mechanisms: Gain was more effective in reducing the reaction time compared to potential loss. Brain data indicate that in the gain context attentional control is executed specifically in incongruent trials, whereas the loss context induces an unspecific increase of attentional control. These findings extend previous studies by providing evidence for diverging neural mechanisms for the effects of different types of motivation on attentional control, specifying the underlying activity patterns in task- and stimulus-related regions. Copyright © 2015 Elsevier Inc. All rights reserved.

Variations in body morphology explain sex differences in thermoeffector function during compensable heat stress.

PubMed

Notley, Sean R; Park, Joonhee; Tagami, Kyoko; Ohnishi, Norikazu; Taylor, Nigel A S

2017-05-01

What is the central question of this study? Can sex-related differences in cutaneous vascular and sudomotor responses be explained primarily by variations in the ratio between body surface area and mass during compensable exercise that elicits equivalent heat-loss requirements and mean body temperature changes across participants? What is the main finding and its importance? Mass-specific surface area was a significant determinant of vasomotor and sudomotor responses in men and women, explaining 10-48% of the individual thermoeffector variance. Nonetheless, after accounting for changes in mean body temperature and morphological differences, sex explained only 5% of that inter-individual variability. It was concluded that sex differences in thermoeffector function are morphologically dependent, but not sex dependent. Sex is sometimes thought to be an independent modulator of cutaneous vasomotor and sudomotor function during heat exposure. Nevertheless, it was hypothesized that, when assessed during compensable exercise that evoked equal heat-loss requirements across participants, sex differences in those thermoeffectors would be explained by variations in the ratio between body surface area and mass (specific surface area). To evaluate that possibility, vasomotor and sudomotor functions were assessed in 60 individuals (36 men and 24 women) with widely varying (overlapping) specific surface areas (range, 232.3-292.7 and 241.2-303.1 cm 2  kg -1 , respectively). Subjects completed two trials in compensable conditions (28°C, 36% relative humidity) involving rest (20 min) and steady-state cycling (45 min) at fixed, area-specific metabolic heat-production rates (light, ∼135 W m -2 ; moderate, ∼200 W m -2 ). Equivalent heat-loss requirements and mean body temperature changes were evoked across participants. Forearm blood flow and vascular conductance were positively related to specific surface area during light work in men (r = 0.67 and r = 0.66, respectively; both P < 0.05) and during both exercise intensities in women (light, r = 0.57 and r = 0.69; and moderate, r = 0.64 and r = 0.68; all P < 0.05). Whole-body and local sweat rates were negatively related to that ratio (correlation coefficient range, -0.33 to -0.62; all P < 0.05) during both work rates in men and women. Those relationships accounted for 10-48% of inter-individual thermoeffector variance (P < 0.05). Furthermore, after accounting for morphological differences, sex explained no more than 5% of that variability (P < 0.05). It was concluded that, when assessed during compensable exercise, sex differences in thermoeffector function were largely determined morphologically, rather than being sex dependent. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Economic losses and burden of disease by medical conditions in Norway.

PubMed

Kinge, Jonas Minet; Sælensminde, Kjartan; Dieleman, Joseph; Vollset, Stein Emil; Norheim, Ole Frithjof

2017-06-01

We explore the correlation between disease specific estimates of economic losses and the burden of disease. This is based on data for Norway in 2013 from the Global Burden of Disease (GBD) project and the Norwegian Directorate of Health. The diagnostic categories were equivalent to the ICD-10 chapters. Mental disorders topped the list of the costliest conditions in Norway in 2013, and musculoskeletal disorders caused the highest production loss, while neoplasms caused the greatest burden in terms of DALYs. There was a positive and significant association between economic losses and burden of disease. Neoplasms, circulatory diseases, mental and musculoskeletal disorders all contributed to large health care expenditures. Non-fatal conditions with a high prevalence in working populations, like musculoskeletal and mental disorders, caused the largest production loss, while fatal conditions such as neoplasms and circulatory disease did not, since they occur mostly at old age. The magnitude of the production loss varied with the estimation method. The estimations presented in this study did not include reductions in future consumption, by net-recipients, due to premature deaths. Non-fatal diseases are thus even more burdensome, relative to fatal diseases, than the production loss in this study suggests. Hence, ignoring production losses may underestimate the economic losses from chronic diseases in countries with an epidemiological profile similar to Norway. Copyright © 2017 Elsevier B.V. All rights reserved.

The influence of diurnal temperatures on the hydrochemistry of a tufa-depositing stream

NASA Astrophysics Data System (ADS)

Drysdale, R.; Lucas, S.; Carthew, K.

2003-12-01

At-a-station diurnal variations in carbonate hydrochemistry were measured during four observation periods at Davys Creek, a tufa-depositing stream in central NSW, Australia. Major ion concentrations and continuously logged measurements of specific conductivity, pH and temperature showed that changes in the amount of CaCO3 deposited upstream of the study reach were directly related to changes in diurnal water temperatures, which control the rate of CO2 efflux to the atmosphere. The greatest upstream losses occurred during the mid-afternoon water temperature peak, whereas the lowest upstream losses occurred at sunrise, when water temperatures were at their lowest. Cloudy days at all times of the year produced small diurnal water temperatures ranges (c. 2-5°C) and, consequently, relatively small changes in upstream CaCO3 loss (23-50 mg L-1) through the day. Clear sunny days, especially during summer months, produced large diurnal water temperature changes (up to c. 11°C), which in turn triggered diurnal changes in upstream CaCO3 loss of up to 100 mg L-1. By implication, the active reach of tufa deposition must advance downstream and increase in length during the evening and vice versa during the day. Given that the temperature of Davys Creek waters are a function of insolation, changes in the reach of tufa deposition under baseflow conditions are a direct function of the prevailing weather. This has implications for the palaeoclimatic interpretation of fossil tufa deposits. Copyright

Genetic Dissection of Midbrain Dopamine Neuron Development in vivo

PubMed Central

Ellisor, Debra; Rieser, Caroline; Voelcker, Bettina; Machan, Jason T.; Zervas, Mark

2012-01-01

Midbrain dopamine (MbDA) neurons are partitioned into medial and lateral cohorts that control complex functions. However, the genetic underpinnings of MbDA neuron heterogeneity are unclear. While it is known that Wnt1-expressing progenitors contribute to MbDA neurons, the role of Wnt1 in MbDA neuron development in vivo is unresolved. We show that mice with a spontaneous point mutation in Wnt1 have a unique phenotype characterized by the loss of medial MbDA neurons concomitant with a severe depletion of Wnt1-expressing progenitors and diminished LMX1a-expressing progenitors. Wnt1 mutant embryos also have alterations in a hierarchical gene regulatory loop suggesting multiple gene involvement in the Wnt1 mutant MbDA neuron phenotype. To investigate this possibility, we conditionally deleted Gbx2, Fgf8, and En1/2 after their early role in patterning and asked whether these genetic manipulations phenocopied the depletion of MbDA neurons in Wnt1 mutants. The conditional deletion of Gbx2 did not result in re-positioning or distribution of MbDA neurons. The temporal deletion of Fgf8 did not result in the loss of either LMX1a-expressing progenitors nor the initial population of differentiated MbDA neurons, but did result in a complete loss of MbDA neurons at later stages. The temporal deletion and species specific manipulation of En1/2 demonstrated a continued and species specific role of Engrailed genes in MbDA neuron development. Notably, our conditional deletion experiments revealed phenotypes dissimilar to Wnt1 mutants indicating the unique role of Wnt1 in MbDA neuron development. By placing Wnt1, Fgf8, and En1/2 in the context of their temporal requirement for MbDA neuron development, we further deciphered the developmental program underpinning MbDA neuron progenitors. PMID:23041116

DOE Office of Scientific and Technical Information (OSTI.GOV)

RoyChowdhury, Taniya; Bramer, Lisa; Hoyt, David W.

Earth System Models predict climate extremes that will impact regional and global hydrology. Aquatic-terrestrial transition zones like wetlands are subjected to the immediate consequence of climate change with shifts in the magnitude and dynamics of hydrologic flow. Such fluctuating hydrology can alter the nature and rate of biogeochemical transformations and significantly impact the carbon balance of the ecosystem. We tested the impacts of fluctuating hydrology and, specifically, the role of antecedent moisture conditions in determining the dominant carbon loss mechanisms in soils sampled from a tidal freshwater wetland system in the lower Columbia River, WA, USA. The objective was tomore » understand shifts in biogeochemical processes in response to changing soil moisture, based on soil respiration and methane production rates, and to elucidate such responses based on the observed electron acceptor and metabolite profiles under laboratory conditions. Metabolomics and biogeochemical process rates provided evidence that soil redox was the principal factor driving metabolic function. Fluctuating redox conditions altered terminal electron acceptor and donor availability and recovery strengths of their concentrations in soil such that a disproportionate release of carbon dioxide stemmed from alternative anaerobic degradation processes like sulfate and iron reduction compared to carbon loss due to methanogenesis. These results show that extended and short-term saturation created conditions conducive to increasing metabolite availability for anaerobic decomposition processes, with a significant lag in methanogenesis. In contrast, extended drying caused a cellular-level stress response and rapid recycling of alternate electron acceptors.« less

Conditional suicide system of Escherichia coli released into soil that uses the Bacillus subtilis sacB gene.

PubMed Central

Recorbet, G; Robert, C; Givaudan, A; Kudla, B; Normand, P; Faurie, G

1993-01-01

The sacB gene from Bacillus subtilis confers sucrose sensitivity upon gram-negative bacteria. The gene was investigated for use as a potential conditional suicide system for Escherichia coli released into soil. To ensure against the loss of the cell death function encoded under nonselective conditions, the nptI-sacR-B suicide cassette was inserted into the E. coli chromosome by using a circular nonreplicative integration vector. Stability studies yielded no loss of the suicide cassette in the integrated E. coli EL1026 strain. sacB induction in the absence of a selective pressure resulted in a lysis efficiency of up to 99.9%. The microcosm experiments confirmed the ability of the suicide cassette to limit the growth and reduce the survival of E. coli strains released into soil. Sucrose addition to sterile soil resulted in a 10(-3)-fold reduction of the final E. coli population density. sacB induction prevented the proliferation and triggered the rapid disappearance of E. coli from natural soil. Mutation to sucrose tolerance occurred at a frequency of 10(-5), making E. coli EL1026 a potential counterselectable donor strain for gene transfer studies. Specificity and potential adaptability to a wide range of gram-negative bacteria are additional conveniences of this conditional suicide system for the containment and counterselection of engineered microorganisms. PMID:8517732

Conditional suicide system of Escherichia coli released into soil that uses the Bacillus subtilis sacB gene.

PubMed

Recorbet, G; Robert, C; Givaudan, A; Kudla, B; Normand, P; Faurie, G

1993-05-01

The sacB gene from Bacillus subtilis confers sucrose sensitivity upon gram-negative bacteria. The gene was investigated for use as a potential conditional suicide system for Escherichia coli released into soil. To ensure against the loss of the cell death function encoded under nonselective conditions, the nptI-sacR-B suicide cassette was inserted into the E. coli chromosome by using a circular nonreplicative integration vector. Stability studies yielded no loss of the suicide cassette in the integrated E. coli EL1026 strain. sacB induction in the absence of a selective pressure resulted in a lysis efficiency of up to 99.9%. The microcosm experiments confirmed the ability of the suicide cassette to limit the growth and reduce the survival of E. coli strains released into soil. Sucrose addition to sterile soil resulted in a 10(-3)-fold reduction of the final E. coli population density. sacB induction prevented the proliferation and triggered the rapid disappearance of E. coli from natural soil. Mutation to sucrose tolerance occurred at a frequency of 10(-5), making E. coli EL1026 a potential counterselectable donor strain for gene transfer studies. Specificity and potential adaptability to a wide range of gram-negative bacteria are additional conveniences of this conditional suicide system for the containment and counterselection of engineered microorganisms.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaothekar, Sachin, E-mail: sackaothekar@gmail.com

I have studied the effects of finite electron inertia, finite ion Larmor radius (FLR) corrections, and radiative heat-loss function on the thermal instability of an infinite homogeneous, viscous plasma incorporating the effect of thermal conductivity for star formation in interstellar medium (ISM). A general dispersion relation is derived using the normal mode analysis method with the help of relevant linearized perturbation equations of the problem. The wave propagation is discussed for longitudinal and transverse directions to the external magnetic field and the conditions of modified thermal instabilities and stabilities are discussed in different cases. We find that the thermal instabilitymore » criterion is get modified into radiative instability criterion by inclusion of radiative heat-loss functions with thermal conductivity. The viscosity of medium removes the effect of FLR corrections from the condition of radiative instability. Numerical calculation shows stabilizing effect of heat-loss function, viscosity and FLR corrections, and destabilizing effect of finite electron inertia on the thermal instability. Results carried out in this paper shows that stars are formed in interstellar medium mainly due to thermal instability.« less

[Range of Hip Joint Motion and Weight of Lower Limb Function under 3D Dynamic Marker].

PubMed

Xia, Q; Zhang, M; Gao, D; Xia, W T

2017-12-01

To explore the range of reasonable weight coefficient of hip joint in lower limb function. When the hip joints of healthy volunteers under normal conditions or fixed at three different positions including functional, flexed and extension positions, the movements of lower limbs were recorded by LUKOtronic motion capture and analysis system. The degree of lower limb function loss was calculated using Fugl-Meyer lower limb function assessment form when the hip joints were fixed at the aforementioned positions. One-way analysis of variance and Tamhane's T2 method were used to proceed statistics analysis and calculate the range of reasonable weight coefficient of hip joint. There were significant differences between the degree of lower limb function loss when the hip joints fixed at flexed and extension positions and at functional position. While the differences between the degree of lower limb function loss when the hip joints fixed at flexed position and extension position had no statistical significance. In 95% confidence interval, the reasonable weight coefficient of hip joint in lower limb function was between 61.05% and 73.34%. Expect confirming the reasonable weight coefficient, the effects of functional and non-functional positions on the degree of lower limb function loss should also be considered for the assessment of hip joint function loss. Copyright© by the Editorial Department of Journal of Forensic Medicine

Is SOD1 loss of function involved in amyotrophic lateral sclerosis?

PubMed Central

Saccon, Rachele A.; Bunton-Stasyshyn, Rosie K. A.; Fisher, Elizabeth M.C.; Fratta, Pietro

2013-01-01

Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a—still unknown—toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1–amyotrophic lateral sclerosis. From analysing published data from patients with SOD1–amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1–amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis. PMID:23687121

Regulator Loss Functions and Hierarchical Modeling for Safety Decision Making.

PubMed

Hatfield, Laura A; Baugh, Christine M; Azzone, Vanessa; Normand, Sharon-Lise T

2017-07-01

Regulators must act to protect the public when evidence indicates safety problems with medical devices. This requires complex tradeoffs among risks and benefits, which conventional safety surveillance methods do not incorporate. To combine explicit regulator loss functions with statistical evidence on medical device safety signals to improve decision making. In the Hospital Cost and Utilization Project National Inpatient Sample, we select pediatric inpatient admissions and identify adverse medical device events (AMDEs). We fit hierarchical Bayesian models to the annual hospital-level AMDE rates, accounting for patient and hospital characteristics. These models produce expected AMDE rates (a safety target), against which we compare the observed rates in a test year to compute a safety signal. We specify a set of loss functions that quantify the costs and benefits of each action as a function of the safety signal. We integrate the loss functions over the posterior distribution of the safety signal to obtain the posterior (Bayes) risk; the preferred action has the smallest Bayes risk. Using simulation and an analysis of AMDE data, we compare our minimum-risk decisions to a conventional Z score approach for classifying safety signals. The 2 rules produced different actions for nearly half of hospitals (45%). In the simulation, decisions that minimize Bayes risk outperform Z score-based decisions, even when the loss functions or hierarchical models are misspecified. Our method is sensitive to the choice of loss functions; eliciting quantitative inputs to the loss functions from regulators is challenging. A decision-theoretic approach to acting on safety signals is potentially promising but requires careful specification of loss functions in consultation with subject matter experts.

Establishment of functional acinar-like cultures from human salivary glands.

PubMed

Jang, S I; Ong, H L; Gallo, A; Liu, X; Illei, G; Alevizos, I

2015-02-01

Disorders of human salivary glands resulting from therapeutic radiation treatment for head and neck cancers or from the autoimmune disease Sjögren syndrome (SS) frequently result in the reduction or complete loss of saliva secretion. Such irreversible dysfunction of the salivary glands is due to the impairment of acinar cells, the major glandular cells of protein, salt secretion, and fluid movement. Availability of primary epithelial cells from human salivary gland tissue is critical for studying the underlying mechanisms of these irreversible disorders. We applied 2 culture system techniques on human minor salivary gland epithelial cells (phmSG) and optimized the growth conditions to achieve the maintenance of phmSG in an acinar-like phenotype. These phmSG cells exhibited progenitor cell markers (keratin 5 and nanog) as well as acinar-specific markers-namely, α-amylase, cystatin C, TMEM16A, and NKCC1. Importantly, with an increase of the calcium concentration in the growth medium, these phmSG cells were further promoted to acinar-like cells in vitro, as indicated by an increase in AQP5 expression. In addition, these phmSG cells also demonstrated functional calcium mobilization, formation of epithelial monolayer with high transepithelial electrical resistance (TER), and polarized secretion of α-amylase secretion after β-adrenergic receptor stimulation. Taken together, suitable growth conditions have been established to isolate and support culture of acinar-like cells from the human salivary gland. These primary epithelial cells can be useful for study of molecular mechanisms involved in regulating the function of acinar cells and in the loss of salivary gland function in patients. © International & American Associations for Dental Research 2014.

Learning at different satiation levels reveals parallel functions for the cAMP-protein kinase A cascade in formation of long-term memory.

PubMed

Friedrich, Anke; Thomas, Ulf; Müller, Uli

2004-05-05

Learning and memory formation in intact animals is generally studied under defined parameters, including the control of feeding. We used associative olfactory conditioning of the proboscis extension response in honeybees to address effects of feeding status on processes of learning and memory formation. Comparing groups of animals with different but defined feeding status at the time of conditioning reveals new and characteristic features in memory formation. In animals fed 18 hr earlier, three-trial conditioning induces a stable memory that consists of different phases: a mid-term memory (MTM), translation-dependent early long-term memory (eLTM; 1-2 d), and a transcription-dependent late LTM (lLTM; > or =3 d). Additional feeding of a small amount of sucrose 4 hr before conditioning leads to a loss of all of these memory phases. Interestingly, the basal activity of the cAMP-dependent protein kinase A (PKA), a key player in LTM formation, differs in animals with different satiation levels. Pharmacological rescue of the low basal PKA activity in animals fed 4 hr before conditioning points to a specific function of cAMP-PKA cascade in mediating satiation-dependent memory formation. An increase in PKA activity during conditioning rescues only transcription-dependent lLTM; acquisition, MTM, and eLTM are still impaired. Thus, during conditioning, the cAMP-PKA cascade mediates the induction of the transcription-dependent lLTM, depending on the satiation level. This result provides the first evidence for a central and distinct function of the cAMP-PKA cascade connecting satiation level with learning.

Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects

PubMed Central

Chang, Howard C.; Sen, Anindya; Kalloo, Geetika; Harris, Jevede; Barsby, Tom; Walsh, Melissa B.; Satterlee, John S.; Li, Chris; Van Vactor, David; Artavanis-Tsakonas, Spyros; Hart, Anne C.

2010-01-01

Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species. PMID:21124729

Magnetic and Electrical Characteristics of Permalloy Thin Tape Bobbin Cores

NASA Technical Reports Server (NTRS)

Schwarze, Gene E.; Wieserman, William R.; Niedra, Janis M.

2005-01-01

The core loss, that is, the power loss, of a soft ferromagnetic material is a function of the flux density, frequency, temperature, excitation type (voltage or current), excitation waveform (sine, square, etc.) and lamination or tape thickness. In previously published papers we have reported on the specific core loss and dynamic B-H loop results for several polycrystalline, nanocrystalline, and amorphous soft magnetic materials. In this previous research we investigated the effect of flux density, frequency, temperature, and excitation waveform for voltage excitation on the specific core loss and dynamic B-H loop. In this paper, we will report on an experimental study to investigate the effect of tape thicknesses of 1, 1/2, 1/4, and 1/8-mil Permalloy type magnetic materials on the specific core loss. The test cores were fabricated by winding the thin tapes on ceramic bobbin cores. The specific core loss tests were conducted at room temperature and over the frequency range of 10 kHz to 750 kHz using sine wave voltage excitation. The results of this experimental investigation will be presented primarily in graphical form to show the effect of tape thickness, frequency, and magnetic flux density on the specific core loss. Also, the experimental results when applied to power transformer design will be briefly discussed.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.

PubMed

Stroh, Matthew A; Winter, Michelle K; Swerdlow, Russell H; McCarson, Kenneth E; Zhu, Hao

2016-08-01

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. (59)Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

PubMed Central

Stroh, Matthew A.; Winter, Michelle K.; Swerdlow, Russell H.; McCarson, Kenneth E.; Zhu, Hao

2018-01-01

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. 59Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 weeks and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain. PMID:27188291

Acellularization-Induced Changes in Tensile Properties Are Organ Specific - An In-Vitro Mechanical and Structural Analysis of Porcine Soft Tissues

PubMed Central

Aust, Gabriela; Boldt, Andreas; Fritsch, Sebastian; Keil, Isabel; Koch, Holger; Möbius, Robert; Scheidt, Holger A.; Wagner, Martin F. X.; Hammer, Niels

2016-01-01

Introduction Though xenogeneic acellular scaffolds are frequently used for surgical reconstruction, knowledge of their mechanical properties is lacking. This study compared the mechanical, histological and ultrastructural properties of various native and acellular specimens. Materials and Methods Porcine esophagi, ureters and skin were tested mechanically in a native or acellular condition, focusing on the elastic modulus, ultimate tensile stress and maximum strain. The testing protocol for soft tissues was standardized, including the adaption of the tissue’s water content and partial plastination to minimize material slippage as well as templates for normed sample dimensions and precise cross-section measurements. The native and acellular tissues were compared at the microscopic and ultrastructural level with a focus on type I collagens. Results Increased elastic modulus and ultimate tensile stress values were quantified in acellular esophagi and ureters compared to the native condition. In contrast, these values were strongly decreased in the skin after acellularization. Acellularization-related decreases in maximum strain were found in all tissues. Type I collagens were well-preserved in these samples; however, clotting and a loss of cross-linking type I collagens was observed ultrastructurally. Elastins and fibronectins were preserved in the esophagi and ureters. A loss of the epidermal layer and decreased fibronectin content was present in the skin. Discussion Acellularization induces changes in the tensile properties of soft tissues. Some of these changes appear to be organ specific. Loss of cross-linking type I collagen may indicate increased mechanical strength due to decreasing transverse forces acting upon the scaffolds, whereas fibronectin loss may be related to decreased load-bearing capacity. Potentially, the alterations in tissue mechanics are linked to organ function and to the interplay of cells and the extracellular matrix, which is different in hollow organs when compared to skin. PMID:26960134

Environmental and plant community determinants of species loss following nitrogen enrichment

USGS Publications Warehouse

Clark, C.M.; Cleland, E.E.; Collins, S.L.; Fargione, J.E.; Gough, L.; Gross, K.L.; Pennings, S.C.; Suding, K.N.; Grace, J.B.

2007-01-01

Global energy use and food production have increased nitrogen inputs to ecosystems worldwide, impacting plant community diversity, composition, and function. Previous studies show considerable variation across terrestrial herbaceous ecosystems in the magnitude of species loss following nitrogen (N) enrichment. What controls this variation remains unknown. We present results from 23 N-addition experiments across North America, representing a range of climatic, soil and plant community properties, to determine conditions that lead to greater diversity decline. Species loss in these communities ranged from 0 to 65% of control richness. Using hierarchical structural equation modelling, we found greater species loss in communities with a lower soil cation exchange capacity, colder regional temperature, and larger production increase following N addition, independent of initial species richness, plant productivity, and the relative abundance of most plant functional groups. Our results indicate sensitivity to N addition is co-determined by environmental conditions and production responsiveness, which overwhelm the effects of initial community structure and composition. ?? 2007 Blackwell Publishing Ltd/CNRS.

Rapid Recovery of Visual Function Associated with Blue Cone Ablation in Zebrafish

PubMed Central

Hagerman, Gordon F.; Noel, Nicole C. L.; Cao, Sylvia Y.; DuVal, Michèle G.; Oel, A. Phillip; Allison, W. Ted

2016-01-01

Hurdles in the treatment of retinal degeneration include managing the functional rewiring of surviving photoreceptors and integration of any newly added cells into the remaining second-order retinal neurons. Zebrafish are the premier genetic model for such questions, and we present two new transgenic lines allowing us to contrast vision loss and recovery following conditional ablation of specific cone types: UV or blue cones. The ablation of each cone type proved to be thorough (killing 80% of cells in each intended cone class), specific, and cell-autonomous. We assessed the loss and recovery of vision in larvae via the optomotor behavioural response (OMR). This visually mediated behaviour decreased to about 5% or 20% of control levels following ablation of UV or blue cones, respectively (P<0.05). We further assessed ocular photoreception by measuring the effects of UV light on body pigmentation, and observed that photoreceptor deficits and recovery occurred (p<0.01) with a timeline coincident to the OMR results. This corroborated and extended previous conclusions that UV cones are required photoreceptors for modulating body pigmentation, addressing assumptions that were unavoidable in previous experiments. Functional vision recovery following UV cone ablation was robust, as measured by both assays, returning to control levels within four days. In contrast, robust functional recovery following blue cone ablation was unexpectedly rapid, returning to normal levels within 24 hours after ablation. Ablation of cones led to increased proliferation in the retina, though the rapid recovery of vision following blue cone ablation was demonstrated to not be mediated by blue cone regeneration. Thus rapid visual recovery occurs following ablation of some, but not all, cone subtypes, suggesting an opportunity to contrast and dissect the sources and mechanisms of outer retinal recovery during cone photoreceptor death and regeneration. PMID:27893779

Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants.

PubMed

Gross, Joshua D; Kaski, Shane W; Schroer, Adam B; Wix, Kimberley A; Siderovski, David P; Setola, Vincent

2018-02-01

Regulators of G protein signaling are proteins that accelerate the termination of effector stimulation after G protein-coupled receptor activation. Many regulators of G protein signaling proteins are highly expressed in the brain and therefore considered potential drug discovery targets for central nervous system pathologies; for example, here we show that RGS12 is highly expressed in microdissected mouse ventral striatum. Given a role for the ventral striatum in psychostimulant-induced locomotor activity, we tested whether Rgs12 genetic ablation affected behavioral responses to amphetamine and cocaine. RGS12 loss significantly decreased hyperlocomotion to lower doses of both amphetamine and cocaine; however, other outcomes of administration (sensitization and conditioned place preference) were unaffected, suggesting that RGS12 does not function in support of the rewarding properties of these psychostimulants. To test whether observed response changes upon RGS12 loss were caused by changes to dopamine transporter expression and/or function, we prepared crude membranes from the brains of wild-type and RGS12-null mice and measured dopamine transporter-selective [ 3 H]WIN 35428 binding, revealing an increase in dopamine transporter levels in the ventral-but not dorsal-striatum of RGS12-null mice. To address dopamine transporter function, we prepared striatal synaptosomes and measured [ 3 H]dopamine uptake. Consistent with increased [ 3 H]WIN 35428 binding, dopamine transporter-specific [ 3 H]dopamine uptake in RGS12-null ventral striatal synaptosomes was found to be increased. Decreased amphetamine-induced locomotor activity and increased [ 3 H]WIN 35428 binding were recapitulated with an independent RGS12-null mouse strain. Thus, we propose that RGS12 regulates dopamine transporter expression and function in the ventral striatum, affecting amphetamine- and cocaine-induced increases in dopamine levels that specifically elicit acute hyperlocomotor responses.

Coping with heat stress during match-play tennis: Does an individualised hydration regimen enhance performance and recovery?

PubMed Central

Périard, Julien D; Racinais, Sebastien; Knez, Wade L; Herrera, Christopher P; Christian, Ryan J; Girard, Olivier

2014-01-01

Objectives To determine whether an individualised hydration regimen reduces thermal, physiological and perceptual strain during match-play tennis in the heat, and minimises alterations in neuromuscular function and physical performance postmatch and into recovery. Methods 10 men undertook two matches for an effective playing time (ball in play) of 20 min (∼113 min) in ∼37°C and ∼33% RH conditions. Participants consumed fluids ad libitum during the first match (HOT) and followed a hydration regimen (HYD) in the second match based on undertaking play euhydrated, standardising sodium intake and minimising body mass losses. Results HYD improved prematch urine specific gravity (1.013±0.006 vs 1.021±0.009 g/mL; p<0.05). Body mass losses (∼0.3%), fluid intake (∼2 L/h) and sweat rates (∼1.6 L/h) were similar between conditions. Core temperature was higher during the first 10 min of effective play in HOT (p<0.05), but increased similarly (∼39.3°C) on match completion. Heart rate was higher (∼11 bpm) throughout HOT (p<0.001). Thermal sensation was higher during the first 7.5 min of effective play in HOT (p<0.05). Postmatch knee extensor and plantar flexor strength losses, along with reductions in 15 m sprint time and repeated-sprint ability (p<0.05), were similar in both conditions, and were restored within 24 h. Conclusions Both the hydration regimen and ad libitum fluid consumption allowed for minimal body mass losses (<1%). However, undertaking match-play in a euhydrated state attenuated thermal, physiological and perceptual strain. Maximal voluntary strength in the lower limbs and repeated-sprint ability deteriorated similarly in both conditions, but were restored within 24 h. PMID:24668383

Nanomaterial Solutions for the Protection of Insulin Producing Beta Cells

NASA Astrophysics Data System (ADS)

Atchison, Nicole Ann

Islet transplantation is a promising treatment for type 1 diabetes. However, even with the many successes, islet transplantation has yet to reach its full potential. Limited islet sources, loss of cell viability during isolation and culture, and post-transplant graft loss are a few of the issues preventing extensive use of islet transplantation. The application of biomaterial systems to alleviate some of the stresses affecting islet viability has led to improvements in isolation and transplantation outcomes, but problems persist. In this work we approach two distinct issues affecting islet viability; ischemic conditions and immunological attack post-transplant. Ischemic conditions have been linked to a loss of islet graft function and occur during organ preservation, islet isolation and culture, and after islets are transplanted. We show that liposomal delivery of adenosine triphosphate (ATP) to beta cells can limit cell death and loss of function in ischemic conditions. We demonstrate that by functionalizing liposomes with the fibronectin-mimetic peptide PR_b, delivery of liposomes to porcine islets and rat beta cells is increased compared to nontargeted controls. Additionally, liposomes are shown to protect by providing both ATP and lipids to the ischemic cells. The delivery of ATP was investigated here but application of PR_b functionalized liposomes could be extended to other interesting cargos as well. The second area of investigation involves encapsulation of islets with silica nanoparticles to create a permselective barrier. Silica nanoparticles are an interesting material for encapsulation given their ability to be fine-tuned and further functionalized. We demonstrate that size-tunable, fluorescent silica nanoparticles can be assembled layer-by-layer on the surface of cells and that silica nanoparticle encapsulated islets are able to secrete insulin in response to a glucose challenge.

Unit Specific Crew Rest Strategies: Phase 1 Evaluation of the 1/212th Aviation Battalion during Shiftwork Transitions

DTIC Science & Technology

1994-01-01

but do not provide strategies or specific schedules of crew rest tailored to the- unit’s specific mission demands, environmental conditions, and...and the impact of mission driven work schedules and environmental conditions on crew rest quality. Phase II provides rhythms, sleep/wake cycles...shiftwork schedules , and methods for regulating the body’s biological clock to prevent sleep loss during characteristic mission. This report contains a

Musculoskeletal findings in obese subjects before and after weight loss following bariatric surgery.

PubMed

Hooper, M M; Stellato, T A; Hallowell, P T; Seitz, B A; Moskowitz, R W

2007-01-01

To determine the point prevalence of painful musculoskeletal (MSK) conditions in obese subjects before and after weight loss following bariatric surgery. Longitudinal, interventional, unblended. Forty-eight obese subjects (47 women, one man, mean age 44+/-9 years; mean body mass index (BMI) 51+/-8 kg/m(2)) recruited from an academic medical center bariatric surgery program. Comorbid medical conditions; MSK findings; BMI; Western Ontario McMaster Osteoarthritis Index (WOMAC) for pain, stiffness and function; and SF-36 for quality of life. Consecutive subjects were recruited from the University Hospitals of Cleveland Bariatric Surgery Program. Musculoskeletal signs and symptoms and non-MSK comorbid conditions were documented at baseline and at follow-up. SUBJECTS completed the SF-36 and the WOMAC questionnaires. Analyses were carried out for each MSK site, fibromyalgia syndrome (FMS) and for the cumulative effect on the spine, upper and lower extremities. The impact of change in comorbid medical conditions, BMI, physical and mental health domains of the SF-36 on the WOMAC pain subscale score was evaluated. SF-36 outcomes were compared to normal published controls. Forty-eight subjects were available for baseline and a follow-up assessment 6-12 months after gastric bypass surgery. They lost an average of 41+/-15 kg and the mean BMI decreased from 51+/-8 to 36+/-7 kg/m(2). Baseline comorbid medical conditions were present in 96% before surgery and 23% after weight loss. There was an increased prevalence of painful MSK conditions at baseline compared to general population frequencies. Musculoskeletal complaints had been present in 100% of obese subjects before, and 23% after weight loss. The greatest improvements occurred in the cervical and lumbar spine, the foot and in FMS (decreased by 90, 83, 83 and 92%, respectively). Seventy-nine percent had upper extremity MSK conditions before and 40% after weight loss. Before surgery, 100% had lower extremity MSK conditions and only 37% did after weight loss. The WOMAC subscale and composite scores all improved significantly, as did the SF-36((R)). Change in BMI was the main factor impacting the WOMAC pain score. There was a higher frequency of multiple MSK complaints, including non-weight-bearing sites compared to historical controls, before surgery, which decreased significantly at most sites following weight loss and physical activity. These benefits may improve further, as weight loss may continue for up to 24 months. The benefits seen with weight loss indicate that prevention and treatment of obesity can improve MSK health and function.

[Specific weight loss in hyper- and hypothyroidism (author's transl)].

PubMed

Schlick, W; Schmid, P; Irsigler, K

1975-02-07

By means of a new method of extremely precise weight measurement (buoyancy scale) it is possible to measure the continuous weight loss of the human body. This weight loss is made up of three components, viz. the weight difference between produced CO2 and consumed O2, water loss through the lungs and transpiration through the skin. In relation to body weight it is called "specific weight loss." This parameter was measured in healthy human subjects and found to be within a relatively narrow range (16.42 plus or minus 2.55 mg/min/kp body weight). In four patients with hypothyroidism the values were very low (5.5 to 8.5 mg/min/kp). An increased specific weight loss was found in patients with hyperthyroidism (38 to 102 mg/min/kp in clinically severe cases). The applicability of this method to examination of thyroid function is discussed. It is compared to the classical method of basal metabolic rate measurement and its advantages are enumerated.

Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.

PubMed

Benninger, R K P; Head, W Steven; Zhang, Min; Satin, Leslie S; Piston, David W

2011-11-15

Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.

MANTIS: a phylogenetic framework for multi-species genome comparisons.

PubMed

Tzika, Athanasia C; Helaers, Raphaël; Van de Peer, Yves; Milinkovitch, Michel C

2008-01-15

Practitioners of comparative genomics face huge analytical challenges as whole genome sequences and functional/expression data accumulate. Furthermore, the field would greatly benefit from a better integration of this wealth of data with evolutionary concepts. Here, we present MANTIS, a relational database for the analysis of (i) gains and losses of genes on specific branches of the metazoan phylogeny, (ii) reconstructed genome content of ancestral species and (iii) over- or under-representation of functions/processes and tissue specificity of gained, duplicated and lost genes. MANTIS estimates the most likely positions of gene losses on the true phylogeny using a maximum-likelihood function. A user-friendly interface and an extensive query system allow to investigate questions pertaining to gene identity, phylogenetic mapping and function/expression parameters. MANTIS is freely available at http://www.mantisdb.org and constitutes the missing link between multi-species genome comparisons and functional analyses.

Retinoic acid regulates size, pattern and alignment of tissues at the head-trunk transition.

PubMed

Lee, Keun; Skromne, Isaac

2014-11-01

At the head-trunk transition, hindbrain and spinal cord alignment to occipital and vertebral bones is crucial for coherent neural and skeletal system organization. Changes in neural or mesodermal tissue configuration arising from defects in the specification, patterning or relative axial placement of territories can severely compromise their integration and function. Here, we show that coordination of neural and mesodermal tissue at the zebrafish head-trunk transition crucially depends on two novel activities of the signaling factor retinoic acid (RA): one specifying the size and the other specifying the axial position relative to mesodermal structures of the hindbrain territory. These activities are each independent but coordinated with the well-established function of RA in hindbrain patterning. Using neural and mesodermal landmarks we demonstrate that the functions of RA in aligning neural and mesodermal tissues temporally precede the specification of hindbrain and spinal cord territories and the activation of hox transcription. Using cell transplantation assays we show that RA activity in the neuroepithelium regulates hindbrain patterning directly and territory size specification indirectly. This indirect function is partially dependent on Wnts but independent of FGFs. Importantly, RA specifies and patterns the hindbrain territory by antagonizing the activity of the spinal cord specification gene cdx4; loss of Cdx4 rescues the defects associated with the loss of RA, including the reduction in hindbrain size and the loss of posterior rhombomeres. We propose that at the head-trunk transition, RA coordinates specification, patterning and alignment of neural and mesodermal tissues that are essential for the organization and function of the neural and skeletal systems. © 2014. Published by The Company of Biologists Ltd.

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia

PubMed Central

Stateman, William A.; Knöppel, Alexandra B.; Flegel, Willy A.; Henkin, Robert I.

2015-01-01

PURPOSE Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls. PMID:27968956

Effects of pterostilbene and resveratrol on brain and behavior

USDA-ARS?s Scientific Manuscript database

Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than ...

Lymphocyte Functions in Microgravity

NASA Technical Reports Server (NTRS)

Pellis, Neal R.; Risin, Diane; Sundaresan, A.; Cooper, D.; Dawson, David L. (Technical Monitor)

1999-01-01

To understand the mechanism of immunity impairment in space it is important to analyze the direct effects of space-related conditions on different lymphocytes functions. Since 1992, we are investigating the effect of modeled and true microgravity (MG) on numerous lymphocyte functions. We had shown that modeled (MMG) and true microgravity inhibit lymphocyte locomotion through type I collagen. Modeled microgravity also suppresses polyclonal and antigen-specific lymphocyte activation. Polyclonal activation of lymphocytes prior to exposure to MMG abrogates the MG-induced inhibition of lymphocyte locomotion. The relationship between activation deficits and the loss of locomotion in MG was investigated using PKC activation by phorbol ester (PMA) and calcium ionophore (ionomycin). Direct activation of PKC by PMA substantially restored the MMG-inhibited lymphocyte locomotion and PHA-induced lymphocyte activation lonomycin by itself did not restore either locomotion or activation of the lymphocytes, indicating that these changes are not related to the impairment in the calcium flux in MMG. Treatment of lymphocytes with PMA before exposure to MMG prevented the loss of locomotion. It was observed that DNA synthesis is not necessary for restoration of locomotion since mitomicin C treated and untreated cells recovered their locomotion to the same level after PKC activation. Our recent data indicate that microgravity may selectively effect the expression of novel Ca2+ independent isoforms of PKC, in particularly PKC sigma and delta. This provides a new insight in understanding of the mechanisms of MG-sensitive cellular functions.

[Recurrent pregnancy loss: a literature review].

PubMed

Mateo-Sánez, H A; Mateo-Sánez, E; Hernández-Arroyo, L; Rivera-Ramírez, P; Mateo-Madrigal, M; Mateo-Madrigal, V; Mateo-Madrigal, D

2016-08-01

The definition of recurrent pregnancy loss varies according different authors and consensus: the American Society for Reproductive Medicine (ASRM) defines RPL when two or more pregnancy losses occur, and the European Society of Human Reproduction and Embryology (ESHRE) defines it as three or more pregnancy losses, not necessarily intrauterine. To this day, there is no uniform approach that serves as a guide in the diagnosis and treatment of this condition; this is why, in up to 50% of the cases of RPL, it will not be possible to identify the specific etiology. To report on the recurrent pregnancy loss, in order to harmonize concepts and suggest a diagnosis and treatment for this condition approach. The search strategy included, but was not limited to keywords like: recurrent abortion, infertility, habitual abortion, primary antiphospholipid syndrome, lupus anticoagulant, anti-cardiolipin antibodies and anti B2 glycoprotein I.

A hydrothermal after-ripening time model for seed dormancy loss in Bromus tectorum L.

Treesearch

Necia B. Bair; Susan E. Meyer; Phil S. Allen

2006-01-01

After-ripening, the loss of dormancy under dry conditions, is associated with a decrease in mean base water potential for germination of Bromus tectorum L. seeds. After-ripening rate is a linear function of temperature above a base temperature, so that dormancy loss can be quantified using a thermal after-ripening time (TAR) model. To incorporate storage water...

Dielectric properties, optimum formulation and microwave baking conditions of chickpea cakes.

PubMed

Alifakı, Yaşar Özlem; Şakıyan, Özge

2017-03-01

The aim of this study was to correlate dielectric properties with quality parameters, and to optimize cake formulation and baking conditions by response surface methodology. Weight loss, color, specific volume, hardness and porosity were evaluated. The samples with different DATEM (0.4, 0.8 and 1.2%) and chickpea flour concentrations (30, 40 and 50%) were baked in microwave oven at different power (300, 350, 400 W) and baking times (2.50, 3.0, 3.50 min). It was found that microwave power showed significant effect on color, while baking time showed effect on weight loss, porosity, hardness, specific volume and dielectric properties. Emulsifier level affected porosity, specific volume and dielectric constant. Chickpea flour level affected porosity, color, hardness and dielectric properties of cakes. The optimum microwave power, baking time, DATEM level and chickpea flour level were found as 400 W, 2.84 min, 1.2% and 30%, respectively. The comparison between conventionally baked and the microwave baked cakes at optimum points showed that color difference, weight loss, specific volume and porosity values of microwave baked cakes were less than those of conventionally baked cakes, on the other hand, hardness values were higher. Moreover, a negative correlation between dielectric constant and porosity, and weight loss values were detected for microwave baked samples. A negative correlation between dielectric loss factor and porosity was observed. These correlations indicated that quality characteristics of a microwave baked cake sample can be assessed from dielectric properties. These correlations provides understanding on the behavior of food material during microwave processing.

Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer

PubMed Central

Malkoski, Stephen P.; Wang, Xiao-Jing

2012-01-01

TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies. PMID:22321641

IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system

PubMed Central

Raasch, Jenni; Zeller, Nicolas; van Loo, Geert; Merkler, Doron; Mildner, Alexander; Erny, Daniel; Knobeloch, Klaus-Peter; Bethea, John R.; Waisman, Ari; Knust, Markus; Del Turco, Domenico; Deller, Thomas; Blank, Thomas; Priller, Josef; Brück, Wolfgang

2011-01-01

The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases. PMID:21310728

Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia

PubMed Central

Tolmachova, Tanya; Anders, Ross; Abrink, Magnus; Bugeon, Laurence; Dallman, Margaret J.; Futter, Clare E.; Ramalho, José S.; Tonagel, Felix; Tanimoto, Naoyuki; Seeliger, Mathias W.; Huxley, Clare; Seabra, Miguel C.

2006-01-01

Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choroid, caused by loss of function of the CHM/REP1 gene. REP1 is involved in lipid modification (prenylation) of Rab GTPases, key regulators of intracellular vesicular transport and organelle dynamics. To study the pathogenesis of CHM and to develop a model for assessing gene therapy, we have created a conditional mouse knockout of the Chm gene. Heterozygous-null females exhibit characteristic hallmarks of CHM: progressive degeneration of the photoreceptors, patchy depigmentation of the RPE, and Rab prenylation defects. Using tamoxifen-inducible and tissue-specific Cre expression in combination with floxed Chm alleles, we show that CHM pathogenesis involves independently triggered degeneration of photoreceptors and the RPE, associated with different subsets of defective Rabs. PMID:16410831

Vascular functioning and the water balance of ripening kiwifruit (Actinidia chinensis) berries

PubMed Central

Clearwater, Michael J.; Luo, Zhiwei; Ong, Sam Eng Chye; Blattmann, Peter; Thorp, T. Grant

2012-01-01

Indirect evidence suggests that water supply to fleshy fruits during the final stages of development occurs through the phloem, with the xylem providing little water, or acting as a pathway for water loss back to the plant. This inference was tested by examining the water balance and vascular functioning of ripening kiwifruit berries (Actinidia chinensis var. chinensis ‘Hort16A’) exhibiting a pre-harvest ‘shrivel’ disorder in California, and normal development in New Zealand. Dye labelling and mass balance experiments indicated that the xylem and phloem were both functional and contributed approximately equally to the fruit water supply during this stage of development. The modelled fruit water balance was dominated by transpiration, with net water loss under high vapour pressure deficit (Da) conditions in California, but a net gain under cooler New Zealand conditions. Direct measurement of pedicel sap flow under controlled conditions confirmed inward flows in both the phloem and xylem under conditions of both low and high Da. Phloem flows were required for growth, with gradual recovery after a step increase in Da. Xylem flows alone were unable to support growth, but did supply transpiration and were responsive to Da-induced pressure fluctuations. The results suggest that the shrivel disorder was a consequence of a high fruit transpiration rate, and that the perception of complete loss or reversal of inward xylem flows in ripening fruits should be re-examined. PMID:22155631

Sensitivity and Specificity of Self-Reported Olfactory Function in a Home-Based Study of Independent-Living, Healthy Older Women

PubMed Central

Rawal, Shristi; Hoffman, Howard J.; Chapo, Audrey K.

2015-01-01

Introduction The 2011–14 US National Health and Nutrition Examination Survey chemosensory protocol asks adults to self-rate their orthonasal (via nostrils) and retronasal (via mouth) smell abilities for subsequent odor identification testing. From data collected with a similar protocol, we aimed to identify a self-reported olfactory index that showed the best sensitivity (correctly identifying dysfunction) and specificity (correctly indentifying normosmia) with measured olfaction. Methods In home-based testing, 121 independent-living older women (age 73±7 years) reported their olfactory function by interviewer-administered survey. Olfactory function was measured orthonasally via composite (odor threshold, identification task) or identification task alone. Results Only 16 % of women self-rated “below average” smell function. More women perceived loss of smell (38 %) or flavor (30 %) with aging. The rate of measured dysfunction was 30 % by composite (threshold and identification) and 21.5 % by identification task, the latter misclassifying some mild dysfunction as normosmia. An index of self-rated smell function and perceived loss yielded the most favorable sensitivity (65 %) and specificity (77 %) to measured function. Self-rated olfaction showed better agreement with severe measured dysfunction; mild dysfunction was less noticed. Conclusions Self-reported indices that query about current and perceived changes in smell and flavor with aging showed better sensitivity estimates than those previously reported. Specificity was somewhat lower—some older adults may correctly perceive loss unidentified in a single assessment, or have a retronasal impairment that was undetected by an orthonasal measure. Implications Our findings should inform self-rated measures that screen for severe olfactory dysfunction in clinical/community settings where testing is not routine. PMID:25866597

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

PubMed

Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A; Rankin, Kelsey A; Stebbins, Karin J; Lorrain, Daniel S; Pekarek, Kara; A Sagan, Sharon; Xiao, Lan; Teuscher, Cory; von Büdingen, H-Christian; Wess, Jürgen; Lawrence, J Josh; Green, Ari J; Fancy, Stephen Pj; Zamvil, Scott S; Chan, Jonah R

2016-09-27

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.

Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila.

PubMed

Barton, Lacy J; Wilmington, Shameika R; Martin, Melinda J; Skopec, Hannah M; Lovander, Kaylee E; Pinto, Belinda S; Geyer, Pamela K

2014-06-01

The nuclear lamina is an extensive protein network that contributes to nuclear structure and function. LEM domain (LAP2, emerin, MAN1 domain, LEM-D) proteins are components of the nuclear lamina, identified by a shared ∼45-amino-acid motif that binds Barrier-to-autointegration factor (BAF), a chromatin-interacting protein. Drosophila melanogaster has three nuclear lamina LEM-D proteins, named Otefin (Ote), Bocksbeutel (Bocks), and dMAN1. Although these LEM-D proteins are globally expressed, loss of either Ote or dMAN1 causes tissue-specific defects in adult flies that differ from each other. The reason for such distinct tissue-restricted defects is unknown. Here, we generated null alleles of bocks, finding that loss of Bocks causes no overt adult phenotypes. Next, we defined phenotypes associated with lem-d double mutants. Although the absence of individual LEM-D proteins does not affect viability, loss of any two proteins causes lethality. Mutant phenotypes displayed by lem-d double mutants differ from baf mutants, suggesting that BAF function is retained in animals with a single nuclear lamina LEM-D protein. Interestingly, lem-d double mutants displayed distinct developmental and cellular mutant phenotypes, suggesting that Drosophila LEM-D proteins have developmental functions that are differentially shared with other LEM-D family members. This conclusion is supported by studies showing that ectopically produced LEM-D proteins have distinct capacities to rescue the tissue-specific phenotypes found in single lem-d mutants. Our findings predict that cell-specific mutant phenotypes caused by loss of LEM-D proteins reflect both the constellation of LEM-D proteins within the nuclear lamina and the capacity of functional compensation of the remaining LEM-D proteins. Copyright © 2014 by the Genetics Society of America.

Unique and Shared Functions of Nuclear Lamina LEM Domain Proteins in Drosophila

PubMed Central

Barton, Lacy J.; Wilmington, Shameika R.; Martin, Melinda J.; Skopec, Hannah M.; Lovander, Kaylee E.; Pinto, Belinda S.; Geyer, Pamela K.

2014-01-01

The nuclear lamina is an extensive protein network that contributes to nuclear structure and function. LEM domain (LAP2, emerin, MAN1 domain, LEM-D) proteins are components of the nuclear lamina, identified by a shared ∼45-amino-acid motif that binds Barrier-to-autointegration factor (BAF), a chromatin-interacting protein. Drosophila melanogaster has three nuclear lamina LEM-D proteins, named Otefin (Ote), Bocksbeutel (Bocks), and dMAN1. Although these LEM-D proteins are globally expressed, loss of either Ote or dMAN1 causes tissue-specific defects in adult flies that differ from each other. The reason for such distinct tissue-restricted defects is unknown. Here, we generated null alleles of bocks, finding that loss of Bocks causes no overt adult phenotypes. Next, we defined phenotypes associated with lem-d double mutants. Although the absence of individual LEM-D proteins does not affect viability, loss of any two proteins causes lethality. Mutant phenotypes displayed by lem-d double mutants differ from baf mutants, suggesting that BAF function is retained in animals with a single nuclear lamina LEM-D protein. Interestingly, lem-d double mutants displayed distinct developmental and cellular mutant phenotypes, suggesting that Drosophila LEM-D proteins have developmental functions that are differentially shared with other LEM-D family members. This conclusion is supported by studies showing that ectopically produced LEM-D proteins have distinct capacities to rescue the tissue-specific phenotypes found in single lem-d mutants. Our findings predict that cell-specific mutant phenotypes caused by loss of LEM-D proteins reflect both the constellation of LEM-D proteins within the nuclear lamina and the capacity of functional compensation of the remaining LEM-D proteins. PMID:24700158

Rate laws for water-assisted compaction and stress-induced water-rock interaction in sandstones

NASA Astrophysics Data System (ADS)

Dewers, Thomas; Hajash, Andrew

1995-07-01

Mineral-water interactions under conditions of nonhydrostatic stress play a role in subjects as diverse as ductile creep in fault zones, phase relations in metamorphic rocks, mass redistribution and replacement reactions during diagenesis, and loss of porosity in deep sedimentary basins. As a step toward understanding the fundamental geochemical processes involved, using naturally rounded St. Peter sand, we have investigated the kinetics of pore volume loss and quartz-water reactions under nonhydrostatic, hydrothermal conditions in flow-through reactors. Rate laws for creep and mineral-water reaction are derived from the time rate of change of pore volume, sand-water dissolution kinetics, and (flow rate independent) steady state silica concentrations, and reveal functional dependencies of rates on grain size, volume strain, temperature, effective pressure (confining minus pore pressure), and specific surface areas. Together the mechanical and chemical rate laws form a self-consistent model for coupled deformation and water-rock interaction of porous sands under nonhydrostatic conditions. Microstructural evidence shows a progressive widening of nominally circular and nominally flat grain-grain contacts with increasing strain or, equivalently, porosity loss, and small quartz overgrowths occurring at grain contact peripheries. The mechanical and chemical data suggest that the dominant creep mechanism is due to removal of mass from grain contacts (termed pressure solution or solution transfer), with a lesser component of time-dependent crack growth and healing. The magnitude of a stress-dependent concentration increase is too large to be accounted for by elastic or dislocation strain energy-induced supersaturations, favoring instead the normal stress dependence of molar Gibbs free energy associated with grain-grain interfaces.

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

PubMed

Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

2016-05-17

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Molecular regulation of urea cycle function by the liver glucocorticoid receptor.

PubMed

Okun, Jürgen G; Conway, Sean; Schmidt, Kathrin V; Schumacher, Jonas; Wang, Xiaoyue; de Guia, Roldan; Zota, Annika; Klement, Johanna; Seibert, Oksana; Peters, Achim; Maida, Adriano; Herzig, Stephan; Rose, Adam J

2015-10-01

One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function. Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.

Regenerative and Rehabilitative Medicine: A Necessary Synergy for Functional Recovery from Volumetric Muscle Loss Injury.

PubMed

Greising, Sarah M; Dearth, Christopher L; Corona, Benjamin T

2016-01-01

Volumetric muscle loss (VML) is a complex and heterogeneous problem due to significant traumatic or surgical loss of skeletal muscle tissue. The consequences of VML are substantial functional deficits in joint range of motion and skeletal muscle strength, resulting in life-long dysfunction and disability. Traditional physical medicine and rehabilitation paradigms do not address the magnitude of force loss due to VML and related musculoskeletal comorbidities. Recent advancements in regenerative medicine have set forth encouraging and emerging therapeutic options for VML injuries. There is significant potential that combined rehabilitative and regenerative therapies can restore limb and muscle function following VML injury in a synergistic manner. This review presents the current state of the VML field, spanning clinical and preclinical literature, with particular focus on rehabilitation and regenerative medicine in addition to their synergy. Moving forward, multidisciplinary collaboration between clinical and research fields is encouraged in order to continue to improve the treatment of VML injuries and specifically address the encompassing physiology, pathology, and specific needs of this patient population. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.

33 CFR 325.4 - Conditioning of permits.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., the Endangered Species Act, and requirements imposed by conditions on state section 401 water quality certifications. (2) Where appropriate, the district engineer may take into account the existence of controls... off-site for mitigation of significant losses which are specifically identifiable, reasonably likely...

The Impact of Change in Visual Field on Health-Related Quality of Life: The Los Angeles Latino Eye Study

PubMed Central

Patino, Cecilia M.; Varma, Rohit; Azen, Stanley P.; Conti, David V.; Nichol, Michael B.; McKean-Cowdin, Roberta

2010-01-01

Purpose To assess the impact of change in visual field (VF) on change in health related quality of life (HRQoL) at the population level. Design Prospective cohort study Participants 3,175 Los Angles Latino Eye Study (LALES) participants Methods Objective measures of VF and visual acuity and self-reported HRQoL were collected at baseline and 4-year follow-up. Analysis of covariance was used to evaluate mean differences in change of HRQoL across severity levels of change in VF and to test for effect modification by covariates. Main outcome measures General and vision-specific HRQoL. Results Of 3,175 participants, 1430 (46%) showed a change in VF (≥1 decibel [dB]) and 1651, 1715 (54%) reported a clinically important change (≥5 points) in vision-specific HRQoL. Progressive worsening and improvement in the VF were associated with increasing losses and gains in vision-specific HRQoL for the composite score and 10 of its 11 subscales (all Ptrends<0.05). Losses in VF > 5 dB and gains > 3 dB were associated with clinically meaningful losses and gains in vision-specific HRQoL, respectively. Areas of vision-specific HRQoL most affected by greater losses in VF were driving, dependency, role-functioning, and mental health. The effect of change in VF (loss or gain) on mean change in vision-specific HRQoL varied by level of baseline vision loss (in visual field and/or visual acuity) and by change in visual acuity (all P-interactions<0.05). Those with moderate/severe VF loss at baseline and with a > 5 dB loss in visual field during the study period had a mean loss of vision-specific HRQoL of 11.3 points, while those with no VF loss at baseline had a mean loss of 0.97 points Similarly, with a > 5 dB loss in VF and baseline visual acuity impairment (mild/severe) there was a loss in vision-specific HRQoL of 10.5 points, whereas with no visual acuity impairment at baseline there was a loss of vision-specific HRQoL of 3.7 points. Conclusion Both losses and gains in VF produce clinically meaningful changes in vision-specific HRQoL. In the presence of pre-existing vision loss (VF and visual acuity), similar levels of visual field change produce greater losses in quality of life. PMID:21458074

Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.

PubMed

Madeira, Mila F M; Queiroz-Junior, Celso M; Montero-Melendez, Trinidad; Werneck, Silvia M C; Corrêa, Jôice D; Soriani, Frederico M; Garlet, Gustavo P; Souza, Daniele G; Teixeira, Mauro M; Silva, Tarcilia A; Perretti, Mauro

2016-12-01

Alveolar bone loss is a result of an aggressive form of periodontal disease (PD) associated with Aggregatibacter actinomycetemcomitans (Aa) infection. PD is often observed with other systemic inflammatory conditions, including arthritis. Melanocortin peptides activate specific receptors to exert antiarthritic properties, avoiding excessing inflammation and modulating macrophage function. Recent work has indicated that melanocortin can control osteoclast development and function, but whether such protection takes place in infection-induced alveolar bone loss has not been investigated. The purpose of this study was to evaluate the role of melanocortin in Aa-induced PD. Mice were orally infected with Aa and treated with the melanocortin analog DTrp 8 -γMSH or vehicle daily for 30 d. Then, periodontal tissue was collected and analyzed. Aa-infected mice treated with DTrp 8 -γMSH presented decreased alveolar bone loss and a lower degree of neutrophil infiltration in the periodontium than vehicle-treated animals; these actions were associated with reduced periodontal levels of TNF-α, IFN-γ, and IL-17A. In vitro experiments with cells differentiated into osteoclasts showed that osteoclast formation and resorptive activity were attenuated after treatment with DTrp 8 -γMSH. Thus, melanocortin agonism could represent an innovative way to tame overexuberant inflammation and, at the same time, preserve bone physiology, as seen after Aa infection.-Madeira, M. F. M., Queiroz-Junior, C. M., Montero-Melendez, T., Werneck, S. M. C., Corrêa, J. D., Soriani, F. M., Garlet, G. P., Souza, D. G., Teixeira, M. M., Silva, T. A., Perretti, M. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection. © FASEB.

Effects of Plant Diversity, Functional Group Composition, and Fertilization on Soil Microbial Properties in Experimental Grassland

PubMed Central

Strecker, Tanja; Barnard, Romain L.; Niklaus, Pascal A.; Scherer-Lorenzen, Michael; Weigelt, Alexandra; Scheu, Stefan; Eisenhauer, Nico

2015-01-01

Background Loss of biodiversity and increased nutrient inputs are two of the most crucial anthropogenic factors driving ecosystem change. Although both received considerable attention in previous studies, information on their interactive effects on ecosystem functioning is scarce. In particular, little is known on how soil biota and their functions are affected by combined changes in plant diversity and fertilization. Methodology/Principal Findings We investigated the effects of plant diversity, functional community composition, and fertilization on the biomass and respiration of soil microbial communities in a long-term biodiversity experiment in semi-natural grassland (Jena Experiment). Plant species richness enhanced microbial basal respiration and microbial biomass, but did not significantly affect microbial specific respiration. In contrast, the presence of legumes and fertilization significantly decreased microbial specific respiration, without altering microbial biomass. The effect of legumes was superimposed by fertilization as indicated by a significant interaction between the presence of legumes and fertilization. Further, changes in microbial stoichiometry (C-to-N ratio) and specific respiration suggest the presence of legumes to reduce N limitation of soil microorganisms and to modify microbial C use efficiency. Conclusions/Significance Our study highlights the role of plant species and functional group diversity as well as interactions between plant community composition and fertilizer application for soil microbial functions. Our results suggest soil microbial stoichiometry to be a powerful indicator of microbial functioning under N limited conditions. Although our results support the notion that plant diversity and fertilizer application independently affect microbial functioning, legume effects on microbial N limitation were superimposed by fertilization, indicating significant interactions between the functional composition of plant communities and nutrient inputs for soil processes. PMID:25938580

Changes in ion transport in inflammatory disease.

PubMed

Eisenhut, Michael

2006-03-29

Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalities in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed.

Changes in ion transport in inflammatory disease

PubMed Central

Eisenhut, Michael

2006-01-01

Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalites in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed. PMID:16571116

Physiological state influences evaporative water loss and microclimate preference in the snake Vipera aspis.

PubMed

Dupoué, Andréaz; Stahlschmidt, Zachary R; Michaud, Bruno; Lourdais, Olivier

2015-05-15

Animals typically respond to environmental variation by adjusting their physiology, behavior, or both. Ectothermic animals are particularly sensitive to microclimatic conditions and behaviorally thermoregulate to optimize physiological performance. Yet, thermoregulation can be costly and may obligate a physiological tradeoff with water loss. Presumably, this tradeoff intensifies when animals undergo necessary life-history events (e.g., pregnancy or digestion) that impose significant behavioral and physiological changes, including shifts in behavioral thermoregulation and increased metabolic rate. Thus, behavioral responses, such as modified microclimatic preferences, may help mitigate the physiological tradeoff between thermoregulation and water loss. Herein, we examined the influence of major physiological states (specifically, pregnancy, ecdysis, and digestion) on evaporative water loss and on behavioral adjustments in a viviparous snake, Vipera aspis. First, we used open-flow respirometry to measure the effects of physiological states and microclimatic conditions (temperature and humidity) on the rate of total evaporative water loss (TEWL) and metabolic rate (rate of O2 consumption, V˙O2). Then, we experimentally tested the influence of physiological state on microclimate selection. We found that energy-demanding physiological states were associated with i) an increased rate of TEWL and V˙O2 compared to control states and ii) a slight preference (statistically marginal) for both warm and humid conditions compared to controls, suggesting a state-specificity in behavioral response. Overall our results underline the impact of physiological state on water loss and demonstrate the potential for behavior to mitigate the physiological tradeoff between thermoregulation and water balance. Copyright © 2015 Elsevier Inc. All rights reserved.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

PubMed

Petchey, Louisa K; Risebro, Catherine A; Vieira, Joaquim M; Roberts, Tom; Bryson, John B; Greensmith, Linda; Lythgoe, Mark F; Riley, Paul R

2014-07-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

PubMed Central

Petchey, Louisa K.; Risebro, Catherine A.; Vieira, Joaquim M.; Roberts, Tom; Bryson, John B.; Greensmith, Linda; Lythgoe, Mark F.; Riley, Paul R.

2014-01-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease. PMID:24938781

Functional Diversity as a New Framework for Understanding the Ecology of an Emerging Generalist Pathogen.

PubMed

Morris, Aaron; Guégan, Jean-François; Benbow, M Eric; Williamson, Heather; Small, Pamela L C; Quaye, Charles; Boakye, Daniel; Merritt, Richard W; Gozlan, Rodolphe E

2016-09-01

Emerging infectious disease outbreaks are increasingly suspected to be a consequence of human pressures exerted on natural ecosystems. Previously, host taxonomic communities have been used as indicators of infectious disease emergence, and the loss of their diversity has been implicated as a driver of increased presence. The mechanistic details in how such pathogen-host systems function, however, may not always be explained by taxonomic variation or loss. Here we used machine learning and methods based on Gower's dissimilarity to quantify metrics of invertebrate functional diversity, in addition to functional groups and their taxonomic diversity at sites endemic and non-endemic for the model generalist pathogen Mycobacterium ulcerans, the causative agent of Buruli ulcer. Changes in these metrics allowed the rapid categorisation of the ecological niche of the mycobacterium's hosts and the ability to relate specific host traits to its presence in aquatic ecosystems. We found that taxonomic diversity of hosts and overall functional diversity loss and evenness had no bearing on the mycobacterium's presence, or whether the site was in an endemic area. These findings, however, provide strong evidence that generalist environmentally persistent bacteria such as M. ulcerans can be associated with specific functional traits rather than taxonomic groups of organisms, increasing our understanding of emerging disease ecology and origin.

Epidemiological aspects of ageing.

PubMed Central

Khaw, K T

1997-01-01

A major societal challenge is to improve quality of life and prevent or reduce disability and dependency in an ageing population. Increasing age is associated with increasing risk of disability and loss of independence, due to functional impairments such as loss of mobility, hearing and vision; a major issue must be how far disability can be prevented. Ageing is associated with loss of bone tissue, reduction in muscle mass, reduced respiratory function, decline in cognitive function, rise in blood pressure and macular degeneration which predispose to disabling conditions such as osteoporosis, heart disease, dementia and blindness. However, there are considerable variations in different communities in terms of the rate of age-related decline. Large geographic and secular variations in the age-adjusted incidence of major chronic diseases such as stroke, hip fracture, coronary heart disease, cancer, visual loss from cataract, glaucoma and macular degeneration suggest strong environmental determinants in diet, physical activity and smoking habit. The evidence suggests that a substantial proportion of chronic disabling conditions associated with ageing are preventable, or at least postponable and not an inevitable accompaniment of growing old. Postponement or prevention of these conditions may not only increase longevity, but, more importantly, reduce the period of illnesses such that the majority of older persons may live high-quality lives, free of disability, until very shortly before death. We need to understand better the factors influencing the onset of age-related disability in the population, so that we have appropriate strategies to maintain optimal health in an ageing population. PMID:9460067

Epidemiological aspects of ageing.

PubMed

Khaw, K T

1997-12-29

A major societal challenge is to improve quality of life and prevent or reduce disability and dependency in an ageing population. Increasing age is associated with increasing risk of disability and loss of independence, due to functional impairments such as loss of mobility, hearing and vision; a major issue must be how far disability can be prevented. Ageing is associated with loss of bone tissue, reduction in muscle mass, reduced respiratory function, decline in cognitive function, rise in blood pressure and macular degeneration which predispose to disabling conditions such as osteoporosis, heart disease, dementia and blindness. However, there are considerable variations in different communities in terms of the rate of age-related decline. Large geographic and secular variations in the age-adjusted incidence of major chronic diseases such as stroke, hip fracture, coronary heart disease, cancer, visual loss from cataract, glaucoma and macular degeneration suggest strong environmental determinants in diet, physical activity and smoking habit. The evidence suggests that a substantial proportion of chronic disabling conditions associated with ageing are preventable, or at least postponable and not an inevitable accompaniment of growing old. Postponement or prevention of these conditions may not only increase longevity, but, more importantly, reduce the period of illnesses such that the majority of older persons may live high-quality lives, free of disability, until very shortly before death. We need to understand better the factors influencing the onset of age-related disability in the population, so that we have appropriate strategies to maintain optimal health in an ageing population.

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells.

PubMed

Grahammer, Florian; Ramakrishnan, Suresh K; Rinschen, Markus M; Larionov, Alexey A; Syed, Maryam; Khatib, Hazim; Roerden, Malte; Sass, Jörn Oliver; Helmstaedter, Martin; Osenberg, Dorothea; Kühne, Lucas; Kretz, Oliver; Wanner, Nicola; Jouret, Francois; Benzing, Thomas; Artunc, Ferruh; Huber, Tobias B; Theilig, Franziska

2017-01-01

Renal proximal tubular cells constantly recycle nutrients to ensure minimal loss of vital substrates into the urine. Although most of the transport mechanisms have been discovered at the molecular level, little is known about the factors regulating these processes. Here, we show that mTORC1 and mTORC2 specifically and synergistically regulate PTC endocytosis and transport processes. Using a conditional mouse genetic approach to disable nonredundant subunits of mTORC1, mTORC2, or both, we showed that mice lacking mTORC1 or mTORC1/mTORC2 but not mTORC2 alone develop a Fanconi-like syndrome of glucosuria, phosphaturia, aminoaciduria, low molecular weight proteinuria, and albuminuria. Interestingly, proteomics and phosphoproteomics of freshly isolated kidney cortex identified either reduced expression or loss of phosphorylation at critical residues of different classes of specific transport proteins. Functionally, this resulted in reduced nutrient transport and a profound perturbation of the endocytic machinery, despite preserved absolute expression of the main scavenger receptors, MEGALIN and CUBILIN. Our findings highlight a novel mTOR-dependent regulatory network for nutrient transport in renal proximal tubular cells. Copyright © 2016 by the American Society of Nephrology.

Altered blood-brain barrier transport in neuro-inflammatory disorders.

PubMed

Schenk, Geert J; de Vries, Helga E

2016-06-01

During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive mediated endocytosis and receptor-mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. In contrast, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this review we will briefly discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group.

PubMed

Bauer, Jürgen; Biolo, Gianni; Cederholm, Tommy; Cesari, Matteo; Cruz-Jentoft, Alfonso J; Morley, John E; Phillips, Stuart; Sieber, Cornel; Stehle, Peter; Teta, Daniel; Visvanathan, Renuka; Volpi, Elena; Boirie, Yves

2013-08-01

New evidence shows that older adults need more dietary protein than do younger adults to support good health, promote recovery from illness, and maintain functionality. Older people need to make up for age-related changes in protein metabolism, such as high splanchnic extraction and declining anabolic responses to ingested protein. They also need more protein to offset inflammatory and catabolic conditions associated with chronic and acute diseases that occur commonly with aging. With the goal of developing updated, evidence-based recommendations for optimal protein intake by older people, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group). To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.0 to 1.2 g protein per kilogram of body weight per day. Both endurance- and resistance-type exercises are recommended at individualized levels that are safe and tolerated, and higher protein intake (ie, ≥ 1.2 g/kg body weight/d) is advised for those who are exercising and otherwise active. Most older adults who have acute or chronic diseases need even more dietary protein (ie, 1.2-1.5 g/kg body weight/d). Older people with severe kidney disease (ie, estimated GFR <30 mL/min/1.73 m(2)), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake. Protein quality, timing of ingestion, and intake of other nutritional supplements may be relevant, but evidence is not yet sufficient to support specific recommendations. Older people are vulnerable to losses in physical function capacity, and such losses predict loss of independence, falls, and even mortality. Thus, future studies aimed at pinpointing optimal protein intake in specific populations of older people need to include measures of physical function. Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

Residual wood polymers facilitate compounding of microfibrillated cellulose with poly(lactic acid) for 3D printer filaments

NASA Astrophysics Data System (ADS)

Winter, Armin; Mundigler, Norbert; Holzweber, Julian; Veigel, Stefan; Müller, Ulrich; Kovalcik, Adriana; Gindl-Altmutter, Wolfgang

2017-12-01

Microfibrillated cellulose (MFC) is a fascinating material with an obvious potential for composite reinforcement due to its excellent mechanics together with high specific surface area. However, in order to use this potential, commercially viable solutions to important technological challenges have to be found. Notably, the distinct hydrophilicity of MFC prevents efficient drying without loss in specific surface area, necessitating storage and processing in wet condition. This greatly hinders compounding with important technical polymers immiscible with water. Differently from cellulose, the chemistry of the major wood polymers lignin and hemicellulose is much more diverse in terms of functional groups. Specifically, the aromatic moieties present in lignin and acetyl groups in hemicellulose provide distinctly less polar surface-chemical functionality compared to hydroxyl groups which dominate the surface-chemical character of cellulose. It is shown that considerable advantages in the production of MFC-filled poly(lactic acid) filaments for three-dimensional printing can be obtained through the use of MFC containing residual lignin and hemicellulose due to their advantageous surface-chemical characteristics. Specifically, considerably reduced agglomerations of MFC in the filaments in combination with improved printability and improved toughness of printed objects are achieved. This article is part of a discussion meeting issue `New horizons for cellulose nanotechnology'.

Residual wood polymers facilitate compounding of microfibrillated cellulose with poly(lactic acid) for 3D printer filaments.

PubMed

Winter, Armin; Mundigler, Norbert; Holzweber, Julian; Veigel, Stefan; Müller, Ulrich; Kovalcik, Adriana; Gindl-Altmutter, Wolfgang

2018-02-13

Microfibrillated cellulose (MFC) is a fascinating material with an obvious potential for composite reinforcement due to its excellent mechanics together with high specific surface area. However, in order to use this potential, commercially viable solutions to important technological challenges have to be found. Notably, the distinct hydrophilicity of MFC prevents efficient drying without loss in specific surface area, necessitating storage and processing in wet condition. This greatly hinders compounding with important technical polymers immiscible with water. Differently from cellulose, the chemistry of the major wood polymers lignin and hemicellulose is much more diverse in terms of functional groups. Specifically, the aromatic moieties present in lignin and acetyl groups in hemicellulose provide distinctly less polar surface-chemical functionality compared to hydroxyl groups which dominate the surface-chemical character of cellulose. It is shown that considerable advantages in the production of MFC-filled poly(lactic acid) filaments for three-dimensional printing can be obtained through the use of MFC containing residual lignin and hemicellulose due to their advantageous surface-chemical characteristics. Specifically, considerably reduced agglomerations of MFC in the filaments in combination with improved printability and improved toughness of printed objects are achieved.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. © 2017 The Author(s).

Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss

PubMed Central

McGregor, Ronald; Shan, Ling; Wu, Ming-Fung

2017-01-01

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within “non-visible” phenotypically defined cells has fundamental implications for our understanding of brain plasticity. PMID:28570646

Adolescents with Hearing Loss and the International Classification of Functioning, Health, and Disability: Children & Youth Version

PubMed Central

English, Kris; Pajevic, Emily

2016-01-01

In 2007, the World Health Organization published a set of International Classification of Functioning, Disability and Health (ICF) codes designed for children and youth (ICF-CY version). The ICF-CY considers typical developmental changes associated with childhood while describing health status and the effects of intervention. In this article we will describe how a specific intervention (transition planning for adolescents) can be documented with the ICF-CY. Transition planning in health care prepares adolescents and their families for the transfer from pediatric to adult health services and has been demonstrated to be an effective practice for adolescents with many types of chronic health conditions (e.g., cystic fibrosis, epilepsy, diabetes). Audiology has not yet addressed transition planning for adolescents with hearing loss; therefore, we propose using the ICF-CY to design a pathway of care. The ICF-CY can standardize transition planning to the benefit of both teen patients and audiologists: teens and their families would gradually acquire necessary knowledge and skills, and audiologists would develop a meaningful data set to help further inform our pediatric practices, as well as give more structure, depth, and accountability to our role in rehabilitation. PMID:27489402

PubMed Central

Forli, F.; Guglielmi, V.; De Corso, E.; Paludetti, G.; Berrettini, S.; Fetoni, A.R.

2016-01-01

SUMMARY Age-related hearing loss (ARHL) has a multifactorial pathogenesis and it is an inevitable hearing impairment associated with reduction of communicative skills related to ageing. Increasing evidence has linked ARHL to more rapid progression of cognitive decline and incidental dementia. Many aspects of daily living of elderly people have been associated to hearing abilities, showing that hearing loss (HL) affects the quality of life, social relationships, motor skills, psychological aspects and function and morphology in specific brain areas. Epidemiological and clinical studies confirm the assumption of a relationship between these conditions. However, the mechanisms are still unclear and are reviewed herein. Long-term hearing deprivation of auditory inputs can impact cognitive performance by decreasing the quality of communication leading to social isolation and depression and facilitate dementia. On the contrary, the limited cognitive skills may reduce the cognitive resources available for auditory perception, increasing the effects of HL. In addition, hearing loss and cognitive decline may reflect a 'common cause' on the auditory pathway and brain. In fact, some pathogenetic factors are recongised in common microvascular disease factors such as diabetes, atherosclerosis and hypertension. Interdisciplinary efforts to investigate and address HL in the context of brain and cognitive ageing are needed. Surprisingly, few studies have been adressed on the effectiveness of hearing aids in changing the natural history of cognitive decline. Effective interventions with hearing aids or cochlear implant may improve social and emotional function, communication, cognitive function and positively impact quality of life. The aim of this review is to overview new insights on this challenging topic and provide new ideas for future research. PMID:27214827

Bone, body weight, and weight reduction: what are the concerns?

PubMed

Shapses, Sue A; Riedt, Claudia S

2006-06-01

Of the U.S. population, 65% is either overweight or obese, and weight loss is recommended to reduce co-morbid conditions. However, bone mobilization and loss may also occur with weight loss. The risk for bone loss depends on initial body weight, age, gender, physical activity, and conditions of dieting such as the extent of energy restriction and specific levels of nutrient intake. Older populations are more prone to bone loss with weight loss; in women, this is due at least in part to a reduced dietary Ca intake and/or efficiency of absorption. Potential hormonal mechanisms regulating bone loss during weight loss are discussed, including decreases in estrogen, leptin, glucagon-like peptide-2, growth hormone, and insulin-like growth factor-1, or an increase in cortisol. In contrast, the rise in adiponectin and ghrelin with weight reduction should not be detrimental to bone. Combining energy restriction with exercise does not necessarily prevent bone loss, but may attenuate loss as was shown with additional Ca intake or osteoporosis medications. Future controlled weight loss trials should be designed to further address mechanisms influencing the density and quality of bone sites vulnerable to fracture, in the prevention of osteoporosis.

Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis.

PubMed

Schlager, Stefanie; Goeritzer, Madeleine; Jandl, Katharina; Frei, Robert; Vujic, Nemanja; Kolb, Dagmar; Strohmaier, Heimo; Dorow, Juliane; Eichmann, Thomas O; Rosenberger, Angelika; Wölfler, Albert; Lass, Achim; Kershaw, Erin E; Ceglarek, Uta; Dichlberger, Andrea; Heinemann, Akos; Kratky, Dagmar

2015-11-01

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases. © The Author(s).

A modulatory role of the Rax homeobox gene in mature pineal gland function: Investigating the photoneuroendocrine circadian system of a Rax conditional knockout mouse.

PubMed

Rohde, Kristian; Bering, Tenna; Furukawa, Takahisa; Rath, Martin Fredensborg

2017-10-01

The retinal and anterior neural fold homeobox gene (Rax) controls development of the eye and the forebrain. Postnatal expression of Rax in the brain is restricted to the pineal gland, a forebrain structure devoted to melatonin synthesis. The role of Rax in pineal function is unknown. In order to investigate the role of Rax in pineal function while circumventing forebrain abnormalities of the global Rax knockout, we generated an eye and pineal-specific Rax conditional knockout mouse. Deletion of Rax in the pineal gland did not affect morphology of the gland, suggesting that Rax is not essential for pineal gland development. In contrast, deletion of Rax in the eye generated an anophthalmic phenotype. In addition to the loss of central visual pathways, the suprachiasmatic nucleus of the hypothalamus housing the circadian clock was absent, indicating that the retinohypothalamic tract is required for the nucleus to develop. Telemetric analyses confirmed the lack of a functional circadian clock. Arylalkylamine N-acetyltransferase (Aanat) transcripts, encoding the melatonin rhythm-generating enzyme, were undetectable in the pineal gland of the Rax conditional knockout under normal conditions, whereas the paired box 6 homeobox gene, known to regulate pineal development, was up-regulated. By injecting isoproterenol, which mimics a nocturnal situation in the pineal gland, we were able to induce pineal expression of Aanat in the Rax conditional knockout mouse, but Aanat transcript levels were significantly lower than those of Rax-proficient mice. Our data suggest that Rax controls pineal gene expression and via Aanat may modulate melatonin synthesis. © 2017 International Society for Neurochemistry.

The Changing Face of Disability in the US Army: The Operation Enduring Freedom and Operation Iraqi Freedom Effect

DTIC Science & Technology

2012-01-01

osteoarthritis Fibromyalgia Diagnosis of fibromyalgia in which fibromyalgia itself is an unfitting condition Knee Any condition causing pain in or loss of function...ability significantly increased for all orthopaedic conditions, with the ex- ception of amputation, fibromyalgia , other lower extremity conditions...n = 3,143) P Value Amputation 1 0.06 33 1.05 ɘ.0001 Back painb 376 22.47 1,348 42.89 ɘ.0001 Foot and ankle 54 3.23 324 10.31 ɘ.0001 Fibromyalgia

The Arabidopsis sn-1-specific mitochondrial acylhydrolase AtDLAH is positively correlated with seed viability

PubMed Central

Seo, Young Sam; Kim, Eun Yu; Kim, Woo Taek

2011-01-01

Lipid-derived molecules produced by acylhydrolases play important roles in the regulation of diverse cellular functions in plants. In Arabidopsis, the DAD1-like phospholipase A1 family consists of 12 members, all of which possess a lipase 3 domain. In this study, the biochemical and cellular functions of AtDLAH, an Arabidopsis thaliana DAD1-like acylhydrolase, were examined. Bacterially expressed AtDLAH contained phospholipase A1 activity for catalysing the hydrolysis of phospholipids at the sn-1 position. However, AtDLAH displayed an even stronger preference for 1-lysophosphatidylcholine, 1-monodiacylglycerol, and phosphatidic acid, suggesting that AtDLAH is a sn-1-specific acylhydrolase. The AtDLAH gene was highly expressed in young seedlings, and its encoded protein was exclusively localized to the mitochondria. AtDLAH-overexpressing transgenic seeds (35S:AtDLAH) were markedly tolerant to accelerated-ageing treatment and thus had higher germination percentages than wild-type seeds. In contrast, the atdlah loss-of-function knockout mutant seeds were hypersusceptible to accelerated-ageing conditions. The 35S:AtDLAH seeds, as opposed to the atdlah seeds, exhibited a dark red staining pattern following tetrazolium treatment under both normal and accelerated-ageing conditions, suggesting that AtDLAH expression is positively correlated with seed viability. The enhanced viability of 35S:AtDLAH seeds was accompanied by more densely populated epidermal cells, lower levels of accumulated lipid hydroperoxides, and higher levels of polar lipids as compared with wild-type and atdlah mutant seeds. These results suggest that AtDLAH, a mitochondrial-localized sn-1-specific acylhydrolase, plays an important role in Arabidopsis seed viability. PMID:21856645

Calorie Restriction in Overweight SeniorS: Response of Older Adults to a Dieting Study: The CROSSROADS Randomized Controlled Clinical Trial

PubMed Central

Haas, Marilyn C.; Bodner, Eric V.; Brown, Cynthia J.; Bryan, David; Buys, David R.; Keita, Akilah Dulin; Flagg, Lee Anne; Goss, Amy; Gower, Barbara; Hovater, Martha; Hunter, Gary; Ritchie, Christine S.; Roth, David L.; Wingo, Brooks C.; Ard, Jamy; Locher, Julie L.

2014-01-01

We conducted a study designed to evaluate whether the benefits of intentional weight loss exceed the potential risks in a group of community-dwelling, obese, older adults who were at increased risk for cardiometabolic disease. The CROSSROADS trial used a prospective randomized controlled design to compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition and adipose tissue deposition (Specific Aim #1: To compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition, namely visceral adipose tissue (VAT)), cardiometabolic disease risk (Specific Aim #2: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on cardiometabolic disease risk), functional status and quality of life (Specific Aim #3: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on functional status and quality of life). Participants were randomly assigned to one of three groups: Exercise Only (Control) Intervention, Exercise + Diet Quality + Weight Maintenance Intervention, or Exercise + Diet Quality + Weight Loss Intervention. CROSSROADS utilized a lifestyle intervention approach consisting of exercise, dietary, and behavioral components. The development and implementation of the CROSSROADS protocol, including a description of the methodology, detailing specific elements of the lifestyle intervention, assurances of treatment fidelity, and participant retention; outcome measures and adverse event monitoring; as well as unique data management features of the trial results, are presented in this article. PMID:25424512

Calorie restriction in overweight seniors: response of older adults to a dieting study: the CROSSROADS randomized controlled clinical trial.

PubMed

Haas, Marilyn C; Bodner, Eric V; Brown, Cynthia J; Bryan, David; Buys, David R; Keita, Akilah Dulin; Flagg, Lee Anne; Goss, Amy; Gower, Barbara; Hovater, Martha; Hunter, Gary; Ritchie, Christine S; Roth, David L; Wingo, Brooks C; Ard, Jamy; Locher, Julie L

2014-01-01

We conducted a study designed to evaluate whether the benefits of intentional weight loss exceed the potential risks in a group of community-dwelling obese older adults who were at increased risk for cardiometabolic disease. The CROSSROADS trial used a prospective randomized controlled design to compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition and adipose tissue deposition (Specific Aim #1: To compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition, namely visceral adipose tissue), cardiometabolic disease risk (Specific Aim #2: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on cardiometabolic disease risk), and functional status and quality of life (Specific Aim #3: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on functional status and quality of life). Participants were randomly assigned to one of three groups: Exercise Only (Control) Intervention, Exercise + Diet Quality + Weight Maintenance Intervention, or Exercise + Diet Quality + Weight Loss Intervention. CROSSROADS utilized a lifestyle intervention approach consisting of exercise, dietary, and behavioral components. The development and implementation of the CROSSROADS protocol, including a description of the methodology, detailing specific elements of the lifestyle intervention, assurances of treatment fidelity, and participant retention; outcome measures and adverse event monitoring; as well as unique data management features of the trial results, are presented in this article.

The Role of Androgens and Estrogens on Healthy Aging and Longevity

PubMed Central

Dillon, E. Lichar; Urban, Randall J.; Sheffield-Moore, Melinda

2012-01-01

Aging is associated with a loss of sex hormone in both men (andropause) and women (menopause). In men, reductions in testosterone can trigger declines in muscle mass, bone mass, and in physical function. In women, the impact of the loss of sex hormones, such as estradiol, on bone is well elucidated, but evidence is limited on whether the loss of estradiol negatively affects muscle mass and physical function. However, deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons. Thus, consideration should be given as to whether targeted hormone replacement therapies may prove effective at treating clinical conditions, such as age-related sarcopenia, cancer cachexia, and/or acute or chronic illnesses. If initiated carefully in the appropriate clinical population, hormone replacement therapies in men and women may prevent and reverse muscle and bone loss and functional declines and perhaps promote healthy aging and longevity. PMID:22451474

Loss of functional diversity and network modularity in introduced plant–fungal symbioses

PubMed Central

Cooper, Jerry A.; Bufford, Jennifer L.; Hulme, Philip E.; Bates, Scott T.

2017-01-01

The introduction of alien plants into a new range can result in the loss of co-evolved symbiotic organisms, such as mycorrhizal fungi, that are essential for normal plant physiological functions. Prior studies of mycorrhizal associations in alien plants have tended to focus on individual plant species on a case-by-case basis. This approach limits broad scale understanding of functional shifts and changes in interaction network structure that may occur following introduction. Here we use two extensive datasets of plant–fungal interactions derived from fungal sporocarp observations and recorded plant hosts in two island archipelago nations: New Zealand (NZ) and the United Kingdom (UK). We found that the NZ dataset shows a lower functional diversity of fungal hyphal foraging strategies in mycorrhiza of alien when compared with native trees. Across species this resulted in fungal foraging strategies associated with alien trees being much more variable in functional composition compared with native trees, which had a strikingly similar functional composition. The UK data showed no functional difference in fungal associates of alien and native plant genera. Notwithstanding this, both the NZ and UK data showed a substantial difference in interaction network structure of alien trees compared with native trees. In both cases, fungal associates of native trees showed strong modularity, while fungal associates of alien trees generally integrated into a single large module. The results suggest a lower functional diversity (in one dataset) and a simplification of network structure (in both) as a result of introduction, potentially driven by either limited symbiont co-introductions or disruption of habitat as a driver of specificity due to nursery conditions, planting, or plant edaphic-niche expansion. Recognizing these shifts in function and network structure has important implications for plant invasions and facilitation of secondary invasions via shared mutualist populations. PMID:28039116

Linking suspended sediment transport metrics with fish functional traits in the Northwestern Great Plains (Invited)

NASA Astrophysics Data System (ADS)

Schwartz, J. S.; Simon, A.; Klimetz, L.

2009-12-01

Loss of ecological integrity due to excessive suspended sediment in rivers and streams is a major cause of water quality impairment in the United States. Although 32 states have developed numeric criteria for turbidity or suspended solids, or both according to the USEPA (2006), criteria is typically written as a percent exceedance above background and what constitutes background is not well defined. Defining a background level is problematic considering suspended sediments and related turbidity levels change with flow stage and season, and limited scientific data exists on relationships between sediment exposure and biotic response. Current assessment protocols for development of sediment total maximum daily loads (TMDLs) lack a means to link temporally-variable sediment transport rates with specific losses of ecological functions as loads increase. This study, within the in Northwestern Great Plains Ecoregion, co-located 58 USGS gauging stations with existing flow and suspended sediment data, and fish data from federal and state agencies. Suspended sediment concentration (SSC) transport metrics were quantified into exceedance frequencies of a given magnitude, duration as the number of consecutive days a given concentration was equaled or exceeded, dosage as concentration x duration, and mean annual suspended sediment yields. A functional traits-based approach was used to correlate SSC transport metrics with site occurrences of 20 fish traits organized into four main groups: preferred rearing mesohabitat, trophic structure, feeding habits, and spawning behavior. Negative correlations between SSC metrics and trait occurrences were assumed to represent potential conditions for impairment, specifically identifying an ecological loss by functional trait. Potential impairment conditions were linked with presence of the following traits: habitat preferences for stream pool and river shallow waters; feeding generalists, omnivores, piscivores; and several spawning behaviors. Using these results, TMDL targets were proposed such as < 19 mg/l SSC and 1,500 mg/l-day dosage at the 95% recurrence frequency for feeding generalists and omnivores. In general, traits correlated with: 1) a broad range of SSC exceedance frequencies and flow stages, 2) exceedance frequencies near 90-95% occurring at moderate flow stages; and 3) exceedance frequencies near 0.01-10 % occurring during floods. Unstable channels were found to be greater in transported suspended sediment than stable channels over a range of concentration exceedance frequencies, and likely influence physical habitat quality. Pool-preference and gravel spawner traits were greater in stable channels than unstable channels. Overall, a functional traits-based approach utilizing concentration-duration-frequency characteristics of suspended sediment transport was successful in identifying potential “targets” for biological impairment due to excessive sediment, and will aid in developing sediment TMDLs.

MSL1 is a mechanosensitive ion channel that dissipates mitochondrial membrane potential and maintains redox homeostasis in mitochondria during abiotic stress

PubMed Central

Lee, Chun Pong; Maksaev, Grigory; Jensen, Gregory S.; Murcha, Monika W.; Wilson, Margaret E.; Fricker, Mark; Hell, Ruediger; Haswell, Elizabeth S.; Millar, A. Harvey; Sweetlove, Lee

2016-01-01

Mitochondria must maintain tight control over the electrochemical gradient across their inner membrane to allow ATP synthesis while maintaining a redox-balanced electron transport chain and avoiding excessive reactive oxygen species production. However, there is a scarcity of knowledge about the ion transporters in the inner mitochondrial membrane that contribute to control of membrane potential. We show that loss of MSL1, a member of a family of mechanosensitive ion channels related to the bacterial channel MscS, leads to increased membrane potential of Arabidopsis mitochondria under specific bioenergetic states. We demonstrate that MSL1 localises to the inner mitochondrial membrane. When expressed in E. coli, MSL1 forms a stretch-activated ion channel with a slight preference for anions and provides protection against hypo-osmotic shock. In contrast, loss of MSL1 in Arabidopsis did not prevent swelling of isolated mitochondria in hypo-osmotic conditions. Instead, our data suggest that ion transport by MSL1 leads to dissipation of mitochondrial membrane potential when it becomes too high. The importance of MSL1 function was demonstrated by the observation of a higher oxidation state of the mitochondrial glutathione pool in msl1-1 mutants under moderate heat- and heavy-metal-stress. Furthermore, we show that MSL1 function is not directly implicated in mitochondrial membrane potential pulsing but is complementary and appears to be important under similar conditions. PMID:27505616

MSL1 is a mechanosensitive ion channel that dissipates mitochondrial membrane potential and maintains redox homeostasis in mitochondria during abiotic stress.

PubMed

Lee, Chun Pong; Maksaev, Grigory; Jensen, Gregory S; Murcha, Monika W; Wilson, Margaret E; Fricker, Mark; Hell, Ruediger; Haswell, Elizabeth S; Millar, A Harvey; Sweetlove, Lee J

2016-12-01

Mitochondria must maintain tight control over the electrochemical gradient across their inner membrane to allow ATP synthesis while maintaining a redox-balanced electron transport chain and avoiding excessive reactive oxygen species production. However, there is a scarcity of knowledge about the ion transporters in the inner mitochondrial membrane that contribute to control of membrane potential. We show that loss of MSL1, a member of a family of mechanosensitive ion channels related to the bacterial channel MscS, leads to increased membrane potential of Arabidopsis mitochondria under specific bioenergetic states. We demonstrate that MSL1 localises to the inner mitochondrial membrane. When expressed in Escherichia coli, MSL1 forms a stretch-activated ion channel with a slight preference for anions and provides protection against hypo-osmotic shock. In contrast, loss of MSL1 in Arabidopsis did not prevent swelling of isolated mitochondria in hypo-osmotic conditions. Instead, our data suggest that ion transport by MSL1 leads to dissipation of mitochondrial membrane potential when it becomes too high. The importance of MSL1 function was demonstrated by the observation of a higher oxidation state of the mitochondrial glutathione pool in msl1-1 mutants under moderate heat- and heavy-metal-stress. Furthermore, we show that MSL1 function is not directly implicated in mitochondrial membrane potential pulsing, but is complementary and appears to be important under similar conditions. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Visual Space and Object Space in the Cerebral Cortex of Retinal Disease Patients

PubMed Central

Spileers, Werner; Wagemans, Johan; Op de Beeck, Hans P.

2014-01-01

The lower areas of the hierarchically organized visual cortex are strongly retinotopically organized, with strong responses to specific retinotopic stimuli, and no response to other stimuli outside these preferred regions. Higher areas in the ventral occipitotemporal cortex show a weak eccentricity bias, and are mainly sensitive for object category (e.g., faces versus buildings). This study investigated how the mapping of eccentricity and category sensitivity using functional magnetic resonance imaging is affected by a retinal lesion in two very different low vision patients: a patient with a large central scotoma, affecting central input to the retina (juvenile macular degeneration), and a patient where input to the peripheral retina is lost (retinitis pigmentosa). From the retinal degeneration, we can predict specific losses of retinotopic activation. These predictions were confirmed when comparing stimulus activations with a no-stimulus fixation baseline. At the same time, however, seemingly contradictory patterns of activation, unexpected given the retinal degeneration, were observed when different stimulus conditions were directly compared. These unexpected activations were due to position-specific deactivations, indicating the importance of investigating absolute activation (relative to a no-stimulus baseline) rather than relative activation (comparing different stimulus conditions). Data from two controls, with simulated scotomas that matched the lesions in the two patients also showed that retinotopic mapping results could be explained by a combination of activations at the stimulated locations and deactivations at unstimulated locations. Category sensitivity was preserved in the two patients. In sum, when we take into account the full pattern of activations and deactivations elicited in retinotopic cortex and throughout the ventral object vision pathway in low vision patients, the pattern of (de)activation is consistent with the retinal loss. PMID:24505449

Screening for Usher Syndrome: A Hands-On Guide for School Nurses.

ERIC Educational Resources Information Center

Houghton, Joan; Coonts, Teresa; Jordan, Beth; Schafer, Jacqueline, Ed.

This manual was written specifically to help school nurses conduct screenings for Usher syndrome, a genetic condition that involves deafness or hearing loss and the progressive loss of vision. It provides information on the step-by-step process of how to conduct a screening, the actual forms needed for a screening, and resources for referring…

MoSI (Monitoreo de Sobrevivencia Invernal): assessing habitat-specific overwintering survival of neotropical migratory landbirds

Treesearch

David F. DeSante; T. Scott Sillett; Rodney B. Siegel; James F. Saracco; Claudia A. Romo de Vivar Alvarez; Salvadora Morales; Alexis Cerezo; Danielle R. Kaschube; Manuel Grosselet; Borja Mila

2005-01-01

Recent evidence suggests that population declines in many Neotropical-wintering migratory landbird species are caused by habitat loss and degradation on their wintering grounds. Such habitat loss and degradation can lower overwintering survival rates and cause surviving birds to leave their wintering grounds in poor physical condition, leading to high mortality during...

DISCOUNTING OF DELAYED AND PROBABILISTIC LOSSES OVER A WIDE RANGE OF AMOUNTS

PubMed Central

Green, Leonard; Myerson, Joel; Oliveira, Luís; Chang, Seo Eun

2014-01-01

The present study examined delay and probability discounting of hypothetical monetary losses over a wide range of amounts (from $20 to $500,000) in order to determine how amount affects the parameters of the hyperboloid discounting function. In separate conditions, college students chose between immediate payments and larger, delayed payments and between certain payments and larger, probabilistic payments. The hyperboloid function accurately described both types of discounting, and amount of loss had little or no systematic effect on the degree of discounting. Importantly, the amount of loss also had little systematic effect on either the rate parameter or the exponent of the delay and probability discounting functions. The finding that the parameters of the hyperboloid function remain relatively constant across a wide range of amounts of delayed and probabilistic loss stands in contrast to the robust amount effects observed with delayed and probabilistic rewards. At the individual level, the degree to which delayed losses were discounted was uncorrelated with the degree to which probabilistic losses were discounted, and delay and probability loaded on two separate factors, similar to what is observed with delayed and probabilistic rewards. Taken together, these findings argue that although delay and probability discounting involve fundamentally different decision-making mechanisms, nevertheless the discounting of delayed and probabilistic losses share an insensitivity to amount that distinguishes it from the discounting of delayed and probabilistic gains. PMID:24745086

Monte Carlo wave-function description of losses in a one-dimensional Bose gas and cooling to the ground state by quantum feedback

NASA Astrophysics Data System (ADS)

Schemmer, M.; Johnson, A.; Photopoulos, R.; Bouchoule, I.

2017-04-01

The effect of atom losses on a homogeneous one-dimensional Bose gas lying within the quasicondensate regime is investigated using a Monte Carlo wave-function approach. The evolution of the system is calculated, conditioned by the loss sequence, namely, the times of individual losses and the position of the removed atoms. We describe the gas within the linearized Bogoliubov approach. For each mode, we find that, for a given quantum trajectory, the state of the system converges towards a coherent state, i.e., the ground state, displaced in phase space. We show that, provided losses are recorded with a temporal and spatially resolved detector, quantum feedback can be implemented and cooling to the ground state of one or several modes can be realized.

Decline of forest interior conditions in the conterminous United States

Treesearch

Kurt H. Riitters; James D. Wickham

2012-01-01

Forest fragmentation threatens the sustainability of forest interior environments, thereby endangering subordinate ecological attributes and functions. We analyzed the spatial patterns of forest loss and gain for the conterminous United States from 2001 to 2006 to determine whether forest interior environments were maintained at five spatial scales. A 1.1% net loss of...

Recurrent gene loss correlates with the evolution of stomach phenotypes in gnathostome history

PubMed Central

Castro, L. Filipe C.; Gonçalves, Odete; Mazan, Sylvie; Tay, Boon-Hui; Venkatesh, Byrappa; Wilson, Jonathan M.

2014-01-01

The stomach, a hallmark of gnathostome evolution, represents a unique anatomical innovation characterized by the presence of acid- and pepsin-secreting glands. However, the occurrence of these glands in gnathostome species is not universal; in the nineteenth century the French zoologist Cuvier first noted that some teleosts lacked a stomach. Strikingly, Holocephali (chimaeras), dipnoids (lungfish) and monotremes (egg-laying mammals) also lack acid secretion and a gastric cellular phenotype. Here, we test the hypothesis that loss of the gastric phenotype is correlated with the loss of key gastric genes. We investigated species from all the main gnathostome lineages and show the specific contribution of gene loss to the widespread distribution of the agastric condition. We establish that the stomach loss correlates with the persistent and complete absence of the gastric function gene kit—H+/K+-ATPase (Atp4A and Atp4B) and pepsinogens (Pga, Pgc, Cym)—in the analysed species. We also find that in gastric species the pepsinogen gene complement varies significantly (e.g. two to four in teleosts and tens in some mammals) with multiple events of pseudogenization identified in various lineages. We propose that relaxation of purifying selection in pepsinogen genes and possibly proton pump genes in response to dietary changes led to the numerous independent events of stomach loss in gnathostome history. Significantly, the absence of the gastric genes predicts that reinvention of the stomach in agastric lineages would be highly improbable, in line with Dollo's principle. PMID:24307675

Recurrent gene loss correlates with the evolution of stomach phenotypes in gnathostome history.

PubMed

Castro, L Filipe C; Gonçalves, Odete; Mazan, Sylvie; Tay, Boon-Hui; Venkatesh, Byrappa; Wilson, Jonathan M

2014-01-22

The stomach, a hallmark of gnathostome evolution, represents a unique anatomical innovation characterized by the presence of acid- and pepsin-secreting glands. However, the occurrence of these glands in gnathostome species is not universal; in the nineteenth century the French zoologist Cuvier first noted that some teleosts lacked a stomach. Strikingly, Holocephali (chimaeras), dipnoids (lungfish) and monotremes (egg-laying mammals) also lack acid secretion and a gastric cellular phenotype. Here, we test the hypothesis that loss of the gastric phenotype is correlated with the loss of key gastric genes. We investigated species from all the main gnathostome lineages and show the specific contribution of gene loss to the widespread distribution of the agastric condition. We establish that the stomach loss correlates with the persistent and complete absence of the gastric function gene kit--H(+)/K(+)-ATPase (Atp4A and Atp4B) and pepsinogens (Pga, Pgc, Cym)--in the analysed species. We also find that in gastric species the pepsinogen gene complement varies significantly (e.g. two to four in teleosts and tens in some mammals) with multiple events of pseudogenization identified in various lineages. We propose that relaxation of purifying selection in pepsinogen genes and possibly proton pump genes in response to dietary changes led to the numerous independent events of stomach loss in gnathostome history. Significantly, the absence of the gastric genes predicts that reinvention of the stomach in agastric lineages would be highly improbable, in line with Dollo's principle.

Female pattern hair loss: Current treatment concepts

PubMed Central

Dinh, Quan Q; Sinclair, Rodney

2007-01-01

Fewer than 45% of women go through life with a full head of hair. Female pattern hair loss is the commonest cause of hair loss in women and prevalence increases with advancing age. Affected women may experience psychological distress and impaired social functioning. In most cases the diagnosis can be made clinically and the condition treated medically. While many women using oral antiandrogens and topical minoxidil will regrow some hair, early diagnosis and initiation of treatment is desirable as these treatments are more effective at arresting progression of hair loss than stimulating regrowth. Adjunctive nonpharmacological treatment modalities such as counseling, cosmetic camouflage and hair transplantation are important measures for some patients. The histology of female pattern hair loss is identical to that of male androgenetic alopecia. While the clinical pattern of the hair loss differs between men, the response to oral antiandrogens suggests that female pattern hair loss is an androgen dependant condition, at least in the majority of cases. Female pattern hair loss is a chronic progressive condition. All treatments need to be continued to maintain the effect. An initial therapeutic response often takes 12 or even 24 months. Given this delay, monitoring for treatment effect through clinical photography or standardized clinical severity scales is helpful. PMID:18044135

The relationship between loudness intensity functions and the click-ABR wave V latency.

PubMed

Serpanos, Y C; O'Malley, H; Gravel, J S

1997-10-01

To assess the relationship of loudness growth and the click-evoked auditory brain stem response (ABR) wave V latency-intensity function (LIF) in listeners with normal hearing or cochlear hearing loss. The effect of hearing loss configuration on the intensity functions was also examined. Behavioral and electrophysiological intensity functions were obtained using click stimuli of comparable intensities in listeners with normal hearing (Group I; n = 10), and cochlear hearing loss of flat (Group II; n = 10) or sloping (Group III; n = 10) configurations. Individual intensity functions were obtained from measures of loudness growth using the psychophysical methods of absolute magnitude estimation and production of loudness (geometrically averaged to provide the measured loudness function), and from the wave V latency measures of the ABR. Slope analyses for the behavioral and electrophysiological intensity functions were separately performed by group. The loudness growth functions for the groups with cochlear hearing loss approximated the normal function at high intensities, with overall slope values consistent with those reported from previous psychophysical research. The ABR wave V LIF for the group with a flat configuration of cochlear hearing loss approximated the normal function at high intensities, and was displaced parallel to the normal function for the group with sloping configuration. The relationship between the behavioral and electrophysiological intensity functions was examined at individual intensities across the range of the functions for each subject. A significant relationship was obtained between loudness and the ABR wave V LIFs for the groups with normal hearing and flat configuration of cochlear hearing loss; the association was not significant (p = 0.10) for the group with a sloping configuration of cochlear hearing loss. The results of this study established a relationship between loudness and the ABR wave V latency for listeners with normal hearing, and flat cochlear hearing loss. In listeners with a sloping configuration of cochlear hearing loss, the relationship was not significant. This suggests that the click-evoked ABR may be used to estimate loudness growth at least for individuals with normal hearing and those with a flat configuration of cochlear hearing loss. Predictive equations were derived to estimate loudness growth for these groups. The use of frequency-specific stimuli may provide more precise information on the nature of the relationship between loudness growth and the ABR wave V latency, particularly for listeners with sloping configurations of cochlear hearing loss.

The RNA Export Factor, Nxt1, Is Required for Tissue Specific Transcriptional Regulation

PubMed Central

Jiang, Jianqiao; White-Cooper, Helen

2013-01-01

The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores. Nxt1 is essential for viability; using a partial loss of function allele, we reveal a role for this gene in tissue specific transcription. We show that many Drosophila melanogaster testis-specific mRNAs require Nxt1 for their accumulation. The transcripts that require Nxt1 also depend on a testis-specific transcription complex, tMAC. We show that loss of Nxt1 leads to reduced transcription of tMAC targets. A reporter transcript from a tMAC-dependent promoter is under-expressed in Nxt1 mutants, however the same transcript accumulates in mutants if driven by a tMAC-independent promoter. Thus, in Drosophila primary spermatocytes, the transcription factor used to activate expression of a transcript, rather than the RNA sequence itself or the core transcription machinery, determines whether this expression requires Nxt1. We additionally find that transcripts from intron-less genes are more sensitive to loss of Nxt1 function than those from intron-containing genes and propose a mechanism in which transcript processing feeds back to increase activity of a tissue specific transcription complex. PMID:23754955

HOXA5 plays tissue-specific roles in the developing respiratory system.

PubMed

Landry-Truchon, Kim; Houde, Nicolas; Boucherat, Olivier; Joncas, France-Hélène; Dasen, Jeremy S; Philippidou, Polyxeni; Mansfield, Jennifer H; Jeannotte, Lucie

2017-10-01

Hoxa5 is essential for development of several organs and tissues. In the respiratory system, loss of Hoxa5 function causes neonatal death due to respiratory distress. Expression of HOXA5 protein in mesenchyme of the respiratory tract and in phrenic motor neurons of the central nervous system led us to address the individual contribution of these Hoxa5 expression domains using a conditional gene targeting approach. Hoxa5 does not play a cell-autonomous role in lung epithelium, consistent with lack of HOXA5 expression in this cell layer. In contrast, ablation of Hoxa5 in mesenchyme perturbed trachea development, lung epithelial cell differentiation and lung growth. Further, deletion of Hoxa5 in motor neurons resulted in abnormal diaphragm innervation and musculature, and lung hypoplasia. It also reproduced the neonatal lethality observed in null mutants, indicating that the defective diaphragm is the main cause of impaired survival at birth. Thus, Hoxa5 possesses tissue-specific functions that differentially contribute to the morphogenesis of the respiratory tract. © 2017. Published by The Company of Biologists Ltd.

The Mitochondrial DNA-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination[OPEN

PubMed Central

Vercruysse, Jasmien; Van Daele, Twiggy; De Milde, Liesbeth; Benhamed, Moussa; Inzé, Dirk

2017-01-01

In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Efficient DNA repair pathways are crucial in these organelles to fix damage resulting from endogenous and exogenous factors. Plant organellar genomes are complex compared with their animal counterparts, and although several plant-specific mediators of organelle DNA repair have been reported, many regulators remain to be identified. Here, we show that a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein, SWIB5, is capable of associating with mitochondrial DNA (mtDNA) in Arabidopsis thaliana. Gain- and loss-of-function mutants provided evidence for a role of SWIB5 in influencing mtDNA architecture and homologous recombination at specific intermediate-sized repeats both under normal and genotoxic conditions. SWIB5 interacts with other mitochondrial SWIB proteins. Gene expression and mutant phenotypic analysis of SWIB5 and SWIB family members suggests a link between organellar genome maintenance and cell proliferation. Taken together, our work presents a protein family that influences mtDNA architecture and homologous recombination in plants and suggests a link between organelle functioning and plant development. PMID:28420746

Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

PubMed Central

Hasan, Mazahir T.; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

2013-01-01

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

Life-long calorie restriction in Fischer 344 rats attenuates age-related loss in skeletal muscle-specific force and reduces extracellular space.

PubMed

Payne, Anthony M; Dodd, Stephen L; Leeuwenburgh, Christiaan

2003-12-01

The decline in muscle function is associated with an age-related decrease in muscle mass and an age-related decline in strength. However, decreased strength is not solely due to decreased muscle mass. The age-related decline in muscle-specific force (force/muscle cross-sectional area), a measure of intrinsic muscle function, also contributes to age-related strength decline, and the mechanisms by which this occurs are only partially known. Moreover, changes in the extracellular space could have a profound effect on skeletal muscle function. Life-long calorie restriction in rodents has shown to be a powerful anti-aging intervention. In this study, we examine whether calorie restriction is able to attenuate the loss of muscle function and elevations in extracellular space associated with aging. We hypothesize that calorie restriction attenuates the age-associated decline in specific force and increases in extracellular space. Measurements of in vitro contractile properties of the extensor digitorum longus (type II) and soleus (type I) muscles from 12-mo and 26- to 28-mo-old ad libitum-fed, as well as 27- to 28-mo-old life-long calorie-restricted male Fischer 344 rats, were performed. We found that calorie restriction attenuated the age-associated decline in muscle mass-to-body mass ratio (mg/g) and strength-to-body mass ratio (N/kg) in the extensor digitorum longus muscle (P < 0.05) but not in the soleus muscle (P > 0.05). Importantly, muscle-specific force (N/cm2) in the extensor digitorum longus, but not in the soleus muscle, of the old calorie-restricted rats was equal to that of the young 12-mo-old animals. Moreover, the age-associated increase in extracellular space was reduced in the fast-twitch extensor digitorum longus muscle (P < 0.05) but not in the soleus muscle with calorie restriction. We also found a significant correlation between the extracellular space and the muscle-specific force in the extensor digitorum longus (r = -0.58; P < 0.05) but not in the soleus muscle (r = -0.38; P > 0.05). Hence, this study shows a loss of muscle function with age and suggests that long-term calorie restriction is an effective intervention against the loss of muscle function with age.

Recessions, Job Loss, and Mortality Among Older US Adults

PubMed Central

Beckfield, Jason

2014-01-01

Objectives. We analyzed how recessions and job loss jointly shape mortality risks among older US adults. Methods. We used data for 50 states from the Health and Retirement Study and selected individuals who were employed at ages 45 to 66 years during 1992 to 2011. We assessed whether job loss affects mortality risks, whether recessions moderate the effect of job loss on mortality, and whether individuals who do and do not experience job loss are differentially affected by recessions. Results. Compared with individuals not experiencing job loss, mortality risks among individuals losing their job in a recession were strongly elevated (hazard ratio = 1.6; 95% confidence interval = 1.1, 2.3). Job loss during normal times or booms is not associated with mortality. For employed workers, we found a reduction in mortality risks if local labor market conditions were depressed, but this result was not consistent across different model specifications. Conclusions. Recessions increase mortality risks among older US adults who experience job loss. Health professionals and policymakers should target resources to this group during recessions. Future research should clarify which health conditions are affected by job loss during recessions and whether access to health care following job loss moderates this relation. PMID:25211731

The bHLH Repressor Deadpan Regulates the Self-renewal and Specification of Drosophila Larval Neural Stem Cells Independently of Notch

PubMed Central

Younger, Susan; Huang, Yaling; Lee, Tzumin

2012-01-01

Neural stem cells (NSCs) are able to self-renew while giving rise to neurons and glia that comprise a functional nervous system. However, how NSC self-renewal is maintained is not well understood. Using the Drosophila larval NSCs called neuroblasts (NBs) as a model, we demonstrate that the Hairy and Enhancer-of-Split (Hes) family protein Deadpan (Dpn) plays important roles in NB self-renewal and specification. The loss of Dpn leads to the premature loss of NBs and truncated NB lineages, a process likely mediated by the homeobox protein Prospero (Pros). Conversely, ectopic/over-expression of Dpn promotes ectopic self-renewing divisions and maintains NB self-renewal into adulthood. In type II NBs, which generate transit amplifying intermediate neural progenitors (INPs) like mammalian NSCs, the loss of Dpn results in ectopic expression of type I NB markers Asense (Ase) and Pros before these type II NBs are lost at early larval stages. Our results also show that knockdown of Notch leads to ectopic Ase expression in type II NBs and the premature loss of type II NBs. Significantly, dpn expression is unchanged in these transformed NBs. Furthermore, the loss of Dpn does not inhibit the over-proliferation of type II NBs and immature INPs caused by over-expression of activated Notch. Our data suggest that Dpn plays important roles in maintaining NB self-renewal and specification of type II NBs in larval brains and that Dpn and Notch function independently in regulating type II NB proliferation and specification. PMID:23056424

Monoallelic expression of Pax5: a paradigm for the haploinsufficiency of mammalian Pax genes?

PubMed

Nutt, S L; Busslinger, M

1999-06-01

It is generally assumed that most mammalian genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a loss-of-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the 'default' state. However, a minority of genes are semi-dominant, as heterozygous loss-of-function mutation in these genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian Pax genes, which are associated with mouse developmental mutants and human disease syndromes. Recently we have reported that the Pax5 gene is subject to allele-specific regulation during B cell development. Pax5 is predominantly transcribed from only one of its two alleles in early B-lymphoid progenitors and mature B cells, while it transiently switches to a biallelic mode of transcription in pre-B and immature B cells. As a consequence, B-lymphoid tissues are mosaic with regard to the transcribed allele, and heterozygous mutation of Pax5 therefore results in deletion of B lymphocytes expressing only the mutant allele. The allele-specific regulation of Pax5 raises the intriguing possibility that monoallelic expression may also be the mechanism causing the haploinsufficiency of other Pax genes. In this review, we discuss different models accounting for the haploinsufficiency of mammalian Pax genes, provide further evidence in support of the allele-specific regulation of Pax5 and discuss the implication of these findings in the context of the recent literature describing the stochastic and monoallelic activation of other hematopoietic genes.

Molecular Signaling in Muscle Plasticity

NASA Technical Reports Server (NTRS)

Epstein, Henry F.

1999-01-01

Extended spaceflight under microgravity conditions leads to significant atrophy of weight-bearing muscles. Atrophy and hypertrophy are the extreme outcomes of the high degree of plasticity exhibited by skeletal muscle. Stimuli which control muscle plasticity include neuronal, hormonal, nutritional, and mechanical inputs. The mechanical stimulus for muscle is directly related to the work or exercise against a load performed. Little or no work is performed by weight-bearing muscles under microgravity conditions. A major hypothesis is that focal adhesion kinase (FAK) which is associated with integrin at the adherens junctions and costa meres of all skeletal muscles is an integral part of the major mechanism for molecular signaling upon mechanical stimulation in all muscle fibers. Additionally, we propose that myotonic protein kinase (DMPK) and dystrophin (DYSTR) also participate in distinct mechanically stimulated molecular signaling pathways that are most critical in type I and type II muscle fibers, respectively. To test these hypotheses, we will use the paradigms of hindlimb unloading and overloading in mice as models for microgravity conditions and a potential exercise countermeasure, respectively, in mice. We expect that FAK loss-of-function will impair hypertrophy and enhance atrophy in all skeletal muscle fibers whereas DYSTR and DMPK loss-of-function will have similar but more selective effects on Type IT and Type I fibers, respectively. Gene expression will be monitored by muscle-specific creatine kinase M promoter-reporter construct activity and specific MRNA and protein accumulation in the soleus (type I primarily) and plantaris (type 11 primarily) muscles. With these paradigms and assays, the following Specific Project Aims will be tested in genetically altered mice: 1) identify the roles of DYSTR and its pathway; 2) evaluate the roles of the DMPK and its pathway; 3) characterize the roles of FAK and its pathway and 4) genetically analyze the mechanisms and interactions between the FAK, DYSTR, and DMPK-associated pathways in single and specific combinations of mutants. The identification of potential signaling mechanisms may permit future development of pharmacological countermeasures for amelioration and prevention of the microgravity-induced atrophy in extended spaceflight, and the analysis of both overloading and unloading paradigms may provide further support for development of exercise-based countermeasures. Understanding the basic mechanisms of molecular signaling in muscle plasticity may aid our understanding and treatment of skeletal muscle atrophy not only in spaceflight but in similar problems of the aging population, in prolonged bed rest, and in cachexia associated with chronic disease.

Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations

PubMed Central

Liu, Ruijie; Correll, Robert N.; Davis, Jennifer; Vagnozzi, Ronald J.; York, Allen J.; Sargent, Michelle A.; Nairn, Angus C.; Molkentin, Jeffery D.

2015-01-01

There are 3 protein phosphatase 1 (PP1) catalytic isoforms (α, β and γ) encoded within the mammalian genome. These 3 gene products share ~90% amino acid homology within their catalytic domains but each has unique N- and C-termini that likely underlie distinctive subcellular localization or functionality. In this study, we assessed the effect associated with loss of each PP1 isoform in the heart using a conditional Cre-loxP targeting approach in mice. Ppp1ca-loxP, Ppp1cb-loxP and Ppp1cc-oxP alleles were crossed with either an Nkx2.5-Cre knock-in containing allele for early embryonic deletion or a tamoxifen inducible α-myosin heavy chain (αMHC)-MerCreMer transgene for adult and cardiac-specific deletion. We determined that while deletion of Ppp1ca (PP1α) or Ppp1cc (PP1γ) had little effect on the whole heart, deletion of Ppp1cb (PP1β) resulted in concentric remodeling of the heart, interstitial fibrosis and contractile dysregulation, using either the embryonic or adult-specific Cre-expressing alleles. However, myocytes isolated from Ppp1cb deleted hearts surprisingly showed enhanced contractility. Mechanistically we found that deletion of any of the 3 PP1 gene-encoding isoforms had no effect on phosphorylation of phospholamban, nor were Ca2+ handling dynamics altered in adult myocytes from Ppp1cb deleted hearts. However, loss of Ppp1cb from the heart, but not Ppp1ca or Ppp1cc, resulted in elevated phosphorylation of myofilament proteins such as myosin light chain 2 and cardiac myosin binding protein C, consistent with an enriched localization profile of this isoform to the sarcomeres. These results suggest a unique functional role for the PP1β isoform in affecting cardiac contractile function. PMID:26334248

Response to capacitating stimuli indicates extender-related differences in boar sperm function.

PubMed

Schmid, S; Henning, H; Petrunkina, A M; Weitze, K F; Waberski, D

2013-10-01

Spermatozoa, especially those of the porcine species, are highly susceptible to in vitro chilling and ageing. Extenders are continuously developed to protect boar spermatozoa from chilling injury. New semen extenders and other modified preservation strategies require sensitive testing for essential sperm functions. The key process on the pathway of fertilization is capacitation. The aim of the present study was to examine whether the specific response to capacitating stimuli is sensitive enough to indicate different preservation capacities of extenders during hypothermic storage of boar spermatozoa. Semen was diluted in Beltsville Thawing Solution (BTS) and Androstar Plus and kept for 3 h at 22°C or stored at 17°C, 10°C, and 5°C. Semen was analyzed at 24 and 96 h of storage. Motility and membrane integrity remained at high levels, except for lower values when stored in BTS at 5°C. Washed subsamples were incubated in capacitating medium (Tyrode) and control medium and were assessed for intracellular calcium concentration and integrity of plasma membranes using a flow cytometer. On the basis of the loss of low-calcium live cells in a kinetic approach, the specific response to capacitation stimuli was determined. There was a higher loss of response in semen stored hypothermically in the standard extender BTS compared to Androstar Plus. Assessment of the extent of phospholipid disorder under capacitating and control conditions by use of merocyanine staining did not reveal any significant extender-related differences. A field insemination trial with 778 sows was performed to relate in vitro results to fertility. Fertility parameters did not differ in semen stored up to 48 h at 10°C in Androstar Plus compared to controls stored at 17°C in BTS. In conclusion, assessment of specific reactivity to capacitating stimuli appears to be a sensitive tool for detection of extender-dependent alterations in functionality of chilled boar spermatozoa.

The Role for Dietary Omega-3 Fatty Acids Supplementation in Older Adults

PubMed Central

Molfino, Alessio; Gioia, Gianfranco; Fanelli, Filippo Rossi; Muscaritoli, Maurizio

2014-01-01

Optimal nutrition is one of the most important determinants of healthier ageing, reducing the risk of disability, maintaining mental and physical functions, and thus preserving and ensuring a better quality of life. Dietary intake and nutrient absorption decline with age, thus increasing the risk of malnutrition, morbidity and mortality. Specific nutrients, particularly long-chain omega-3 polyunsaturated fatty acids (PUFAs), might have the potential of preventing and reducing co-morbidities in older adults. Omega-3 PUFAs are able to modulate inflammation, hyperlipidemia, platelet aggregation, and hypertension. Different mechanisms contribute to these effects, including conditioning cell membrane function and composition, eicosanoid production, and gene expression. The present review analyzes the influence of omega-3 PUFAs status and intake on brain function, cardiovascular system, immune function, muscle performance and bone health in older adults. Omega-3 FAs may have substantial benefits in reducing the risk of cognitive decline in older people. The available data encourage higher intakes of omega-3 PUFAs in the diet or via specific supplements. More studies are needed to confirm the role of omega-3 FAs in maintaining bone health and preventing the loss of muscle mass and function associated with ageing. In summary, omega-3 PUFAs are now identified as potential key nutrients, safe and effective in the treatment and prevention of several negative consequences of ageing. PMID:25285409

Systems biology approach in plant abiotic stresses.

PubMed

Mohanta, Tapan Kumar; Bashir, Tufail; Hashem, Abeer; Abd Allah, Elsayed Fathi

2017-12-01

Plant abiotic stresses are the major constraint on plant growth and development, causing enormous crop losses across the world. Plants have unique features to defend themselves against these challenging adverse stress conditions. They modulate their phenotypes upon changes in physiological, biochemical, molecular and genetic information, thus making them tolerant against abiotic stresses. It is of paramount importance to determine the stress-tolerant traits of a diverse range of genotypes of plant species and integrate those traits for crop improvement. Stress-tolerant traits can be identified by conducting genome-wide analysis of stress-tolerant genotypes through the highly advanced structural and functional genomics approach. Specifically, whole-genome sequencing, development of molecular markers, genome-wide association studies and comparative analysis of interaction networks between tolerant and susceptible crop varieties grown under stress conditions can greatly facilitate discovery of novel agronomic traits that protect plants against abiotic stresses. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.

PubMed

de Wind, N; Dekker, M; Claij, N; Jansen, L; van Klink, Y; Radman, M; Riggins, G; van der Valk, M; van't Wout, K; te Riele, H

1999-11-01

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.

Introducing electron capture into the unitary-convolution-approximation energy-loss theory at low velocities

NASA Astrophysics Data System (ADS)

Schiwietz, G.; Grande, P. L.

2011-11-01

Recent developments in the theoretical treatment of electronic energy losses of bare and screened ions in gases are presented. Specifically, the unitary-convolution-approximation (UCA) stopping-power model has proven its strengths for the determination of nonequilibrium effects for light as well as heavy projectiles at intermediate to high projectile velocities. The focus of this contribution will be on the UCA and its extension to specific projectile energies far below 100 keV/u, by considering electron-capture contributions at charge-equilibrium conditions.

Epigenetic control of learning and memory in Drosophila by Tip60 HAT action.

PubMed

Xu, Songjun; Wilf, Rona; Menon, Trisha; Panikker, Priyalakshmi; Sarthi, Jessica; Elefant, Felice

2014-12-01

Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Histone acetylation is one of the best characterized of these epigenetic mechanisms that is critical for regulating learning- and memory- associated gene expression profiles, yet the specific histone acetyltransferases (HATs) that mediate these effects have yet to be fully characterized. Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that Tip60 is endogenously expressed in the Kenyon cells, the intrinsic neurons of the MB, and in the MB axonal lobes. Targeted loss of Tip60 HAT activity in the MB causes thinner and shorter axonal lobes while increasing Tip60 HAT levels cause no morphological defects. Functional consequences of both loss and gain of Tip60 HAT levels in the MB are evidenced by defects in immediate-recall memory. Our ChIP-Seq analysis reveals that Tip60 target genes are enriched for functions in cognitive processes, and, accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, we find that both learning and immediate-recall memory deficits that occur under AD-associated, amyloid precursor protein (APP)-induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. Together, our findings uncover an epigenetic transcriptional regulatory role for Tip60 in cognitive function and highlight the potential of HAT activators as a therapeutic option for neurodegenerative disorders. Copyright © 2014 by the Genetics Society of America.

Dietary supplementation with a specific combination of high protein, leucine, and fish oil improves muscle function and daily activity in tumour-bearing cachectic mice

PubMed Central

van Norren, K; Kegler, D; Argilés, J M; Luiking, Y; Gorselink, M; Laviano, A; Arts, K; Faber, J; Jansen, H; van der Beek, E M; van Helvoort, A

2009-01-01

Cancer cachexia is characterised by metabolic alterations leading to loss of adipose tissue and lean body mass and directly compromises physical performance and the quality of life of cancer patients. In a murine cancer cachectic model, the effects of dietary supplementation with a specific combination of high protein, leucine and fish oil on weight loss, muscle function and physical activity were investigated. Male CD2F1 mice, 6–7 weeks old, were divided into body weight-matched groups: (1) control, (2) tumour-bearing, and (3) tumour-bearing receiving experimental diets. Tumours were induced by s.c. inoculation with murine colon adenocarcinoma (C26) cells. Food intake, body mass, tumour size and 24 h-activity were monitored. Then, 20 days after tumour/vehicle inoculation, the animals were killed and muscle function was tested ex vivo. Tumour-bearing mice showed reduced carcass, muscle and fat mass compared with controls. EDL muscle performance and total daily activity were impaired in the tumour-bearing mice. Addition of single nutrients resulted in no or modest effects. However, supplementation of the diet with the all-in combination of high protein, leucine and fish oil significantly reduced loss of carcass, muscle and fat mass (loss in mass 45, 52 and 65% of TB-con, respectively (P<0.02)) and improved muscle performance (loss of max force reduced to 55–64% of TB-con (P<0.05)). Moreover, total daily activity normalised after intervention with the specific nutritional combination (50% of the reduction in activity of TB-con (P<0.05)). In conclusion, a nutritional combination of high protein, leucine and fish oil reduced cachectic symptoms and improved functional performance in cancer cachectic mice. Comparison of the nutritional combination with its individual modules revealed additive effects of the single components provided. PMID:19259092

Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice.

PubMed

Hayashi, Atsushi; Mikami, Yohei; Miyamoto, Kentaro; Kamada, Nobuhiko; Sato, Toshiro; Mizuno, Shinta; Naganuma, Makoto; Teratani, Toshiaki; Aoki, Ryo; Fukuda, Shinji; Suda, Wataru; Hattori, Masahira; Amagai, Masayuki; Ohyama, Manabu; Kanai, Takanori

2017-08-15

Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin-deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology. Copyright © 2017. Published by Elsevier Inc.

Identification of a unique loss-of-function mutation in IGF1R and a crosstalk between IGF1R and Wnt/β-catenin signaling pathways.

PubMed

Jamwal, Gayatri; Singh, Gurjinder; Dar, Mohd Saleem; Singh, Paramjeet; Bano, Nasima; Syed, Sajad Hussain; Sandhu, Padmani; Akhter, Yusuf; Monga, Satdarshan P; Dar, Mohd Jamal

2018-06-01

IGF1R is a ubiquitous receptor tyrosine kinase that plays critical roles in cell proliferation, growth and survival. Clinical studies have demonstrated upregulation of IGF1R mediated signaling in a number of malignancies including colon, breast, and lung cancers. Overexpression of the IGF1R in these malignancies is associated with a poor prognosis and overall survival. IGF1R specific kinase inhibitors have failed in multiple clinical trials partly because of the complex nature of IGF1R signaling. Thus identifying new binding partners and allosteric sites on IGF1R are emerging areas of research. More recently, IGF1R has been shown to translocate into the nucleus and perform many functions. In this study, we generated a library of IGF1R deletion and point mutants to examine IGF1R subcellular localization and activation of downstream signaling pathways. We show that the nuclear localization of IGF1R is primarily defined by its cytoplasmic domain. We identified a cross-talk between IGF1R and Wnt/β-catenin signaling pathways and showed, for the first time, that IGF1R is associated with upregulation of TCF-mediated β-catenin transcriptional activity. Using loss-of-function mutants, deletion analysis and IGF1R specific inhibitor(s), we show that cytoplasmic and nuclear activities are two independent functions of IGF1R. Furthermore, we identified a unique loss-of-function mutation in IGF1R. This unique loss-of-function mutant retains only nuclear functions and sits in a pocket, outside ATP and substrate binding region, that is suited for designing allosteric inhibitors of IGF1R. Copyright © 2018 Elsevier B.V. All rights reserved.

Overexpression of AtPYL5 under the control of guard cell specific promoter improves drought stress tolerance in Arabidopsis.

PubMed

Quan, Wenli; Hu, Yuanlei; Mu, Zixin; Shi, Haitao; Chan, Zhulong

2018-05-31

PYR/PYLs function as ABA receptors and are key regulators during plant drought stress response. Previously we screened drought tolerance of Arabidopsis ABA receptors PYR/PYLs under the control of five different promoters. In this study, we characterized drought stress tolerance of AtPYL5 transgene under the control of one guard cell specific promoter, pGC1. pGC1::AtPYL5 transgenic Arabidopsis exhibited reduced transpiration rate and decreased water loss after drought treatment. Transformation of pGC1::AtPYL5 in Arabidopsis also decreased oxidative stress damage and improved photosynthesis under drought stress condition. These results indicated that pGC1::AtPYL5 construct is effective and might pave new way to develop genetically engineered plants to improve drought stress tolerance. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A Screening Model to Predict Microalgae Biomass Growth in Photobioreactors and Raceway Ponds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huesemann, Michael H.; Van Wagenen, Jonathan M.; Miller, Tyler W.

A microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in photobioreactors or outdoor ponds. Growth is modeled by first estimating the light attenuation by biomass according to Beer-Lambert’s law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model requires only two physical and two species-specific biological input parameters, all of which are relatively easy to determine: incident light intensity, culture depth, as well as the biomass light absorption coefficient and the specific growth ratemore » as a function of light intensity. Roux bottle culture experiments were performed with Nannochloropsis salina at constant temperature (23 °C) at six different incident light intensities (5, 10, 25, 50, 100, 250, and 850 μmol/m2∙ sec) to determine both the specific growth rate under non-shading conditions and the biomass light absorption coefficient as a function of light intensity. The model was successful in predicting the biomass growth rate in these Roux bottle cultures during the light-limited linear phase at different incident light intensities. Model predictions were moderately sensitive to minor variations in the values of input parameters. The model was also successful in predicting the growth performance of Chlorella sp. cultured in LED-lighted 800 L raceway ponds operated at constant temperature (30 °C) and constant light intensity (1650 μmol/m2∙ sec). Measurements of oxygen concentrations as a function of time demonstrated that following exposure to darkness, it takes at least 5 seconds for cells to initiate dark respiration. As a result, biomass loss due to dark respiration in the aphotic zone of a culture is unlikely to occur in highly mixed small-scale photobioreactors where cells move rapidly in and out of the light. By contrast, as supported also by the growth model, biomass loss due to dark respiration occurs in the dark zones of the relatively less well mixed pond cultures. In addition to screening novel microalgae strains for high biomass productivities, the model can also be used for optimizing the pond design and operation. Additional research is needed to validate the biomass growth model for other microalgae species and for the more realistic case of fluctuating temperatures and light intensities observed in outdoor pond cultures.« less

A screening model to predict microalgae biomass growth in photobioreactors and raceway ponds.

PubMed

Huesemann, M H; Van Wagenen, J; Miller, T; Chavis, A; Hobbs, S; Crowe, B

2013-06-01

A microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in photobioreactors or outdoor ponds. Growth is modeled by first estimating the light attenuation by biomass according to Beer-Lambert's Law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model uses only two physical and two species-specific biological input parameters, all of which are relatively easy to determine: incident light intensity, culture depth, as well as the biomass light absorption coefficient and the specific growth rate as a function of light intensity. Roux bottle culture experiments were performed with Nannochloropsis salina at constant temperature (23°C) at six different incident light intensities (10, 25, 50, 100, 250, and 850 µmol/m(2)  s) to determine both the specific growth rate under non-shading conditions and the biomass light absorption coefficient as a function of light intensity. The model was successful in predicting the biomass growth rate in these Roux bottle batch cultures during the light-limited linear phase at different incident light intensities. Model predictions were moderately sensitive to minor variations in the values of input parameters. The model was also successful in predicting the growth performance of Chlorella sp. cultured in LED-lighted 800 L raceway ponds operated in batch mode at constant temperature (30°C) and constant light intensity (1,650 µmol/m(2)  s). Measurements of oxygen concentrations as a function of time demonstrated that following exposure to darkness, it takes at least 5 s for cells to initiate dark respiration. As a result, biomass loss due to dark respiration in the aphotic zone of a culture is unlikely to occur in highly mixed small-scale photobioreactors where cells move rapidly in and out of the light. By contrast, as supported also by the growth model, biomass loss due to dark respiration occurs in the dark zones of the relatively less well-mixed pond cultures. In addition to screening novel microalgae strains for high biomass productivities, the model can also be used for optimizing the pond design and operation. Additional research is needed to validate the biomass growth model for other microalgae species and for the more realistic case of fluctuating temperatures and light intensities observed in outdoor pond cultures. Copyright © 2012 Wiley Periodicals, Inc.

Establishment of a tissue-specific RNAi system in C. elegans.

PubMed

Qadota, Hiroshi; Inoue, Makiko; Hikita, Takao; Köppen, Mathias; Hardin, Jeffrey D; Amano, Mutsuki; Moerman, Donald G; Kaibuchi, Kozo

2007-10-01

In C. elegans, mosaic analysis is a powerful genetic tool for determining in which tissue or specific cells a gene of interest is required. For traditional mosaic analysis, a loss-of-function mutant and a genomic fragment that can rescue the mutant phenotype are required. Here we establish an easy and rapid mosaic system using RNAi (RNA mediated interference), using a rde-1 mutant that is resistant to RNAi. Tissue-specific expression of the wild type rde-1 cDNA in rde-1 mutants limits RNAi sensitivity to a specific tissue. We established hypodermal-and muscle-specific RNAi systems by expressing rde-1 cDNA under the control of the lin-26 and hlh-1 promoters, respectively. We confirmed tissue-specific RNAi using two assays: (1) tissue-specific knockdown of GFP expression, and (2) phenocopy of mutations in essential genes that were previously known to function in a tissue-specific manner. We also applied this system to an essential gene, ajm-1, expressed in hypodermis and gut, and show that lethality in ajm-1 mutants is due to loss of expression in hypodermal cells. Although we demonstrate tissue-specific RNAi in hypodermis and muscle, this method could be easily applied to other tissues.

Establishment of a tissue-specific RNAi system in C. elegans

PubMed Central

Qadota, Hiroshi; Inoue, Makiko; Hikita, Takao; Köppen, Mathias; Hardin, Jeffrey D.; Amano, Mutsuki; Moerman, Donald G.; Kaibuchi, Kozo

2011-01-01

In C. elegans, mosaic analysis is a powerful genetic tool for determining in which tissue or specific cells a gene of interest is required. For traditional mosaic analysis, a loss-of-function mutant and a genomic fragment that can rescue the mutant phenotype are required. Here we establish an easy and rapid mosaic system using RNAi (RNA mediated interference), using a rde-1 mutant that is resistant to RNAi. Tissue-specific expression of the wild type rde-1 cDNA in rde-1 mutants limits RNAi sensitivity to a specific tissue. We established hypodermal- and muscle-specific RNAi systems by expressing rde-1 cDNA under the control of the lin-26 and hlh-1 promoters, respectively. We confirmed tissue-specific RNAi using two assays: (1) tissue-specific knockdown of GFP expression, and (2) phenocopy of mutations in essential genes that were previously known to function in a tissue-specific manner. We also applied this system to an essential gene, ajm-1, expressed in hypodermis and gut, and show that lethality in ajm-1 mutants is due to loss of expression in hypodermal cells. Although we demonstrate tissue-specific RNAi in hypodermis and muscle, this method could be easily applied to other tissues. PMID:17681718

Decoupling degradation in exciton formation and recombination during lifetime testing of organic light-emitting devices

NASA Astrophysics Data System (ADS)

Hershey, Kyle W.; Suddard-Bangsund, John; Qian, Gang; Holmes, Russell J.

2017-09-01

The analysis of organic light-emitting device degradation is typically restricted to fitting the overall luminance loss as a function of time or the characterization of fully degraded devices. To develop a more complete understanding of degradation, additional specific data are needed as a function of luminance loss. The overall degradation in luminance during testing can be decoupled into a loss in emitter photoluminescence efficiency and a reduction in the exciton formation efficiency. Here, we demonstrate a method that permits separation of these component efficiencies, yielding the time evolution of two additional specific device parameters that can be used in interpreting and modeling degradation without modification to the device architecture or introduction of any additional post-degradation characterization steps. Here, devices based on the phosphor tris[2-phenylpyridinato-C2,N]iridium(III) (Ir(ppy)3) are characterized as a function of initial luminance and emissive layer thickness. The overall loss in device luminance is found to originate primarily from a reduction in the exciton formation efficiency which is exacerbated in devices with thinner emissive layers. Interestingly, the contribution to overall degradation from a reduction in the efficiency of exciton recombination (i.e., photoluminescence) is unaffected by thickness, suggesting a fixed exciton recombination zone width and degradation at an interface.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Habercorn, Lasse; Merkl, Jan-Philip; Kloust, Hauke Christian

With the polymer encapsulation of quantum dots via seeded emulsion polymerization we present a powerful tool for the preparation of fluorescent nanoparticles with an extraordinary stability in aqueous solution. The method of the seeded emulsion polymerization allows a straightforward and simple in situ functionalization of the polymer shell under preserving the optical properties of the quantum dots. These requirements are inevitable for the application of semiconductor nanoparticles as markers for biomedical applications. Polymer encapsulated quantum dots have shown only a marginal loss of quantum yields when they were exposed to copper(II)-ions. Under normal conditions the quantum dots were totally quenchedmore » in presence of copper(II)-ions. Furthermore, a broad range of in situ functionalized polymer-coated quantum dots were obtained by addition of functional monomers or surfactants like fluorescent dye molecules, antibodies or specific DNA aptamers. Furthermore the emulsion polymerization can be used to prepare multifunctional hybrid systems, combining different nanoparticles within one construct without any adverse effect of the properties of the starting materials.{sup 1,2}.« less

Correlation between microstructural characteristics and weight loss of natural stones exposed to simulated acid rain.

PubMed

Franzoni, Elisa; Sassoni, Enrico

2011-12-15

The correlation between stone microstructural characteristics and material degradation (in terms of weight loss), in given environmental conditions, was investigated. Seven lithotypes, having very different microstructural characteristics, were used. Four acidic aqueous solutions were prepared to simulate acid rain (two adding H(2)SO(4) and two adding HNO(3) to deionized water, in order to reach, for each acid, pH values of 5.0 and 4.0), and deionized water at pH=5.6 was used to simulate clean rain. Stone samples were then immersed in such aqueous solutions, the surface alteration being periodically inspected and the weight loss periodically measured. After 14 days of immersion, a good correlation was found between weight loss and the product of carbonate content and specific surface area in the starting materials. This was explained considering that this product accounts for the weight loss owing to the sample's fraction actually composed of calcite (the most soluble fraction) and the effective surface area exposed to dissolving solution (which depends on stone porosity and pore size distribution). Such correlation between stone microstructure and degradation may be useful for comparing the durability of different lithotypes, in given environmental conditions, and quantitatively predicting the weight loss of a lithotype, compared to another one. Hence, the correlation found in this study may be used to specifically tailor to various stone types, with different microstructural characteristics, some results that have been calculated in literature for specific stone types and then proposed as possibly representative for a broad category of stones with similar characteristics. Copyright © 2011 Elsevier B.V. All rights reserved.

Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.

PubMed

Gan, T; Jude, C D; Zaffuto, K; Ernst, P

2010-10-01

The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.

Ecological consequences of changing hydrological conditions in wetland forests of coastal Louisiana

Treesearch

Richard F. Keim; Jim L. Chambers; Melinda S. Hughes; J. Andrew Nyman; Craig A. Miller; Blake J. Amos; William H. Conner; John W. Day; Stephen P. Faulkner; Emile S. Gardiner; Sammy L. King; Kenneth W. McLeod; Gary P. Shaffer

2006-01-01

Large-scale and localized alterations of processes affecting deltaic coastal wetlands have caused the complete loss of some coastal wetland forests and reduced the productivity and vigor of many areas in coastal Louisiana. This loss and degradation threatens ecosystem functions and the services they provide. This paper summarizes ecological relationships controlled by...

Diminished anabolic signaling responses to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity

USDA-ARS?s Scientific Manuscript database

The loss of skeletal muscle mass is observed in many pathophysiological conditions including, aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and characterized by a mismatch between skeletal muscle protein synthesis (MPS) and breakdown. Characteristic meta...

Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

PubMed

Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

2014-05-01

Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology. Copyright © 2014 Elsevier Inc. All rights reserved.

J-2X Abort System Development

NASA Technical Reports Server (NTRS)

Santi, Louis M.; Butas, John P.; Aguilar, Robert B.; Sowers, Thomas S.

2008-01-01

The J-2X is an expendable liquid hydrogen (LH2)/liquid oxygen (LOX) gas generator cycle rocket engine that is currently being designed as the primary upper stage propulsion element for the new NASA Ares vehicle family. The J-2X engine will contain abort logic that functions as an integral component of the Ares vehicle abort system. This system is responsible for detecting and responding to conditions indicative of impending Loss of Mission (LOM), Loss of Vehicle (LOV), and/or catastrophic Loss of Crew (LOC) failure events. As an earth orbit ascent phase engine, the J-2X is a high power density propulsion element with non-negligible risk of fast propagation rate failures that can quickly lead to LOM, LOV, and/or LOC events. Aggressive reliability requirements for manned Ares missions and the risk of fast propagating J-2X failures dictate the need for on-engine abort condition monitoring and autonomous response capability as well as traditional abort agents such as the vehicle computer, flight crew, and ground control not located on the engine. This paper describes the baseline J-2X abort subsystem concept of operations, as well as the development process for this subsystem. A strategy that leverages heritage system experience and responds to an evolving engine design as well as J-2X specific test data to support abort system development is described. The utilization of performance and failure simulation models to support abort system sensor selection, failure detectability and discrimination studies, decision threshold definition, and abort system performance verification and validation is outlined. The basis for abort false positive and false negative performance constraints is described. Development challenges associated with information shortfalls in the design cycle, abort condition coverage and response assessment, engine-vehicle interface definition, and abort system performance verification and validation are also discussed.

Mariner 9 data storage subsystem flight performance summary

NASA Technical Reports Server (NTRS)

Thomas, N. E.; Larman, B. T.

1973-01-01

The performance is summarized of the Mariner 9 Data Storage Subsystem (DSS) throughout the primary and extended missions. Information presented is limited to reporting of anomalies which occurred during the playback sequences. Tables and figures describe the anomalies (dropouts, missing and added bits, in the imaging data) as a function of time (accumulated tape passes). The data results indicate that the performance of the DSS was satisfactory and within specification throughout the mission. The data presented is taken from the Spacecraft Team Incident/Surprise Anomaly Log recorded during the mission. Pertinent statistics concerning the tape transport performance are given. Also presented is a brief description of DSS operation, particularly that related to the recorded anomalies. This covers the video data encoding and how it is interpreted/decoded by ground data processing and the functional operation of the DSS in abnormal conditions such as loss of lock to the playback signal.

MLH1 function is context dependent in colorectal cancers.

PubMed

Jackson, Thomas; Ahmed, Mohamed A H; Seth, Rashmi; Jackson, Darryl; Ilyas, Mohammad

2011-02-01

Loss of mismatch repair (MMR) function in sporadic colorectal cancer occurs most commonly because of inactivation of MLH1, and it causes an increase in mutation rate. However, it is uncertain whether loss of MMR alters any other cellular function. The aim of this study was to investigate the role of MMR in regulating cell numbers and apoptosis. MLH1 protein levels were manipulated by (a) cloning and forcibly expressing MLH1 in HCT116 (a cell line with MLH1 mutation) and RKO (a cell line with MLH1 silencing), and (b) knockdown of MLH1 in SW480 (a cell line with normal MMR function). Cell number and apoptotic bodies were measured in standard and 'high stress' (ie, after staurosporine exposure) conditions. Restoration of MLH1 function in HCT116 and RKO resulted in increased cell number (p<0.001 for both cell lines) and decreased numbers of floating apoptotic bodies (p<0.01 in HCT116) in standard culture conditions. However, on induction of apoptotic stress, restoration of MLH1 resulted in reduced cell numbers (p<0.005). Knockdown of MLH1 in SW480 had no effect on cell numbers or apoptosis. MLH1 function may be context dependent: in 'low stress' conditions it may act to inhibit apoptosis, while in 'high stress' conditions it may induce apoptosis. However, within the context of chromosomal instability, the effect of MLH1 on cell numbers is limited.

Relations Between Self-reported Executive Functioning and Speech Perception Skills in Adult Cochlear Implant Users.

PubMed

Moberly, Aaron C; Patel, Tirth R; Castellanos, Irina

2018-02-01

As a result of their hearing loss, adults with cochlear implants (CIs) would self-report poorer executive functioning (EF) skills than normal-hearing (NH) peers, and these EF skills would be associated with performance on speech recognition tasks. EF refers to a group of high order neurocognitive skills responsible for behavioral and emotional regulation during goal-directed activity, and EF has been found to be poorer in children with CIs than their NH age-matched peers. Moreover, there is increasing evidence that neurocognitive skills, including some EF skills, contribute to the ability to recognize speech through a CI. Thirty postlingually deafened adults with CIs and 42 age-matched NH adults were enrolled. Participants and their spouses or significant others (informants) completed well-validated self-reports or informant-reports of EF, the Behavior Rating Inventory of Executive Function - Adult (BRIEF-A). CI users' speech recognition skills were assessed in quiet using several measures of sentence recognition. NH peers were tested for recognition of noise-vocoded versions of the same speech stimuli. CI users self-reported difficulty on EF tasks of shifting and task monitoring. In CI users, measures of speech recognition correlated with several self-reported EF skills. The present findings provide further evidence that neurocognitive factors, including specific EF skills, may decline in association with hearing loss, and that some of these EF skills contribute to speech processing under degraded listening conditions.

Pharmacological strategies for protection of extrahepatic islet transplantation.

PubMed

Omori, K; Komatsu, H; Rawson, J; Mullen, Y

2015-06-01

The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote β-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

PubMed

van Wijk, Nick; Broersen, Laus M; de Wilde, Martijn C; Hageman, Robert J J; Groenendijk, Martine; Sijben, John W C; Kamphuis, Patrick J G H

2014-01-01

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

Correlation between hearing loss and scala media area in guinea pigs with long-standing endolymphatic hydrops.

PubMed

Hott, Morgan E; Graham, Martin; Bonassar, Lawrence J; Megerian, Cliff A

2003-01-01

Histologic analysis of the hydropic and normal guinea pig cochleae was undertaken to assess a potential correlation between the magnitude of endolymphatic hydrops and hearing loss. It was hypothesized that a greater correlation than previously reported might be found by looking at long-standing endolymphatic hydrops and high-frequency range hearing. Surgically induced endolymphatic hydrops in guinea pigs is the most widely used animal model for the study of human Ménière's Disease and recapitulates both endolymphatic hydrops and progressive sensorineural hearing loss. A strong correlation between the magnitude of hydrops and severity of hearing loss has been reported in the human condition, but not in the animal model. Nine albino guinea pigs were each subjected to surgical obstruction of the endolymphatic sac and duct of the right ear. The left ears remained as internal histologic controls. Hearing was assessed from 2 kHz to 32 kHz by auditory brain stem response testing for 16 to 25 weeks after surgery. Histologic morphometry after the animals were killed was used to quantify both turn-specific and weighted overall hydrops. These measures were correlated with hearing loss in each animal at all tested frequencies. A statistically significant correlation between the magnitude of hydrops and the severity of hearing loss was observed for 2 kHz and 16 kHz. These frequencies correlated with both turn-specific hydrops and overall hydrops. However, turn-specific hydrops did not reliably correlate with the magnitude of hearing loss at anatomically appropriate frequency ranges. Where such a correlation did exist, it might well have been simply part of an expression of an overall correlation between hydrops and hearing loss. There may be a greater correlation between hydrops and hearing loss in guinea pigs with long-standing surgically induced hydrops than has previously been reported in animals with less advanced disease. These findings help to validate continued use of the model for hearing loss related to Ménière's Disease, verify the rationale of treatment modalities aimed at reducing hydrops in the human condition, and may indicate that efforts at reducing hydrops in such patients has benefits toward long-term hearing preservation.

Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions

PubMed Central

Cardin, Velia

2016-01-01

Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID:27242405

Protection of total body water content and absence of hyperthermia despite 2% body mass loss ('voluntary dehydration') in soldiers drinking ad libitum during prolonged exercise in cool environmental conditions.

PubMed

Nolte, Heinrich W; Noakes, Timothy D; van Vuuren, Bernard

2011-11-01

The extent to which humans need to replace fluid losses during exercise remains contentious despite years of focused research. The primary objective was to evaluate ad libitum drinking on hydration status to determine whether body mass loss can be used as an accurate surrogate for changes in total body water (TBW) during exercise. Data were collected during a 14.6-km route march (wet bulb globe temperature of 14.1°C ). 18 subjects with an average age of 26 ± 2.5 (SD) years participated. Their mean ad libitum total fluid intake was 2.1 ± 1.4 litres during the exercise. Predicted sweat rate was 1.289 ± 0.530 l/h. There were no significant changes (p>0.05) in TBW, urine specific gravity or urine osmolality despite an average body mass loss (p<0.05) of 1.3 ± 0.45 kg during the march. Core temperature rose as a function of marching speed and was unrelated to the % change in body mass. This suggests that changes in mass do not accurately predict changes in TBW (r=-0.16) because either the body mass loss during exercise includes losses other than water or there is an endogenous body water source that is released during exercise not requiring replacement during exercise, or both. Ad libitum water replacement between 65% and 70% of sweat losses maintained safe levels of hydration during the experiment. The finding that TBW was protected by ad libitum drinking despite approximately 2% body mass loss suggests that the concept of 'voluntary dehydration' may require revision.

Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice

PubMed Central

Wang, I-Ting Judy; Yue, Cuiyong; Takano, Hajime; Terzic, Barbara

2017-01-01

Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking CDKL5 display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knock-out mice. Hippocampal pyramidal neurons lacking CDKL5 show decreased dendritic complexity but a trend toward increased spine density. This morphological change is accompanied by an increase in the frequency of spontaneous miniature EPSCs and interestingly, miniature IPSCs. Using voltage-sensitive dye imaging to interrogate the evoked response of the CA1 microcircuit, we find that CA1 pyramidal neurons lacking CDKL5 show hyperexcitability in their dendritic domain that is constrained by elevated inhibition in a spatially and temporally distinct manner. These results suggest a novel role for CDKL5 in the regulation of synaptic function and uncover an intriguing microcircuit mechanism underlying impaired learning and memory. SIGNIFICANCE STATEMENT Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although Cdkl5 constitutive knock-out mice have recapitulated key aspects of human symptomatology, the cellular origins of CDKL5 deficiency-related phenotypes are unknown. Here, using conditional knock-out mice, we show that hippocampal-dependent learning and memory deficits in CDKL5 deficiency have origins in glutamatergic neurons of the forebrain and that loss of CDKL5 results in the enhancement of synaptic transmission and disruptions in neural circuit dynamics in a spatially and temporally specific manner. Our findings demonstrate that CDKL5 is an important regulator of synaptic function in glutamatergic neurons and serves a critical role in learning and memory. PMID:28674172

Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice.

PubMed

Tang, Sheng; Wang, I-Ting Judy; Yue, Cuiyong; Takano, Hajime; Terzic, Barbara; Pance, Katarina; Lee, Jun Y; Cui, Yue; Coulter, Douglas A; Zhou, Zhaolan

2017-08-02

Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking CDKL5 display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knock-out mice. Hippocampal pyramidal neurons lacking CDKL5 show decreased dendritic complexity but a trend toward increased spine density. This morphological change is accompanied by an increase in the frequency of spontaneous miniature EPSCs and interestingly, miniature IPSCs. Using voltage-sensitive dye imaging to interrogate the evoked response of the CA1 microcircuit, we find that CA1 pyramidal neurons lacking CDKL5 show hyperexcitability in their dendritic domain that is constrained by elevated inhibition in a spatially and temporally distinct manner. These results suggest a novel role for CDKL5 in the regulation of synaptic function and uncover an intriguing microcircuit mechanism underlying impaired learning and memory. SIGNIFICANCE STATEMENT Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although Cdkl5 constitutive knock-out mice have recapitulated key aspects of human symptomatology, the cellular origins of CDKL5 deficiency-related phenotypes are unknown. Here, using conditional knock-out mice, we show that hippocampal-dependent learning and memory deficits in CDKL5 deficiency have origins in glutamatergic neurons of the forebrain and that loss of CDKL5 results in the enhancement of synaptic transmission and disruptions in neural circuit dynamics in a spatially and temporally specific manner. Our findings demonstrate that CDKL5 is an important regulator of synaptic function in glutamatergic neurons and serves a critical role in learning and memory. Copyright © 2017 the authors 0270-6474/17/377420-18$15.00/0.

Tissue-specific root ion profiling reveals essential roles of the CAX and ACA calcium transport systems in response to hypoxia in Arabidopsis

PubMed Central

Wang, Feifei; Chen, Zhong-Hua; Liu, Xiaohui; Colmer, Timothy David; Zhou, Meixue; Shabala, Sergey

2016-01-01

Waterlogging is a major abiotic stress that limits the growth of plants. The crucial role of Ca2+ as a second messenger in response to abiotic and biotic stimuli has been widely recognized in plants. However, the physiological and molecular mechanisms of Ca2+ distribution within specific cell types in different root zones under hypoxia is poorly understood. In this work, whole-plant physiological and tissue-specific Ca2+ changes were studied using several ACA (Ca2+-ATPase) and CAX (Ca2+/proton exchanger) knock-out Arabidopsis mutants subjected to waterlogging treatment. In the wild-type (WT) plants, several days of hypoxia decreased the expression of ACA8, CAX4, and CAX11 by 33% and 50% compared with the control. The hypoxic treatment also resulted in an up to 11-fold tissue-dependent increase in Ca2+ accumulation in root tissues as revealed by confocal microscopy. The increase was much higher in stelar cells in the mature zone of Arabidopsis mutants with loss of function for ACA8, ACA11, CAX4, and CAX11. In addition, a significantly increased Ca2+ concentration was found in the cytosol of stelar cells in the mature zone after hypoxic treatment. Three weeks of waterlogging resulted in dramatic loss of shoot biomass in cax11 plants (67% loss in shoot dry weight), while in the WT and other transport mutants this decline was only 14–22%. These results were also consistent with a decline in leaf chlorophyll fluorescence (F v/F m). It is suggested that CAX11 plays a key role in maintaining cytosolic Ca2+ homeostasis and/or signalling in root cells under hypoxic conditions. PMID:26889007

Monte Carlo simulation of single accident airport risk profile

NASA Technical Reports Server (NTRS)

1979-01-01

A computer simulation model was developed for estimating the potential economic impacts of a carbon fiber release upon facilities within an 80 kilometer radius of a major airport. The model simulated the possible range of release conditions and the resulting dispersion of the carbon fibers. Each iteration of the model generated a specific release scenario, which would cause a specific amount of dollar loss to the surrounding community. By repeated iterations, a risk profile was generated, showing the probability distribution of losses from one accident. Using accident probability estimates, the risks profile for annual losses was derived. The mechanics are described of the simulation model, the required input data, and the risk profiles generated for the 26 large hub airports.

The sustainable management of ameliorated peatlands on changed land use conditions; scenarios of constrains and possibilities

NASA Astrophysics Data System (ADS)

Shanskiy, , Merrit; Vollmer, Elis; Penu, Priit

2015-04-01

The utilization of organic soils for forestry or agriculture requires the land amelioration that could result on the peat losses from 15 to 20 t ha-1 in a year on following five years. After five years, the peat losses will be 5 - 15 t ha-1 in a year. The agricultural land resource on different types of organic soils (including ameliorated bogs) in Estonia is 360 000 ha that comprises 41% of total agricultural land area. The landscape iself is a valuable resource that considered to be a set of characteristics that satisfy needs of people using the landscape: economical or non-economical value; ecological, social, recreational, aesthetical, educational, scientific or even protective value. More diverse landscapes have higher biodiversity and yield more services to public, they are also seen as more sustainable and resilient to short-term changes. In order to maintain landscape diversity, sustainable maintenance is important. The purpose of current study was to estimate the land use potential on three different ameliorated peat areas and to develop the methodology for the futher sustainable utilization in order to secure the best ecological functioning of soil while taking into account maintaining and increasing landscape value. Therefore, site specific soil sampling (n=77) was carried out on predetermined eight study sites. Soil samples were analyzed for main agrochemical parameters (n=17; pHKCl, P, K, C%, N%, S%, ash, main anions and cations). This enables determing site-specific best suitable crops and land use scenarios. For the land resource description (soils type, topology) the digital soil map (1: 10,000) and field sudy based database were used for describing the model areas. For more specific identification of the field layers the Agricultural Registers and Information Board (ARIB) and databases of the Common Agricultural Policy (CAP) payments were used for subsidy schemes chekout. Estonian Nature Information System map tool was used to specify the restrictions on study sites by nature conversation on the maps data about nature protected objects and buffer zones or forming restricted areas around those objects. The results will indicate the utilization possibility and most sustainable scenarios for different land use cases. Moreover, the possible changes in soil functioning accordingly to site specific soil conditions will be discussed and presented.

Large-scale turnover of functional transcription factor bindingsites in Drosophila

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moses, Alan M.; Pollard, Daniel A.; Nix, David A.

2006-07-14

The gain and loss of functional transcription-factor bindingsites has been proposed as a major source of evolutionary change incis-regulatory DNA and gene expression. We have developed an evolutionarymodel to study binding site turnover that uses multiple sequencealignments to assess the evolutionary constraint on individual bindingsites, and to map gain and loss events along a phylogenetic tree. Weapply this model to study the evolutionary dynamics of binding sites ofthe Drosophila melanogaster transcription factor Zeste, using genome-widein vivo (ChIP-chip) binding data to identify functional Zeste bindingsites, and the genome sequences of D. melanogaster, D. simulans, D.erecta and D. yakuba to study theirmore » evolution. We estimate that more than5 percent of functional Zeste binding sites in D. melanogaster weregained along the D. melanogaster lineage or lost along one of the otherlineages. We find that Zeste bound regions have a reduced rate of bindingsite loss and an increased rate of binding site gain relative to flankingsequences. Finally, we show that binding site gains and losses areasymmetrically distributed with respect to D. melanogaster, consistentwith lineage-specific acquisition and loss of Zeste-responsive regulatoryelements.« less

BCOR regulates myeloid cell proliferation and differentiation

PubMed Central

Cao, Qi; Gearhart, Micah D.; Gery, Sigal; Shojaee, Seyedmehdi; Yang, Henry; Sun, Haibo; Lin, De-chen; Bai, Jing-wen; Mead, Monica; Zhao, Zhiqiang; Chen, Qi; Chien, Wen-wen; Alkan, Serhan; Alpermann, Tamara; Haferlach, Torsten; Müschen, Markus; Bardwell, Vivian J.; Koeffler, H. Phillip

2016-01-01

BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukaemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. PMID:26847029

Activation of Gαq Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

PubMed

Arey, Rachel N; Stein, Geneva M; Kaletsky, Rachel; Kauffman, Amanda; Murphy, Coleen T

2018-05-02

Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G αq signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced G αq signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G αq specifically in aged animals rescues the ability to form memory. Activation of G αq in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity. Copyright © 2018 Elsevier Inc. All rights reserved.

Loss of Peripheral Sensory Function Explains Much of the Increase in Postural Sway in Healthy Older Adults

PubMed Central

Anson, Eric; Bigelow, Robin T.; Swenor, Bonnielin; Deshpande, Nandini; Studenski, Stephanie; Jeka, John J.; Agrawal, Yuri

2017-01-01

Postural sway increases with age and peripheral sensory disease. Whether, peripheral sensory function is related to postural sway independent of age in healthy adults is unclear. Here, we investigated the relationship between tests of visual function (VISFIELD), vestibular function (CANAL or OTOLITH), proprioceptive function (PROP), and age, with center of mass sway area (COM) measured with eyes open then closed on firm and then a foam surface. A cross-sectional sample of 366 community dwelling healthy adults from the Baltimore Longitudinal Study of Aging was tested. Multiple linear regressions examined the association between COM and VISFIELD, PROP, CANAL, and OTOLITH separately and in multi-sensory models controlling for age and gender. PROP dominated sensory prediction of sway across most balance conditions (β's = 0.09–0.19, p's < 0.001), except on foam eyes closed where CANAL function loss was the only significant sensory predictor of sway (β = 2.12, p < 0.016). Age was not a consistent predictor of sway. This suggests loss of peripheral sensory function explains much of the age-associated increase in sway. PMID:28676758

Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis

PubMed Central

Huber, Robert J.; Myre, Michael A.; Cotman, Susan L.

2017-01-01

ABSTRACT Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, refers to a group of severe neurodegenerative disorders that primarily affect children. The most common subtype of the disease is caused by loss-of-function mutations in CLN3, which is conserved across model species from yeast to human. The precise function of the CLN3 protein is not known, which has made targeted therapy development challenging. In the social amoeba Dictyostelium discoideum, loss of Cln3 causes aberrant mid-to-late stage multicellular development. In this study, we show that Cln3-deficiency causes aberrant adhesion and aggregation during the early stages of Dictyostelium development. cln3− cells form ∼30% more multicellular aggregates that are comparatively smaller than those formed by wild-type cells. Loss of Cln3 delays aggregation, but has no significant effect on cell speed or cAMP-mediated chemotaxis. The aberrant aggregation of cln3− cells cannot be corrected by manually pulsing cells with cAMP. Moreover, there are no significant differences between wild-type and cln3− cells in the expression of genes linked to cAMP chemotaxis (e.g., adenylyl cyclase, acaA; the cAMP receptor, carA; cAMP phosphodiesterase, pdsA; g-protein α 9 subunit, gpaI). However, during this time in development, cln3− cells show reduced cell-substrate and cell-cell adhesion, which correlate with changes in the levels of the cell adhesion proteins CadA and CsaA. Specifically, loss of Cln3 decreases the intracellular level of CsaA and increases the amount of soluble CadA in conditioned media. Together, these results suggest that the aberrant aggregation of cln3− cells is due to reduced adhesion during the early stages of development. Revealing the molecular basis underlying this phenotype may provide fresh new insight into CLN3 function. PMID:27669405

Consequences of Early Conductive Hearing Loss on Long-Term Binaural Processing.

PubMed

Graydon, Kelley; Rance, Gary; Dowell, Richard; Van Dun, Bram

The aim of the study was to investigate the long-term effects of early conductive hearing loss on binaural processing in school-age children. One hundred and eighteen children participated in the study, 82 children with a documented history of conductive hearing loss associated with otitis media and 36 controls who had documented histories showing no evidence of otitis media or conductive hearing loss. All children were demonstrated to have normal-hearing acuity and middle ear function at the time of assessment. The Listening in Spatialized Noise Sentence (LiSN-S) task and the masking level difference (MLD) task were used as the two different measures of binaural interaction ability. Children with a history of conductive hearing loss performed significantly poorer than controls on all LiSN-S conditions relying on binaural cues (DV90, p = <0.001 and SV90, p = 0.003). No significant difference was found between the groups in listening conditions without binaural cues. Fifteen children with a conductive hearing loss history (18%) showed results consistent with a spatial processing disorder. No significant difference was observed between the conductive hearing loss group and the controls on the MLD task. Furthermore, no correlations were found between LiSN-S and MLD. Results show a relationship between early conductive hearing loss and listening deficits that persist once hearing has returned to normal. Results also suggest that the two binaural interaction tasks (LiSN-S and MLD) may be measuring binaural processing at different levels. Findings highlight the need for a screening measure of functional listening ability in children with a history of early otitis media.

Differential Impact of Involuntary Job Loss on Physical Disability Among Older Workers Does Predisposition Matter?

PubMed Central

Gallo, William T.; Brand, Jennie E.; Teng, Hsun-Mei; Leo-Summers, Linda; Byers, Amy L.

2009-01-01

Older workers' share of involuntary job losses in the United States has grown fairly consistently in recent decades, prompting greater interest in the health consequences of involuntary unemployment among individuals nearing retirement. In this study, the authors applied the multifactorial model of geriatric health to investigate whether late-career involuntary job loss was associated with subsequent physical disability and whether the effect of involuntary job loss on physical disability varied by predisposition. Using data from the first four waves (1992 to 1998) of the Health and Retirement Survey, the authors measured predisposition with individual risk factors for functional disability and indices of aggregate risk. The results of gender-specific models fit with generalized estimating equations revealed that unmarried women and those with low predisplacement incomes had heightened risk for subsequent functional disability. No differential effects of job loss were found for men. PMID:19924265

Air Conditioning and Refrigeration Book III.

ERIC Educational Resources Information Center

Eckes, William; Fulkerson, Dan

Designed to present theory as a functional aspect, this air conditioning and refrigeration curriculum guide is comprised of nine units of instruction. Unit titles include (1) Job Orientation, (2) Applying for a Job, (3) Customer Relations, (4) Business Management, (5) Psychometrics, (6) Residential Heat Loss and Heat Gain, (7) Duct Design and…

Performance analysis of radiation cooled dc transmission lines for high power space systems

NASA Technical Reports Server (NTRS)

Schwarze, G. E.

1985-01-01

As space power levels increase to meet mission objectives and also as the transmission distance between power source and load increases, the mass, volume, power loss, and operating voltage and temperature become important system design considerations. This analysis develops the dependence of the specific mass and percent power loss on hte power and voltage levels, transmission distance, operating temperature and conductor material properties. Only radiation cooling is considered since the transmission line is assumed to operate in a space environment. The results show that the limiting conditions for achieving low specific mass, percent power loss, and volume for a space-type dc transmission line are the permissible transmission voltage and operating temperature. Other means to achieve low specific mass include the judicious choice of conductor materials. The results of this analysis should be immediately applicable to power system trade-off studies including comparisons with ac transmission systems.

Advancing biodiversity-ecosystem functioning science using high-density tree-based experiments over functional diversity gradients.

PubMed

Tobner, Cornelia M; Paquette, Alain; Reich, Peter B; Gravel, Dominique; Messier, Christian

2014-03-01

Increasing concern about loss of biodiversity and its effects on ecosystem functioning has triggered a series of manipulative experiments worldwide, which have demonstrated a general trend for ecosystem functioning to increase with diversity. General mechanisms proposed to explain diversity effects include complementary resource use and invoke a key role for species' functional traits. The actual mechanisms by which complementary resource use occurs remain, however, poorly understood, as well as whether they apply to tree-dominated ecosystems. Here we present an experimental approach offering multiple innovative aspects to the field of biodiversity-ecosystem functioning (BEF) research. The International Diversity Experiment Network with Trees (IDENT) allows research to be conducted at several hierarchical levels within individuals, neighborhoods, and communities. The network investigates questions related to intraspecific trait variation, complementarity, and environmental stress. The goal of IDENT is to identify some of the mechanisms through which individuals and species interact to promote coexistence and the complementary use of resources. IDENT includes several implemented and planned sites in North America and Europe, and uses a replicated design of high-density tree plots of fixed species-richness levels varying in functional diversity (FD). The design reduces the space and time needed for trees to interact allowing a thorough set of mixtures varying over different diversity gradients (specific, functional, phylogenetic) and environmental conditions (e.g., water stress) to be tested in the field. The intention of this paper is to share the experience in designing FD-focused BEF experiments with trees, to favor collaborations and expand the network to different conditions.

Decision-making after continuous wins or losses in a randomized guessing task: implications for how the prior selection results affect subsequent decision-making.

PubMed

Dong, Guangheng; Lin, Xiao; Zhou, Hongli; Du, Xiaoxia

2014-04-03

Human decision-making is often affected by prior selections and their outcomes, even in situations where decisions are independent and outcomes are unpredictable. In this study, we created a task that simulated real-life non-strategic gambling to examine the effect of prior outcomes on subsequent decisions in a group of male college students. Behavioral performance showed that participants needed more time to react after continuous losses (LOSS) than continuous wins (WIN) and discontinuous outcomes (CONTROL). In addition, participants were more likely to repeat their selections in both WIN and LOSS conditions. Functional MRI data revealed that decisions in WINs were associated with increased activation in the mesolimbic pathway, but decreased activation in the inferior frontal gyrus relative to LOSS. Increased prefrontal cortical activation was observed during LOSS relative to WIN and CONTROL conditions. Taken together, the behavioral and neuroimaging findings suggest that participants tended to repeat previous selections during LOSS trials, a pattern resembling the gambler's fallacy. However, during WIN trials, participants tended to follow their previous lucky decisions, like the 'hot hand' fallacy.

Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation.

PubMed

Lemay, Francis; Doré, François Y; Beaulieu, Jean-Martin

2015-11-16

Polymorphisms in the gene encoding the brain serotonin synthesis enzyme Tph2 have been identified in mental illnesses, with co-morbidity of substance use disorder. However, little is known about the impact of Tph2 gene variants on addiction. Mice expressing a human Tph2 loss of function variant were used to investigate consequences of aversive conditions on ethanol intake. Mice were familiarized either with ethanol or a solution containing both ethanol and the bittering agent quinine. Effect of familiarization to ethanol or an ethanol-quinine solution was then evaluated using a two-bottles preference test in Tph2-KI and control littermates. Mice from both genotypes displayed similar levels of ethanol consumption and quinine avoidance when habituated to ethanol alone. In contrast, addition of quinine to ethanol during the familiarization period resulted in a reduction of avoidance for the quinine-ethanol solution only in mutant mice. These results indicate that loss of function mutation in Tph2 results in greater motivation for ethanol consumption under aversive conditions and may confer enhanced sensitivity to alcohol use disorder. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Sexual conseling of the physically disabled.

PubMed

Anderson, T P; Cole, T M

1975-07-01

Sexual satisfaction and feelings of self-esteem play an important role in the ability to adapt to an acquired physical disability. A framework has been presented to show how sexual function is affected by different types of physical disability, and spinal cord injury has been selected as a specific example. Sexual counseling for the disabled differs little from that for the able-bodied--the same principles apply. It is appropriate to remind not only the counselor but also the disabled that (1) loss of sensation does not mean loss of feelings, (2) loss of potency does not mean loss of ability, (3) loss of urinary continence does not mean loss of penile competence, and (4) loss of genitalia does not mean loss of sexuality.

α5 nAChR modulation of the prefrontal cortex makes attention resilient.

PubMed

Howe, William M; Brooks, Julie L; Tierney, Patrick L; Pang, Jincheng; Rossi, Amie; Young, Damon; Dlugolenski, Keith; Guillmette, Ed; Roy, Marc; Hales, Katherine; Kozak, Rouba

2018-03-01

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.

The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting.

PubMed

Bhatnagar, S; Kumar, A

2012-01-01

The occurrence of skeletal muscle atrophy, a devastating complication of a large number of disease states and inactivity/disuse conditions, provides a never ending quest to identify novel targets for its therapy. Proinflammatory cytokines are considered the mediators of muscle wasting in chronic diseases; however, their role in disuse atrophy has just begun to be elucidated. An inflammatory cytokine, tumor necrosis factor (TNF)- like weak inducer of apoptosis (TWEAK), has recently been identified as a potent inducer of skeletal muscle wasting. TWEAK activates various proteolytic pathways and stimulates the degradation of myofibril protein both in vitro and in vivo. Moreover, TWEAK mediates the loss of skeletal muscle mass and function in response to denervation, a model of disuse atrophy. Adult skeletal muscle express very low to minimal levels of TWEAK receptor, Fn14. Specific catabolic conditions such as denervation, immobilization, or unloading rapidly increase the expression of Fn14 in skeletal muscle which in turn stimulates the TWEAK activation of various catabolic pathways leading to muscle atrophy. In this article, we have discussed the emerging roles and the mechanisms of action of TWEAK-Fn14 system in skeletal muscle with particular reference to different models of muscle atrophy and injury and its potential to be used as a therapeutic target for prevention of muscle loss.

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation

PubMed Central

Ge, Xiaoyan; Gong, Henry; Dumas, Kevin; Litwin, Jessica; Phillips, Joanna J; Waisfisz, Quinten; Weiss, Marjan M; Hendriks, Yvonne; Stuurman, Kyra E; Nelson, Stanley F; Grody, Wayne W; Lee, Hane; Kwok, Pui-Yan; Shieh, Joseph T C

2016-01-01

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss. PMID:28868155

Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

PubMed Central

Rasche, F. M.; Rasche, W. G.; Schiekofer, S.; Boldt, A.; Sack, U.; Fahnert, J.

2016-01-01

Summary IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (ΔGFR < 1·5 ml/min/year) or mild (ΔGFR 1·5–5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (ΔGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high‐dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (ΔGFR). Mycophenolic acid provided further maintenance in non‐randomized trials. Differentiated, precise, larger, randomized, placebo‐controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN. PMID:27283488

Inferring Selective Constraint from Population Genomic Data Suggests Recent Regulatory Turnover in the Human Brain

PubMed Central

Schrider, Daniel R.; Kern, Andrew D.

2015-01-01

The comparative genomics revolution of the past decade has enabled the discovery of functional elements in the human genome via sequence comparison. While that is so, an important class of elements, those specific to humans, is entirely missed by searching for sequence conservation across species. Here we present an analysis based on variation data among human genomes that utilizes a supervised machine learning approach for the identification of human-specific purifying selection in the genome. Using only allele frequency information from the complete low-coverage 1000 Genomes Project data set in conjunction with a support vector machine trained from known functional and nonfunctional portions of the genome, we are able to accurately identify portions of the genome constrained by purifying selection. Our method identifies previously known human-specific gains or losses of function and uncovers many novel candidates. Candidate targets for gain and loss of function along the human lineage include numerous putative regulatory regions of genes essential for normal development of the central nervous system, including a significant enrichment of gain of function events near neurotransmitter receptor genes. These results are consistent with regulatory turnover being a key mechanism in the evolution of human-specific characteristics of brain development. Finally, we show that the majority of the genome is unconstrained by natural selection currently, in agreement with what has been estimated from phylogenetic methods but in sharp contrast to estimates based on transcriptomics or other high-throughput functional methods. PMID:26590212

Effect of Intermittent Energy Restriction on Flow Mediated Dilatation, a Measure of Endothelial Function: A Short Report.

PubMed

Headland, Michelle L; Clifton, Peter M; Keogh, Jennifer B

2018-06-04

Intermittent energy restriction is a popular alternative to daily energy restriction for weight loss; however, it is unknown if endothelial function, a risk factor for cardiovascular disease, is altered by periods of severe energy restriction. The objective of the study was to determine the impact of two consecutive very low energy intake days, which is the core component of the 5:2 intermittent energy restriction diet strategy, on endothelial function compared to consecutive ad libitum eating days. The secondary objective was to explore the effects of these dietary conditions on fasting glucose concentrations. This was a 4-week randomized, single-blinded, crossover study of 35 participants. Participants consumed a very low energy diet (500 calories for women, 600 calories for men) on two consecutive days per week and 5 days of habitual eating. In weeks 3 and 4 of the trial, participants had measurements of flow mediated dilatation (FMD) and blood samples taken following either 2 habitual eating days or 2 energy restricted days in a randomized order. FMD values were not different after the two eating states (8.6% vs. 8.3%, p = 0.7). All other outcome variables were unchanged. Endothelial function, as measured by flow mediated dilatation, was not altered by two consecutive very low energy intake days. Further investigations assessing the impact in specific population groups as well as different testing conditions would be beneficial.

Functional redundancy and sensitivity of fish assemblages in European rivers, lakes and estuarine ecosystems.

PubMed

Teichert, Nils; Lepage, Mario; Sagouis, Alban; Borja, Angel; Chust, Guillem; Ferreira, Maria Teresa; Pasquaud, Stéphanie; Schinegger, Rafaela; Segurado, Pedro; Argillier, Christine

2017-12-14

The impact of species loss on ecosystems functioning depends on the amount of trait similarity between species, i.e. functional redundancy, but it is also influenced by the order in which species are lost. Here we investigated redundancy and sensitivity patterns across fish assemblages in lakes, rivers and estuaries. Several scenarios of species extinction were simulated to determine whether the loss of vulnerable species (with high propensity of extinction when facing threats) causes a greater functional alteration than random extinction. Our results indicate that the functional redundancy tended to increase with species richness in lakes and rivers, but not in estuaries. We demonstrated that i) in the three systems, some combinations of functional traits are supported by non-redundant species, ii) rare species in rivers and estuaries support singular functions not shared by dominant species, iii) the loss of vulnerable species can induce greater functional alteration in rivers than in lakes and estuaries. Overall, the functional structure of fish assemblages in rivers is weakly buffered against species extinction because vulnerable species support singular functions. More specifically, a hotspot of functional sensitivity was highlighted in the Iberian Peninsula, which emphasizes the usefulness of quantitative criteria to determine conservation priorities.

Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

PubMed Central

Yang, Hui; Li, Jing-Jing; Liu, Shuai; Zhao, Jian; Jiang, Ya-Jun; Song, Ai-Xin; Hu, Hong-Yu

2014-01-01

Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration. PMID:25231079

Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading

PubMed Central

2012-01-01

Introduction Critically ill ICU patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life for survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model show that the mechanical silencing associated with CIM is the primary triggering factor. This study aims to unravel the mechanisms underlying CIM, and to evaluate the effects of a specific intervention aiming at reducing mechanical silencing in sedated and mechanically ventilated ICU patients. Methods Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading for 10 hours per day (2.5 hours, four times) for 9 ± 1 days. Results These patients developed a phenotype considered pathognomonic of CIM; that is, severe muscle wasting and a preferential myosin loss (P < 0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of neuronal nitric oxide synthase. Passive mechanical loading for 9 ± 1 days resulted in a 35% higher specific force (P < 0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. Conclusion Mechanical silencing is suggested to be a primary mechanism underlying CIM; that is, triggering the myosin loss, muscle wasting and myosin PTMs. The higher neuronal nitric oxide synthase expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients. PMID:23098317

Unifying measures of gene function and evolution.

PubMed

Wolf, Yuri I; Carmel, Liran; Koonin, Eugene V

2006-06-22

Recent genome analyses revealed intriguing correlations between variables characterizing the functioning of a gene, such as expression level (EL), connectivity of genetic and protein-protein interaction networks, and knockout effect, and variables describing gene evolution, such as sequence evolution rate (ER) and propensity for gene loss. Typically, variables within each of these classes are positively correlated, e.g. products of highly expressed genes also have a propensity to be involved in many protein-protein interactions, whereas variables between classes are negatively correlated, e.g. highly expressed genes, on average, evolve slower than weakly expressed genes. Here, we describe principal component (PC) analysis of seven genome-related variables and propose biological interpretations for the first three PCs. The first PC reflects a gene's 'importance', or the 'status' of a gene in the genomic community, with positive contributions from knockout lethality, EL, number of protein-protein interaction partners and the number of paralogues, and negative contributions from sequence ER and gene loss propensity. The next two PCs define a plane that seems to reflect the functional and evolutionary plasticity of a gene. Specifically, PC2 can be interpreted as a gene's 'adaptability' whereby genes with high adaptability readily duplicate, have many genetic interaction partners and tend to be non-essential. PC3 also might reflect the role of a gene in organismal adaptation albeit with a negative rather than a positive contribution of genetic interactions; we provisionally designate this PC 'reactivity'. The interpretation of PC2 and PC3 as measures of a gene's plasticity is compatible with the observation that genes with high values of these PCs tend to be expressed in a condition- or tissue-specific manner. Functional classes of genes substantially vary in status, adaptability and reactivity, with the highest status characteristic of the translation system and cytoskeletal proteins, highest adaptability seen in cellular processes and signalling genes, and top reactivity characteristic of metabolic enzymes.

Dicer maintains the identity and function of proprioceptive sensory neurons

PubMed Central

O’Toole, Sean M.; Ferrer, Monica M.; Mekonnen, Jennifer; Zhang, Haihan; Shima, Yasuyuki; Ladle, David R.

2017-01-01

Neuronal cell identity is established during development and must be maintained throughout an animal’s life (Fishell G, Heintz N. Neuron 80: 602–612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899–907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359–373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons. NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension, microRNAs are crucially important for maintaining proprioception. Additionally, this study hints at the larger question of how neurons maintain their functional and molecular specificity. PMID:28003412

Dicer maintains the identity and function of proprioceptive sensory neurons.

PubMed

O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer; Zhang, Haihan; Shima, Yasuyuki; Ladle, David R; Nelson, Sacha B

2017-03-01

Neuronal cell identity is established during development and must be maintained throughout an animal's life (Fishell G, Heintz N. Neuron 80: 602-612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899-907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359-373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons. NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension, microRNAs are crucially important for maintaining proprioception. Additionally, this study hints at the larger question of how neurons maintain their functional and molecular specificity. Copyright © 2017 the American Physiological Society.

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in Neurospora crassa.

PubMed

Araujo-Palomares, Cynthia L; Richthammer, Corinna; Seiler, Stephan; Castro-Longoria, Ernestina

2011-01-01

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa.

The Principle of Energetic Consistency

NASA Technical Reports Server (NTRS)

Cohn, Stephen E.

2009-01-01

A basic result in estimation theory is that the minimum variance estimate of the dynamical state, given the observations, is the conditional mean estimate. This result holds independently of the specifics of any dynamical or observation nonlinearity or stochasticity, requiring only that the probability density function of the state, conditioned on the observations, has two moments. For nonlinear dynamics that conserve a total energy, this general result implies the principle of energetic consistency: if the dynamical variables are taken to be the natural energy variables, then the sum of the total energy of the conditional mean and the trace of the conditional covariance matrix (the total variance) is constant between observations. Ensemble Kalman filtering methods are designed to approximate the evolution of the conditional mean and covariance matrix. For them the principle of energetic consistency holds independently of ensemble size, even with covariance localization. However, full Kalman filter experiments with advection dynamics have shown that a small amount of numerical dissipation can cause a large, state-dependent loss of total variance, to the detriment of filter performance. The principle of energetic consistency offers a simple way to test whether this spurious loss of variance limits ensemble filter performance in full-blown applications. The classical second-moment closure (third-moment discard) equations also satisfy the principle of energetic consistency, independently of the rank of the conditional covariance matrix. Low-rank approximation of these equations offers an energetically consistent, computationally viable alternative to ensemble filtering. Current formulations of long-window, weak-constraint, four-dimensional variational methods are designed to approximate the conditional mode rather than the conditional mean. Thus they neglect the nonlinear bias term in the second-moment closure equation for the conditional mean. The principle of energetic consistency implies that, to precisely the extent that growing modes are important in data assimilation, this term is also important.

Auditory Function in Children with Charcot-Marie-Tooth Disease

ERIC Educational Resources Information Center

Rance, Gary; Ryan, Monique M.; Bayliss, Kristen; Gill, Kathryn; O'Sullivan, Caitlin; Whitechurch, Marny

2012-01-01

The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of…

Operant conditioning of autobiographical memory retrieval.

PubMed

Debeer, Elise; Raes, Filip; Williams, J Mark G; Craeynest, Miet; Hermans, Dirk

2014-01-01

Functional avoidance is considered as one of the key mechanisms underlying overgeneral autobiographical memory (OGM). According to this view OGM is regarded as a learned cognitive avoidance strategy, based on principles of operant conditioning; i.e., individuals learn to avoid the emotionally painful consequences associated with the retrieval of specific negative memories. The aim of the present study was to test one of the basic assumptions of the functional avoidance account, namely that autobiographical memory retrieval can be brought under operant control. Here 41 students were instructed to retrieve personal memories in response to 60 emotional cue words. Depending on the condition, they were punished with an aversive sound for the retrieval of specific or nonspecific memories in an operant conditioning procedure. Analyzes showed that the course of memory specificity significantly differed between conditions. After the procedure participants punished for nonspecific memories retrieved significantly more specific memories compared to participants punished for specific memories. However, whereas memory specificity significantly increased in participants punished for specific memories, it did not significantly decrease in participants punished for nonspecific memories. Thus, while our findings indicate that autobiographical memory retrieval can be brought under operant control, they do not support a functional avoidance view on OGM.

Modelling the Impact of Soil Management on Soil Functions

NASA Astrophysics Data System (ADS)

Vogel, H. J.; Weller, U.; Rabot, E.; Stößel, B.; Lang, B.; Wiesmeier, M.; Urbanski, L.; Wollschläger, U.

2017-12-01

Due to an increasing soil loss and an increasing demand for food and energy there is an enormous pressure on soils as the central resource for agricultural production. Besides the importance of soils for biomass production there are other essential soil functions, i.e. filter and buffer for water, carbon sequestration, provision and recycling of nutrients, and habitat for biological activity. All these functions have a direct feed back to biogeochemical cycles and climate. To render agricultural production efficient and sustainable we need to develop model tools that are capable to predict quantitatively the impact of a multitude of management measures on these soil functions. These functions are considered as emergent properties produced by soils as complex systems. The major challenge is to handle the multitude of physical, chemical and biological processes interacting in a non-linear manner. A large number of validated models for specific soil processes are available. However, it is not possible to simulate soil functions by coupling all the relevant processes at the detailed (i.e. molecular) level where they are well understood. A new systems perspective is required to evaluate the ensemble of soil functions and their sensitivity to external forcing. Another challenge is that soils are spatially heterogeneous systems by nature. Soil processes are highly dependent on the local soil properties and, hence, any model to predict soil functions needs to account for the site-specific conditions. For upscaling towards regional scales the spatial distribution of functional soil types need to be taken into account. We propose a new systemic model approach based on a thorough analysis of the interactions between physical, chemical and biological processes considering their site-specific characteristics. It is demonstrated for the example of soil compaction and the recovery of soil structure, water capacity and carbon stocks as a result of plant growth and biological activity. Coupling of the observed nonlinear interactions allows for modeling the stability and resilience of soil systems in terms of their essential functions.

Thalamo-Cortical Disruption Contributes to Short-Term Memory Deficits in Patients with Medial Temporal Lobe Damage.

PubMed

Voets, Natalie L; Menke, Ricarda A L; Jbabdi, Saad; Husain, Masud; Stacey, Richard; Carpenter, Katherine; Adcock, Jane E

2015-11-01

Short-term (STM) and long-term memory (LTM) have largely been considered as separate brain systems reflecting fronto-parietal and medial temporal lobe (MTL) functions, respectively. This functional dichotomy has been called into question by evidence of deficits on aspects of working memory in patients with MTL damage, suggesting a potentially direct hippocampal contribution to STM. As the hippocampus has direct anatomical connections with the thalamus, we tested the hypothesis that damage to thalamic nuclei regulating cortico-cortical interactions may contribute to STM deficits in patients with hippocampal dysfunction. We used diffusion-weighted magnetic resonance imaging-based tractography to identify anatomical subdivisions in patients with MTL epilepsy. From these, we measured resting-state functional connectivity with detailed cortical divisions of the frontal, temporal, and parietal lobes. Whereas thalamo-temporal functional connectivity reflected LTM performance, thalamo-prefrontal functional connectivity specifically predicted STM performance. Notably, patients with hippocampal volume loss showed thalamic volume loss, most prominent in the pulvinar region, not detected in patients with normal hippocampal volumes. Aberrant thalamo-cortical connectivity in the epileptic hemisphere was mirrored in a loss of behavioral association with STM performance specifically in patients with hippocampal atrophy. These findings identify thalamo-cortical disruption as a potential mechanism contributing to STM deficits in the context of MTL damage. © The Author 2015. Published by Oxford University Press.

Morphological and physiological divergences within Quercus ilex support the existence of different ecotypes depending on climatic dryness

PubMed Central

Peguero-Pina, José Javier; Sancho-Knapik, Domingo; Barrón, Eduardo; Camarero, Julio Jesús; Vilagrosa, Alberto; Gil-Pelegrín, Eustaquio

2014-01-01

Background and Aims Several studies show apparently contradictory findings about the functional convergence within the Mediterranean woody flora. In this context, this study evaluates the variability of functional traits within holm oak (Quercus ilex) to elucidate whether provenances corresponding to different morphotypes represent different ecotypes locally adapted to the prevaling stress levels. Methods Several morphological and physiological traits were measured at leaf and shoot levels in 9-year-old seedlings of seven Q. ilex provenances including all recognized morphotypes. Plants were grown in a common garden for 9 years under the same environmental conditions to avoid possible biases due to site-specific characteristics. Key Results Leaf morphometry clearly separates holm oak provenances into ‘ilex’ (more elongated leaves with low vein density) and ‘rotundifolia’ (short and rounded leaves with high vein density) morphotypes. Moreover, these morphotypes represent two consistent and very contrasting functional types in response to dry climates, mainly in terms of leaf area, major vein density, leaf specific conductivity, resistance to drought-induced cavitation and turgor loss point. Conclusions The ‘ilex’ and ‘rotundifolia’ morphotypes correspond to different ecotypes as inferred from their contrasting functional traits. To the best of our knowledge, this is the first time that the combined use of morphological and physiological traits has provided support for the concept of these two holm oak morphotypes being regarded as two different species. PMID:24941998

Influence of physical exercise on microRNAs in skeletal muscle regeneration, aging and diseases

PubMed Central

Ultimo, Simona; Zauli, Giorgio; Martelli, Alberto M.; Vitale, Marco; McCubrey, James A.; Capitani, Silvano; Neri, Luca M.

2018-01-01

Skeletal muscle is a dynamic tissue with remarkable plasticity and its growth and regeneration are highly organized, with the activation of specific transcription factors, proliferative pathways and cytokines. The decline of skeletal muscle tissue with age, is one of the most important causes of functional loss of independence in older adults. Maintaining skeletal muscle function throughout the lifespan is a prerequisite for good health and independent living. Physical activity represents one of the most effective preventive agents for muscle decay in aging. Several studies have underlined the importance of microRNAs (miRNAs) in the control of myogenesis and of skeletal muscle regeneration and function. In this review, we reported an overview and recent advances about the role of miRNAs expressed in the skeletal muscle, miRNAs regulation by exercise in skeletal muscle, the consequences of different physical exercise training modalities in the skeletal muscle miRNA profile, their regulation under pathological conditions and the role of miRNAs in age-related muscle wasting. Specific miRNAs appear to be involved in response to different types of exercise and therefore to play an important role in muscle fiber identity and myofiber gene expression in adults and elder population. Understanding the roles and regulation of skeletal muscle miRNAs during muscle regeneration may result in new therapeutic approaches in aging or diseases with impaired muscle function or re-growth. PMID:29682218

Impact-parameter dependence of the energy loss of fast molecular clusters in hydrogen

NASA Astrophysics Data System (ADS)

Fadanelli, R. C.; Grande, P. L.; Schiwietz, G.

2008-03-01

The electronic energy loss of molecular clusters as a function of impact parameter is far less understood than atomic energy losses. For instance, there are no analytical expressions for the energy loss as a function of impact parameter for cluster ions. In this work, we describe two procedures to evaluate the combined energy loss of molecules: Ab initio calculations within the semiclassical approximation and the coupled-channels method using atomic orbitals; and simplified models for the electronic cluster energy loss as a function of the impact parameter, namely the molecular perturbative convolution approximation (MPCA, an extension of the corresponding atomic model PCA) and the molecular unitary convolution approximation (MUCA, a molecular extension of the previous unitary convolution approximation UCA). In this work, an improved ansatz for MPCA is proposed, extending its validity for very compact clusters. For the simplified models, the physical inputs are the oscillators strengths of the target atoms and the target-electron density. The results from these models applied to an atomic hydrogen target yield remarkable agreement with their corresponding ab initio counterparts for different angles between cluster axis and velocity direction at specific energies of 150 and 300 keV/u.

The assessment and impact of sarcopenia in lung cancer: a systematic literature review.

PubMed

Collins, Jemima; Noble, Simon; Chester, John; Coles, Bernadette; Byrne, Anthony

2014-01-02

There is growing awareness of the relationship between sarcopenia (loss of muscle mass and function), and outcomes in cancer, making it a potential target for future therapies. In order to inform future research and practice, we undertook a systematic review of factors associated with loss of muscle mass, and the relationship between muscle function and muscle mass in lung cancer, a common condition associated with poor outcomes. We conducted a computerised systematic literature search on five databases. Studies were included if they explored muscle mass as an outcome measure in patients with lung cancer, and were published in English. Secondary care. Patients with lung cancer. Factors associated with loss of muscle mass and muscle function, or sarcopenia, and the clinical impact thereof in patients with lung cancer. We reviewed 5726 citations, and 35 articles were selected for analysis. Sarcopenia, as defined by reduced muscle mass alone, was found to be very prevalent in patients with lung cancer, regardless of body mass index, and where present was associated with poorer functional status and overall survival. There were diverse studies exploring molecular and metabolic factors in the development of loss of muscle mass; however, the precise mechanisms that contribute to sarcopenia and cachexia remain uncertain. The effect of nutritional supplements and ATP infusions on muscle mass showed conflicting results. There are very limited data on the correlation between degree of sarcopenia and muscle function, which has a non-linear relationship in older non-cancer populations. Loss of muscle mass is a significant contributor to morbidity in patients with lung cancer. Loss of muscle mass and function may predate clinically overt cachexia, underlining the importance of evaluating sarcopenia, rather than weight loss alone. Understanding this relationship and its associated factors will provide opportunities for focused intervention to improve clinical outcomes.

Functional brain imaging in 14 patients with dissociative amnesia reveals right inferolateral prefrontal hypometabolism.

PubMed

Brand, Matthias; Eggers, Carsten; Reinhold, Nadine; Fujiwara, Esther; Kessler, Josef; Heiss, Wolf-Dieter; Markowitsch, Hans J

2009-10-30

Dissociative amnesia is a condition usually characterized by severely impaired retrograde memory functioning in the absence of structural brain damage. Recent case studies nevertheless found functional brain changes in patients suffering from autobiographical-episodic memory loss in the cause of dissociative amnesia. Functional changes were demonstrated in both resting state and memory retrieval conditions. In addition, some but not all cases also showed other neuropsychological impairments beyond retrograde memory deficits. However, there is no group study available that examined potential functional brain abnormalities and accompanying neuropsychological deteriorations in larger samples of patients with dissociative retrograde amnesia. We report functional imaging and neuropsychological data acquired in 14 patients with dissociative amnesia following stressful or traumatic events. All patients suffered from autobiographical memory loss. In addition, approximately half of the patients had deficits in anterograde memory and executive functioning. Accompanying functional brain changes were measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Regional glucose utilization of the patients was compared with that of 19 healthy subjects, matched for age and gender. We found significantly decreased glucose utilization in the right inferolateral prefrontal cortex in the patients. Hypometabolism in this brain region, known to be involved in retrieval of autobiographical memories and self-referential processing, may be a functional brain correlate of dissociative amnesia.

Effect of phase-encoding direction on group analysis of resting-state functional magnetic resonance imaging.

PubMed

Mori, Yasuo; Miyata, Jun; Isobe, Masanori; Son, Shuraku; Yoshihara, Yujiro; Aso, Toshihiko; Kouchiyama, Takanori; Murai, Toshiya; Takahashi, Hidehiko

2018-05-17

Echo-planar imaging is a common technique used in functional magnetic resonance imaging (fMRI), however it suffers from image distortion and signal loss because of large susceptibility effects that are related to the phase-encoding direction of the scan. Despite this relationship, the majority of neuroimaging studies have not considered the influence of phase-encoding direction. Here, we aimed to clarify how phase-encoding direction can affect the outcome of an fMRI connectivity study of schizophrenia. Resting-state fMRI using anterior to posterior (A-P) and posterior to anterior (P-A) directions was used to examine 25 patients with schizophrenia (SC) and 37 matched healthy controls (HC). We conducted a functional connectivity analysis using independent component analysis and performed three group comparisons: A-P vs. P-A (all participants), SC vs. HC for the A-P and P-A datasets, and the interaction between phase-encoding direction and participant group. The estimated functional connectivity differed between the two phase-encoding directions in areas that were more extensive than those where signal loss has been reported. Although functional connectivity in the SC group was lower than that in the HC group for both directions, the A-P and P-A conditions did not exhibit the same specific pattern of differences. Further, we observed an interaction between participant group and the phase-encoding direction in the left temporo-parietal junction and left fusiform gyrus. Phase-encoding direction can influence the results of functional connectivity studies. Thus, appropriate selection and documentation of phase-encoding direction will be important in future resting-state fMRI studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea

PubMed Central

Salehi, Pezhman; Gundimeda, Usha; Lael Cantu, Homero; Lavinsky, Joel; Myint, Anthony; Wang, Juemei; Abdala, Carolina; Ohyama, Takahiro; Coate, Thomas Matthew

2017-01-01

Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL. PMID:29059194

Simulating star clusters with the AMUSE software framework. I. Dependence of cluster lifetimes on model assumptions and cluster dissolution modes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whitehead, Alfred J.; McMillan, Stephen L. W.; Vesperini, Enrico

2013-12-01

We perform a series of simulations of evolving star clusters using the Astrophysical Multipurpose Software Environment (AMUSE), a new community-based multi-physics simulation package, and compare our results to existing work. These simulations model a star cluster beginning with a King model distribution and a selection of power-law initial mass functions and contain a tidal cutoff. They are evolved using collisional stellar dynamics and include mass loss due to stellar evolution. After studying and understanding that the differences between AMUSE results and results from previous studies are understood, we explored the variation in cluster lifetimes due to the random realization noisemore » introduced by transforming a King model to specific initial conditions. This random realization noise can affect the lifetime of a simulated star cluster by up to 30%. Two modes of star cluster dissolution were identified: a mass evolution curve that contains a runaway cluster dissolution with a sudden loss of mass, and a dissolution mode that does not contain this feature. We refer to these dissolution modes as 'dynamical' and 'relaxation' dominated, respectively. For Salpeter-like initial mass functions, we determined the boundary between these two modes in terms of the dynamical and relaxation timescales.« less

Losing grip: Senescent decline in physical strength in a small-bodied primate in captivity and in the wild.

PubMed

Hämäläinen, Anni; Dammhahn, Melanie; Aujard, Fabienne; Kraus, Cornelia

2015-01-01

Muscle strength reflects physical functioning, declines at old age and predicts health and survival in humans and laboratory animals. Age-associated muscle deterioration causes loss of strength and may impair fitness of wild animals. However, the effects of age and life-history characteristics on muscle strength in wild animals are unknown. We investigated environment- and sex-specific patterns of physical functioning by measuring grip strength in wild and captive gray mouse lemurs. We expected more pronounced strength senescence in captivity due to condition-dependent, extrinsic mortality found in nature. Males were predicted to be stronger but potentially experience more severe senescence than females as predicted by life history theory. We found similar senescent declines in captive males and females as well as wild females, whereas wild males showed little decline, presumably due to their early mortality. Captive animals were generally weaker and showed earlier declines than wild animals. Unexpectedly, females tended to be stronger than males, especially in the reproductive season. Universal intrinsic mechanisms (e.g. sarcopenia) likely cause the similar patterns of strength loss across settings. The female advantage in muscle strength merits further study; it may follow higher reproductive investment by males, or be an adaptation associated with female social dominance. Copyright © 2014 Elsevier Inc. All rights reserved.

The colours of humanity: the evolution of pigmentation in the human lineage.

PubMed

Jablonski, Nina G; Chaplin, George

2017-07-05

Humans are a colourful species of primate, with human skin, hair and eye coloration having been influenced by a great variety of evolutionary forces throughout prehistory. Functionally naked skin has been the physical interface between the physical environment and the human body for most of the history of the genus Homo , and hence skin coloration has been under intense natural selection. From an original condition of protective, dark, eumelanin-enriched coloration in early tropical-dwelling Homo and Homo sapiens , loss of melanin pigmentation occurred under natural selection as Homo sapiens dispersed into non-tropical latitudes of Africa and Eurasia. Genes responsible for skin, hair and eye coloration appear to have been affected significantly by population bottlenecks in the course of Homo sapiens dispersals. Because specific skin colour phenotypes can be created by different combinations of skin colour-associated genetic markers, loss of genetic variability due to genetic drift appears to have had negligible effects on the highly redundant genetic 'palette' for the skin colour. This does not appear to have been the case for hair and eye coloration, however, and these traits appear to have been more strongly influenced by genetic drift and, possibly, sexual selection.This article is part of the themed issue 'Animal coloration: production, perception, function and application'. © 2017 The Author(s).

Mass-loss rates of cool stars

NASA Astrophysics Data System (ADS)

Katrien Els Decin, Leen

2015-08-01

Over much of the initial mass function, stars lose a significant fraction of their mass through a stellar wind during the late stages of their evolution when being a (super)giant star. As of today, we can not yet predict the mass-loss rate during the (super)giant phase for a given star with specific stellar parameters from first principles. This uncertainty directly impacts the accuracy of current stellar evolution and population synthesis models that predict the enrichment of the interstellar medium by these stellar winds. Efforts to establish the link between the initial physical and chemical conditions at stellar birth and the mass-loss rate during the (super)giant phase have proceeded on two separate tracks: (1) more detailed studies of the chemical and morpho-kinematical structure of the stellar winds of (super)giant stars in our own Milky Way by virtue of the proximity, and (2) large scale and statistical studies of a (large) sample of stars in other galaxies (such as the LMC and SMC) and globular clusters eliminating the uncertainty on the distance estimate and providing insight into the dependence of the mass-loss rate on the metallicity. In this review, I will present recent results of both tracks, will show how recent measurements confirm (some) theoretical predictions, but also how results from the first track admonish of common misconceptions inherent in the often more simplified analysis used to analyse the large samples from track 2.

Suppressing aberrant GluN3A expression rescues NMDA receptor dysfunction, synapse loss and motor and cognitive decline in Huntington's disease models

PubMed Central

Marco, Sonia; Giralt, Albert; Petrovic, Milos M.; Pouladi, Mahmoud A.; Martínez-Turrillas, Rebeca; Martínez-Hernández, José; Kaltenbach, Linda S.; Torres-Peraza, Jesús; Graham, Rona K.; Watanabe, Masahiko; Luján, Rafael; Nakanishi, Nobuki; Lipton, Stuart A.; Lo, Donald C.; Hayden, Michael R.; Alberch, Jordi; Wesseling, John F.

2013-01-01

Huntington's disease is caused by an expanded polyglutamine repeat in huntingtin (Htt), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in NMDA-type glutamate receptors (NMDARs) have been implicated, yet it remains unclear how the Htt mutation impacts NMDAR function and direct evidence for a causative role is missing. Here we show that mutant Htt re-directs an intracellular store of juvenile NMDARs to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the GluN3A subunit-specific endocytic adaptor PACSIN1. Overexpressing GluN3A in wild-type striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline, and reduced striatal atrophy and neuronal loss in the YAC128 model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease, and suggest that therapies targeting GluN3A or pathogenic Htt-PACSIN1 interactions might prevent or delay disease progression. PMID:23852340

A mechanism of bone tissue loss in monkeys (BION - 11).

NASA Astrophysics Data System (ADS)

Rodionova, N. V.; Oganov, V. S.

The elucidation of mechanisms of bone tissue loss under the spaceflight conditions remains an actual problem until now It was established that primary reactions to a mechanical stress evolve at the cellular level therefore the main attention of the researchers was aimed at studying bone tissue cells and their interactions With the use of electron microscopy we studied osteoblasts osteocytes osteoclasts and stromal cells in bioptats of the iliac bone crest from monkeys flown on board the satellite guillemotleft BION - 11 guillemotright during 2 weeks The flight samples were compared with the vivarium and simulation controls The functional state of cells was evaluated by the degree of development of organelles for specific biosyntheses rough endoplasmic reticulum Golgy complex nucleus state interrelation with a mineralized matrix The analysis of the obtained results and data of other authors Klein -- Nulend et al 2003 etc permits to suppose that the following sequence of cell interactions underlies the bone tissue loss during mechanical stress microgravity reaction of mechano-sensitive osteocytes to a mechanical stimulus consisting in enhancement of osteolytic processes in cells which results in a partial bone tissue loss along the local unloading Simultaneously the modulating signals are transmitted through a system of canals and processes towards active osteoblasts surface osteocytes and bone marrow stromal cells as well As a reply to a mechanical stimulus there occurs a reduction slowing down of proliferation

Mutant Alleles of Photoperiod-1 in Wheat (Triticum aestivum L.) That Confer a Late Flowering Phenotype in Long Days

PubMed Central

Shaw, Lindsay M.; Turner, Adrian S.; Herry, Laurence; Griffiths, Simon; Laurie, David A.

2013-01-01

Flowering time in wheat and barley is known to be modified by mutations in the Photoperiod-1 (Ppd-1) gene. Semi-dominant Ppd-1a mutations conferring an early flowering phenotype are well documented in wheat but gene sequencing has also identified candidate loss of function mutations for Ppd-A1 and Ppd-D1. By analogy to the recessive ppd-H1 mutation in barley, loss of function mutations in wheat are predicted to delay flowering under long day conditions. To test this experimentally, introgression lines were developed in the spring wheat variety ‘Paragon’. Plants lacking a Ppd-B1 gene were identified from a gamma irradiated ‘Paragon’ population. These were crossed with the other introgression lines to generate plants with candidate loss of function mutations on one, two or three genomes. Lines lacking Ppd-B1 flowered 10 to 15 days later than controls under long days. Candidate loss of function Ppd-A1 alleles delayed flowering by 1 to 5 days while candidate loss of function Ppd-D1 alleles did not affect flowering time. Loss of Ppd-A1 gave an enhanced effect, and loss of Ppd-D1 became detectable in lines where Ppd-B1 was absent, indicating effects may be buffered by functional Ppd-1 alleles on other genomes. Expression analysis revealed that delayed flowering was associated with reduced expression of the TaFT1 gene and increased expression of TaCO1. A survey of the GEDIFLUX wheat collection grown in the UK and North Western Europe between the 1940s and 1980s and the A.E. Watkins global collection of landraces from the 1920s and 1930s showed that the identified candidate loss of function mutations for Ppd-D1 were common and widespread, while the identified candidate Ppd-A1 loss of function mutation was rare in countries around the Mediterranean and in the Far East but was common in North Western Europe. This may reflect a possible benefit of the latter in northern locations. PMID:24244507

Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome.

PubMed

Carbonneau, Élise; Royer, Marie-Michelle; Richard, Caroline; Couture, Patrick; Desroches, Sophie; Lemieux, Simone; Lamarche, Benoît

2017-03-19

The objective of this study was to investigate the impact of the Mediterranean diet (MedDiet) consumed before and after weight loss on eating behavioral traits as measured by the Three-Factor Eating Questionnaire (TFEQ) in men with metabolic syndrome (MetS). In this fixed sequence study, 19 men with MetS (National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria), aged between 24 and 62 years, first consumed a five-week standardized North American control diet followed by a five-week MedDiet, both under weight-maintaining controlled-feeding conditions. This was followed by a 20-week caloric restriction weight loss period in free-living conditions, without specific recommendations towards adhering to the principles of the MedDiet. Participants were finally subjected to a final five-week MedDiet phase under isoenergetic controlled-feeding conditions. The MedDiet before weight loss had no impact on eating behavioral traits. Body weight reduction by caloric restriction (-10.2% of initial weight) was associated with increased cognitive restraint ( p < 0.0001) and with reduced disinhibition ( p = 0.02) and susceptibility to hunger ( p = 0.01). Feeding the MedDiet for five weeks under isoenergetic conditions after the weight loss phase had no further impact on eating behavioral traits. Results of this controlled-feeding study suggest that consumption of the MedDiet per se has no effect on eating behavioral traits as measured by TFEQ, unless it is combined with significant weight loss.

Multiple drivers, scales, and interactions influence southern Appalachian stream salamander occupancy

USGS Publications Warehouse

Cecala, Kristen K.; Maerz, John C.; Halstead, Brian J.; Frisch, John R.; Gragson, Ted L.; Hepinstall-Cymerman, Jeffrey; Leigh, David S.; Jackson, C. Rhett; Peterson, James T.; Pringle, Catherine M.

2018-01-01

Understanding how factors that vary in spatial scale relate to population abundance is vital to forecasting species responses to environmental change. Stream and river ecosystems are inherently hierarchical, potentially resulting in organismal responses to fine‐scale changes in patch characteristics that are conditional on the watershed context. Here, we address how populations of two salamander species are affected by interactions among hierarchical processes operating at different scales within a rapidly changing landscape of the southern Appalachian Mountains. We modeled reach‐level occupancy of larval and adult black‐bellied salamanders (Desmognathus quadramaculatus) and larval Blue Ridge two‐lined salamanders (Eurycea wilderae) as a function of 17 different terrestrial and aquatic predictor variables that varied in spatial extent. We found that salamander occurrence varied widely among streams within fully forested catchments, but also exhibited species‐specific responses to changes in local conditions. While D. quadramaculatus declined predictably in relation to losses in forest cover, larval occupancy exhibited the strongest negative response to forest loss as well as decreases in elevation. Conversely, occupancy of E. wilderae was unassociated with watershed conditions, only responding negatively to higher proportions of fast‐flowing stream habitat types. Evaluation of hierarchical relationships demonstrated that most fine‐scale variables were closely correlated with broad watershed‐scale variables, suggesting that local reach‐scale factors have relatively smaller effects within the context of the larger landscape. Our results imply that effective management of southern Appalachian stream salamanders must first focus on the larger scale condition of watersheds before management of local‐scale conditions should proceed. Our findings confirm the results of some studies while refuting the results of others, which may indicate that prescriptive recommendations for range‐wide management of species or the application of a single management focus across large geographic areas is inappropriate.

Caloric Restriction in Older Adults-Differential Effects of Weight Loss and Reduced Weight on Brain Structure and Function.

PubMed

Prehn, Kristin; Jumpertz von Schwartzenberg, Reiner; Mai, Knut; Zeitz, Ulrike; Witte, A Veronica; Hampel, Dierk; Szela, Anna-Maria; Fabian, Sonja; Grittner, Ulrike; Spranger, Joachim; Flöel, Agnes

2017-03-01

Dietary modifications such as caloric restriction (CR) have been suggested as a means to improve memory and prevent age-related decline. However, it is unclear whether those effects remain stable over time or are related specifically to negative energy balance during the weight loss phase of CR. Using a randomized interventional design, we investigated changes in recognition memory and neural correlates in postmenopausal obese women (n = 19): 1) after intense weight loss in the course of a 12-week low-caloric diet (reduced body weight and negative energy balance) and 2) after having sustained the reduced weight over 4 more weeks (reduced body weight, but energy balance equilibrium). Participants were contrasted to a control group (n = 18) instructed not to change dietary habits. In the CR group, we found improved recognition memory, paralleled by increased gray matter volume in inferior frontal gyrus and hippocampus, and augmented hippocampal resting-state functional connectivity to parietal areas. Moreover, effects were specific for transient negative energy balance and could not be detected after subsequent weight maintenance. Our data demonstrate for the first time in humans that beneficial effects of CR on brain structure and function are due to weight loss rather than an overall reduced weight. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A Calcium Sensor-Regulated Protein Kinase, CALCINEURIN B-LIKE PROTEIN-INTERACTING PROTEIN KINASE19, Is Required for Pollen Tube Growth and Polarity1[OPEN

PubMed Central

Zhou, Liming; Lan, Wenzhi; Chen, Binqing; Fang, Wei; Luan, Sheng

2015-01-01

Calcium plays an essential role in pollen tube tip growth. However, little is known concerning the molecular basis of the signaling pathways involved. Here, we identified Arabidopsis (Arabidopsis thaliana) CALCINEURIN B-LIKE PROTEIN-INTERACTING PROTEIN KINASE19 (CIPK19) as an important element to pollen tube growth through a functional survey for CIPK family members. The CIPK19 gene was specifically expressed in pollen grains and pollen tubes, and its overexpression induced severe loss of polarity in pollen tube growth. In the CIPK19 loss-of-function mutant, tube growth and polarity were significantly impaired, as demonstrated by both in vitro and in vivo pollen tube growth assays. Genetic analysis indicated that disruption of CIPK19 resulted in a male-specific transmission defect. Furthermore, loss of polarity induced by CIPK19 overexpression was associated with elevated cytosolic Ca2+ throughout the bulging tip, whereas LaCl3, a Ca2+ influx blocker, rescued CIPK19 overexpression-induced growth inhibition. Our results suggest that CIPK19 may be involved in maintaining Ca2+ homeostasis through its potential function in the modulation of Ca2+ influx. PMID:25713341

Cryptic diversity and ecosystem functioning: a complex tale of differential effects on decomposition.

PubMed

De Meester, N; Gingold, R; Rigaux, A; Derycke, S; Moens, T

2016-10-01

Marine ecosystems are experiencing accelerating population and species loss. Some ecosystem functions are decreasing and there is growing interest in the link between biodiversity and ecosystem functioning. The role of cryptic (morphologically identical but genetically distinct) species in this biodiversity-ecosystem functioning link is unclear and has not yet been formally tested. We tested if there is a differential effect of four cryptic species of the bacterivorous nematode Litoditis marina on the decomposition process of macroalgae. Bacterivorous nematodes can stimulate or slow down bacterial activity and modify the bacterial assemblage composition. Moreover, we tested if interspecific interactions among the four cryptic species influence the decomposition process. A laboratory experiment with both mono- and multispecific nematode cultures was conducted, and loss of organic matter and the activity of two key extracellular enzymes for the degradation of phytodetritus were assessed. L. marina mainly influenced qualitative aspects of the decomposition process rather than its overall rate: an effect of the nematodes on the enzymatic activities became manifest, although no clear nematode effect on bulk organic matter weight loss was found. We also demonstrated that species-specific effects on the decomposition process existed. Combining the four cryptic species resulted in high competition, with one dominant species, but without complete exclusion of other species. These interspecific interactions translated into different effects on the decomposition process. The species-specific differences indicated that each cryptic species may play an important and distinct role in ecosystem functioning. Functional differences may result in coexistence among very similar species.

Effect of weight loss in obese dogs on indicators of renal function or disease.

PubMed

Tvarijonaviciute, A; Ceron, J J; Holden, S L; Biourge, V; Morris, P J; German, A J

2013-01-01

Obesity is a common medical disorder in dogs, and can predispose to a number of diseases. Human obesity is a risk factor for the development and progression of chronic kidney disease. To investigate the possible association of weight loss on plasma and renal biomarkers of kidney health. Thirty-seven obese dogs that lost weight were included in the study. Prospective observational study. Three novel biomarkers of renal functional impairment, disease, or both (homocysteine, cystatin C, and clusterin), in addition to traditional markers of chronic renal failure (serum urea and creatinine, urine specific gravity [USG], urine protein-creatinine ratio [UPCR], and urine albumin corrected by creatinine [UAC]) before and after weight loss in dogs with naturally occurring obesity were investigated. Urea (P = .043) and USG (P = .012) were both greater after weight loss than before loss, whilst UPCR, UAC, and creatinine were less after weight loss (P = .032, P = .006, and P = .026, respectively). Homocysteine (P < .001), cystatin C (P < .001) and clusterin (P < .001) all decreased upon weight loss. Multiple linear regression analysis revealed associations between percentage weight loss (greater weight loss, more lean tissue loss; r = -0.67, r(2) = 0.45, P < .001) and before-loss plasma clusterin concentration (greater clusterin, more lean tissue loss; r = 0.48, r(2) = 0.23, P = .003). These results suggest possible subclinical alterations in renal function in canine obesity, which improve with weight loss. Further work is required to determine the nature of these alterations and, most notably, the reason for the association between before loss plasma clusterin and subsequent lean tissue loss during weight management. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Large-Scale Variation in Combined Impacts of Canopy Loss and Disturbance on Community Structure and Ecosystem Functioning

PubMed Central

Crowe, Tasman P.; Cusson, Mathieu; Bulleri, Fabio; Davoult, Dominique; Arenas, Francisco; Aspden, Rebecca; Benedetti-Cecchi, Lisandro; Bevilacqua, Stanislao; Davidson, Irvine; Defew, Emma; Fraschetti, Simonetta; Golléty, Claire; Griffin, John N.; Herkül, Kristjan; Kotta, Jonne; Migné, Aline; Molis, Markus; Nicol, Sophie K.; Noël, Laure M-L J.; Pinto, Isabel Sousa; Valdivia, Nelson; Vaselli, Stefano; Jenkins, Stuart R.

2013-01-01

Ecosystems are under pressure from multiple human disturbances whose impact may vary depending on environmental context. We experimentally evaluated variation in the separate and combined effects of the loss of a key functional group (canopy algae) and physical disturbance on rocky shore ecosystems at nine locations across Europe. Multivariate community structure was initially affected (during the first three to six months) at six locations but after 18 months, effects were apparent at only three. Loss of canopy caused increases in cover of non-canopy algae in the three locations in southern Europe and decreases in some northern locations. Measures of ecosystem functioning (community respiration, gross primary productivity, net primary productivity) were affected by loss of canopy at five of the six locations for which data were available. Short-term effects on community respiration were widespread, but effects were rare after 18 months. Functional changes corresponded with changes in community structure and/or species richness at most locations and times sampled, but no single aspect of biodiversity was an effective predictor of longer-term functional changes. Most ecosystems studied were able to compensate in functional terms for impacts caused by indiscriminate physical disturbance. The only consistent effect of disturbance was to increase cover of non-canopy species. Loss of canopy algae temporarily reduced community resistance to disturbance at only two locations and at two locations actually increased resistance. Resistance to disturbance-induced changes in gross primary productivity was reduced by loss of canopy algae at four locations. Location-specific variation in the effects of the same stressors argues for flexible frameworks for the management of marine environments. These results also highlight the need to analyse how species loss and other stressors combine and interact in different environmental contexts. PMID:23799082

Large-scale variation in combined impacts of canopy loss and disturbance on community structure and ecosystem functioning.

PubMed

Crowe, Tasman P; Cusson, Mathieu; Bulleri, Fabio; Davoult, Dominique; Arenas, Francisco; Aspden, Rebecca; Benedetti-Cecchi, Lisandro; Bevilacqua, Stanislao; Davidson, Irvine; Defew, Emma; Fraschetti, Simonetta; Golléty, Claire; Griffin, John N; Herkül, Kristjan; Kotta, Jonne; Migné, Aline; Molis, Markus; Nicol, Sophie K; Noël, Laure M-L J; Pinto, Isabel Sousa; Valdivia, Nelson; Vaselli, Stefano; Jenkins, Stuart R

2013-01-01

Ecosystems are under pressure from multiple human disturbances whose impact may vary depending on environmental context. We experimentally evaluated variation in the separate and combined effects of the loss of a key functional group (canopy algae) and physical disturbance on rocky shore ecosystems at nine locations across Europe. Multivariate community structure was initially affected (during the first three to six months) at six locations but after 18 months, effects were apparent at only three. Loss of canopy caused increases in cover of non-canopy algae in the three locations in southern Europe and decreases in some northern locations. Measures of ecosystem functioning (community respiration, gross primary productivity, net primary productivity) were affected by loss of canopy at five of the six locations for which data were available. Short-term effects on community respiration were widespread, but effects were rare after 18 months. Functional changes corresponded with changes in community structure and/or species richness at most locations and times sampled, but no single aspect of biodiversity was an effective predictor of longer-term functional changes. Most ecosystems studied were able to compensate in functional terms for impacts caused by indiscriminate physical disturbance. The only consistent effect of disturbance was to increase cover of non-canopy species. Loss of canopy algae temporarily reduced community resistance to disturbance at only two locations and at two locations actually increased resistance. Resistance to disturbance-induced changes in gross primary productivity was reduced by loss of canopy algae at four locations. Location-specific variation in the effects of the same stressors argues for flexible frameworks for the management of marine environments. These results also highlight the need to analyse how species loss and other stressors combine and interact in different environmental contexts.

Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging.

PubMed

Wend, Korinna; Wend, Peter; Krum, Susan A

2012-01-01

The roles of estrogens have been best studied in the breast, breast cancers, and in the female reproductive tract. However, estrogens have important functions in almost every tissue in the body. Recent clinical trials such as the Women's Health Initiative have highlighted both the importance of estrogens and how little we know about the molecular mechanism of estrogens in these other tissues. In this review, we illustrate the diverse functions of estrogens in the bone, adipose tissue, skin, hair, brain, skeletal muscle and cardiovascular system, and how the loss of estrogens during aging affects these tissues. Early transcriptional targets of estrogen are reviewed in each tissue. We also describe the tissue-specific effects of selective estrogen receptor modulators (SERMs) used for the treatment of breast cancers and postmenopausal symptoms.

Plant litter functional diversity effects on litter mass loss depend on the macro-detritivore community.

PubMed

Patoine, Guillaume; Thakur, Madhav P; Friese, Julia; Nock, Charles; Hönig, Lydia; Haase, Josephine; Scherer-Lorenzen, Michael; Eisenhauer, Nico

2017-11-01

A better understanding of the mechanisms driving litter diversity effects on decomposition is needed to predict how biodiversity losses affect this crucial ecosystem process. In a microcosm study, we investigated the effects of litter functional diversity and two major groups of soil macro-detritivores on the mass loss of tree leaf litter mixtures. Furthermore, we tested the effects of litter trait community means and dissimilarity on litter mass loss for seven traits relevant to decomposition. We expected macro-detritivore effects on litter mass loss to be most pronounced in litter mixtures of high functional diversity. We used 24 leaf mixtures differing in functional diversity, which were composed of litter from four species from a pool of 16 common European tree species. Earthworms, isopods, or a combination of both were added to each litter combination for two months. Litter mass loss was significantly higher in the presence of earthworms than in that of isopods, whereas no synergistic effects of macro-detritivore mixtures were found. The effect of functional diversity of the litter material was highest in the presence of both macro-detritivore groups, supporting the notion that litter diversity effects are most pronounced in the presence of different detritivore species. Species-specific litter mass loss was explained by nutrient content, secondary compound concentration, and structural components. Moreover, dissimilarity in N concentrations increased litter mass loss, probably because detritivores having access to nutritionally diverse food sources. Furthermore, strong competition between the two macro-detritivores for soil surface litter resulted in a decrease of survival of both macro-detritivores. These results show that the effects of litter functional diversity on decomposition are contingent upon the macro-detritivore community and composition. We conclude that the temporal dynamics of litter trait diversity effects and their interaction with detritivore diversity are key to advancing our understanding of litter mass loss in nature.

Plant litter functional diversity effects on litter mass loss depend on the macro-detritivore community

PubMed Central

Patoine, Guillaume; Thakur, Madhav P.; Friese, Julia; Nock, Charles; Hönig, Lydia; Haase, Josephine; Scherer-Lorenzen, Michael; Eisenhauer, Nico

2017-01-01

A better understanding of the mechanisms driving litter diversity effects on decomposition is needed to predict how biodiversity losses affect this crucial ecosystem process. In a microcosm study, we investigated the effects of litter functional diversity and two major groups of soil macro-detritivores on the mass loss of tree leaf litter mixtures. Furthermore, we tested the effects of litter trait community means and dissimilarity on litter mass loss for seven traits relevant to decomposition. We expected macro-detritivore effects on litter mass loss to be most pronounced in litter mixtures of high functional diversity. We used 24 leaf mixtures differing in functional diversity, which were composed of litter from four species from a pool of 16 common European tree species. Earthworms, isopods, or a combination of both were added to each litter combination for two months. Litter mass loss was significantly higher in the presence of earthworms than in that of isopods, whereas no synergistic effects of macro-detritivore mixtures were found. The effect of functional diversity of the litter material was highest in the presence of both macro-detritivore groups, supporting the notion that litter diversity effects are most pronounced in the presence of different detritivore species. Species-specific litter mass loss was explained by nutrient content, secondary compound concentration, and structural components. Moreover, dissimilarity in N concentrations increased litter mass loss, probably because detritivores having access to nutritionally diverse food sources. Furthermore, strong competition between the two macro-detritivores for soil surface litter resulted in a decrease of survival of both macro-detritivores. These results show that the effects of litter functional diversity on decomposition are contingent upon the macro-detritivore community and composition. We conclude that the temporal dynamics of litter trait diversity effects and their interaction with detritivore diversity are key to advancing our understanding of litter mass loss in nature. PMID:29180828

SoxNeuro orchestrates central nervous system specification and differentiation in Drosophila and is only partially redundant with Dichaete

PubMed Central

2014-01-01

Background Sox proteins encompass an evolutionarily conserved family of transcription factors with critical roles in animal development and stem cell biology. In common with vertebrates, the Drosophila group B proteins SoxNeuro and Dichaete are involved in central nervous system development, where they play both similar and unique roles in gene regulation. Sox genes show extensive functional redundancy across metazoans, but the molecular basis underpinning functional compensation mechanisms at the genomic level are currently unknown. Results Using a combination of genome-wide binding analysis and gene expression profiling, we show that SoxNeuro directs embryonic neural development from the early specification of neuroblasts through to the terminal differentiation of neurons and glia. To address the issue of functional redundancy and compensation at a genomic level, we compare SoxNeuro and Dichaete binding, identifying common and independent binding events in wild-type conditions, as well as instances of compensation and loss of binding in mutant backgrounds. Conclusions We find that early aspects of group B Sox functions in the central nervous system, such as stem cell maintenance and dorsoventral patterning, are highly conserved. However, in contrast to vertebrates, we find that Drosophila group B1 proteins also play prominent roles during later aspects of neural morphogenesis. Our analysis of the functional relationship between SoxNeuro and Dichaete uncovers evidence for redundant and independent functions for each protein, along with unexpected examples of compensation and interdependency, thus providing new insights into the general issue of transcription factor functional redundancy. PMID:24886562

Genetics Home Reference: congenital hypothyroidism

MedlinePlus

... Facebook Twitter Home Health Conditions Congenital hypothyroidism Congenital hypothyroidism Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Congenital hypothyroidism is a partial or complete loss of function ...

Incipient balancing selection through adaptive loss of aquaporins in natural Saccharomyces cerevisiae populations.

PubMed

Will, Jessica L; Kim, Hyun Seok; Clarke, Jessica; Painter, John C; Fay, Justin C; Gasch, Audrey P

2010-04-01

A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw-tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function-providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments-contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection.

Obesity and Diabetes as Accelerators of Functional Decline; Can Lifestyle Interventions Maintain Functional Status in High Risk Older Adults?

PubMed Central

Anton, Stephen D.; Karabetian, Christy; Naugle, Kelly; Buford, Thomas W.

2013-01-01

Obesity and diabetes are known risk factors for the development of physical disability among older adults. With the number of seniors with these conditions rising worldwide, the prevention and treatment of physical disability in these persons has become a major public health challenge. Sarcopenia, the progressive loss of muscle mass and strength, has been identified as a common pathway associated with the initial onset and progression of physical disability among older adults. A growing body of evidence suggests that metabolic dysregulation associated with obesity and diabetes accelerates the progression of sarcopenia, and subsequently functional decline in older adults. The focus of this brief review is on the contributions of obesity and diabetes in accelerating sarcopenia and functional decline among older adults. We also briefly discuss the underexplored interaction between obesity and diabetes that may further accelerate sarcopenia and place obese older adults with diabetes at particularly high risk of disability. Finally, we review findings from studies that have specifically tested the efficacy of lifestyle-based interventions in maintaining the functional status of older persons with obesity and/or diabetes. PMID:23832077

Genetics Home Reference: DOORS syndrome

MedlinePlus

... reduce or eliminate the function of the TBC1D24 protein, but the specific mechanism by which loss of TBC1D24 function leads to the ... RC, Gibbs RA, Lee BH, Sisodiya SM. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 2014 Jan;13(1):44- ...

Applications of fibrous substrates containing insolubilized phase change polymers

NASA Technical Reports Server (NTRS)

Vigo, Tyrone L.; Bruno, Joseph S.

1993-01-01

Incorporation of polyethylene glycols into fibrous substrates produces several improved functional properties when they are insolubilized by crosslinking with a methylolamide resin or by polyacetal formation by their reaction with glyoxal. The range of molecular weights of polyols that may be insolubilized is broad as are the curing conditions (0.25-10 min at 80-200C). Most representative fiber types and blends (natural and synthetic) and all types of fabric constructions (woven, nonwoven and knit) have been modified by incorporation of the bound polyols. The most novel property is the thermal adaptability of the modified substrates to many climatic conditions. This adaptability is due to the high latent heat of the crosslinked polyols that function as phase change materials, the hydrophilic nature of the crosslinked polymer and its enhanced thermal conductivity. Other enhanced properties imparted to fabrics include flex and flat abrasion, antimicrobial activity, reduced static charge, resistance to oily soils, resiliency, wind resistance and reduced lint loss. Applications commercialized in the U.S. and Japan include sportswear and skiwear. Several examples of electric sets of properties useful for specific end uses are given. In addition, other uses are biomedical horticultural, aerospace, indoor insulation, automotive interiors and components and packaging material.

Applications of fibrous substrates containing insolubilized phase change polymers

NASA Astrophysics Data System (ADS)

Vigo, Tyrone L.; Bruno, Joseph S.

1993-02-01

Incorporation of polyethylene glycols into fibrous substrates produces several improved functional properties when they are insolubilized by crosslinking with a methylolamide resin or by polyacetal formation by their reaction with glyoxal. The range of molecular weights of polyols that may be insolubilized is broad as are the curing conditions (0.25-10 min at 80-200C). Most representative fiber types and blends (natural and synthetic) and all types of fabric constructions (woven, nonwoven and knit) have been modified by incorporation of the bound polyols. The most novel property is the thermal adaptability of the modified substrates to many climatic conditions. This adaptability is due to the high latent heat of the crosslinked polyols that function as phase change materials, the hydrophilic nature of the crosslinked polymer and its enhanced thermal conductivity. Other enhanced properties imparted to fabrics include flex and flat abrasion, antimicrobial activity, reduced static charge, resistance to oily soils, resiliency, wind resistance and reduced lint loss. Applications commercialized in the U.S. and Japan include sportswear and skiwear. Several examples of electric sets of properties useful for specific end uses are given. In addition, other uses are biomedical horticultural, aerospace, indoor insulation, automotive interiors and components and packaging material.

Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis.

PubMed

Ciura, Sorana; Lattante, Serena; Le Ber, Isabelle; Latouche, Morwena; Tostivint, Hervé; Brice, Alexis; Kabashi, Edor

2013-08-01

To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development. C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS/FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed. Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS/FTLD patients with normal-size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS/FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. © 2013 American Neurological Association.

Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals

PubMed Central

Charpentier, Caroline J.; Martino, Benedetto De; Sim, Alena L.; Sharot, Tali; Roiser, Jonathan P.

2016-01-01

Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of ‘neural loss aversion’, both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. PMID:26589451

LIMITED RECOVERY OF PINEAL FUNCTION AFTER REGENERATION OF PREGANGLIONIC SYMPATHETIC AXONS: EVIDENCE FOR LOSS OF GANGLIONIC SYNAPTIC SPECIFICITY

PubMed Central

Lingappa, Jaisri R.; Zigmond, Richard E.

2013-01-01

The cervical sympathetic trunks (CST) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCG). Since, regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCG. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm, with activity high at night, which is dependent on the gland’s sympathetic input. Thirty six hours after the CST were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day-night rhythm was present in lesioned animals. Neither the density of the gland’s adrenergic innervation nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CST. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not due to a quantitative deficit in the extent of reinnervation or in synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function. PMID:23486957

How the win-lose balance situation affects subsequent decision-making: functional magnetic resonance imaging evidence from a gambling task.

PubMed

Dong, G; Lin, X; Zhou, H; Lu, Q

2014-07-11

Humans have been consistently shown to be bad at making decisions, especially in disadvantageous situations. In this study, we designed a task that simulates real-life non-strategic gambling to examine the effect of win-lose balance situations (WIN, LOSS, TIE) on decision-making. In behavioral performances, participants showed shorter response time (RT) in LOSS than in WIN and TIE conditions. Imaging results revealed that decisions in WIN are associated with increased brain activations in the posterior cingulate cortex; decisions in LOSS are associated with increased brain activations in the insula and decreased activations in the inferior frontal gyrus (IFG). Positive correlation was found between brain activation in IFG and RT in LOSS. Overall, we concluded that, in disadvantageous conditions, participants are frustrated by their negative results and tend to make a random selection without full consideration. In advantageous conditions, participants' motivations to gamble are elicited and they tend to engage in more endeavors in making decisions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

GATA3 controls the specification of prosensory domain and neuronal survival in the mouse cochlea

PubMed Central

Luo, Xiong-jian; Deng, Min; Xie, Xiaoling; Huang, Liang; Wang, Hui; Jiang, Lichun; Liang, Guoqing; Hu, Fang; Tieu, Roger; Chen, Rui; Gan, Lin

2013-01-01

HDR syndrome (also known as Barakat syndrome) is a developmental disorder characterized by hypoparathyroidism, sensorineural deafness and renal disease. Although genetic mapping and subsequent functional studies indicate that GATA3 haplo-insufficiency causes human HDR syndrome, the role of Gata3 in sensorineural deafness and auditory system development is largely unknown. In this study, we show that Gata3 is continuously expressed in the developing mouse inner ear. Conditional knockout of Gata3 in the developing inner ear disrupts the morphogenesis of mouse inner ear, resulting in a disorganized and shortened cochlear duct with significant fewer hair cells and supporting cells. Loss of Gata3 function leads to the failure in the specification of prosensory domain and subsequently, to increased cell death in the cochlear duct. Moreover, though the initial generation of cochleovestibular ganglion (CVG) cells is not affected in Gata3-null mice, spiral ganglion neurons (SGNs) are nearly depleted due to apoptosis. Our results demonstrate the essential role of Gata3 in specifying the prosensory domain in the cochlea and in regulating the survival of SGNs, thus identifying a molecular mechanism underlying human HDR syndrome. PMID:23666531

The Mitochondrial DNA-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination.

PubMed

Blomme, Jonas; Van Aken, Olivier; Van Leene, Jelle; Jégu, Teddy; De Rycke, Riet; De Bruyne, Michiel; Vercruysse, Jasmien; Nolf, Jonah; Van Daele, Twiggy; De Milde, Liesbeth; Vermeersch, Mattias; des Francs-Small, Catherine Colas; De Jaeger, Geert; Benhamed, Moussa; Millar, A Harvey; Inzé, Dirk; Gonzalez, Nathalie

2017-05-01

In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Efficient DNA repair pathways are crucial in these organelles to fix damage resulting from endogenous and exogenous factors. Plant organellar genomes are complex compared with their animal counterparts, and although several plant-specific mediators of organelle DNA repair have been reported, many regulators remain to be identified. Here, we show that a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein, SWIB5, is capable of associating with mitochondrial DNA (mtDNA) in Arabidopsis thaliana Gain- and loss-of-function mutants provided evidence for a role of SWIB5 in influencing mtDNA architecture and homologous recombination at specific intermediate-sized repeats both under normal and genotoxic conditions. SWIB5 interacts with other mitochondrial SWIB proteins. Gene expression and mutant phenotypic analysis of SWIB5 and SWIB family members suggests a link between organellar genome maintenance and cell proliferation. Taken together, our work presents a protein family that influences mtDNA architecture and homologous recombination in plants and suggests a link between organelle functioning and plant development. © 2017 American Society of Plant Biologists. All rights reserved.

Analytical and experimental investigation on transmission loss of clamped double panels: implication of boundary effects.

PubMed

Xin, F X; Lu, T J

2009-03-01

The air-borne sound insulation performance of a rectangular double-panel partition clamp mounted on an infinite acoustic rigid baffle is investigated both analytically and experimentally and compared with that of a simply supported one. With the clamped (or simply supported) boundary accounted for by using the method of modal function, a double series solution for the sound transmission loss (STL) of the structure is obtained by employing the weighted residual (Galerkin) method. Experimental measurements with Al double-panel partitions having air cavity are subsequently carried out to validate the theoretical model for both types of the boundary condition, and good overall agreement is achieved. A consistency check of the two different models (based separately on clamped modal function and simply supported modal function) is performed by extending the panel dimensions to infinite where no boundaries exist. The significant discrepancies between the two different boundary conditions are demonstrated in terms of the STL versus frequency plots as well as the panel deflection mode shapes.

A pilot study of loss aversion for drug and non-drug commodities in cocaine users.

PubMed

Strickland, Justin C; Beckmann, Joshua S; Rush, Craig R; Stoops, William W

2017-11-01

Numerous studies in behavioral economics have demonstrated that individuals are more sensitive to the prospect of a loss than a gain (i.e., loss aversion). Although loss aversion has been well described in "healthy" populations, little research exists in individuals with substance use disorders. This gap is notable considering the prominent role that choice and decision-making play in drug use. The purpose of this pilot study was to evaluate loss aversion in active cocaine users. Current cocaine users (N=38; 42% female) participated in this within-subjects laboratory pilot study. Subjects completed a battery of tasks designed to assess loss aversion for drug and non-drug commodities under varying risk conditions. Standardized loss aversion coefficients (λ) were compared to theoretically and empirically relevant normative values (i.e., λ=2). Compared to normative loss aversion coefficient values, a precise and consistent decrease in loss aversion was observed in cocaine users (sample λ≈1). These values were observed across drug and non-drug commodities as well as under certain and risky conditions. These data represent the first systematic study of loss aversion in cocaine-using populations and provide evidence for equal sensitivity to losses and gains or loss equivalence. Futures studies should evaluate the specificity of these effects to a history of cocaine use as well as the impact of manipulations of loss aversion on drug use to determine how this phenomenon may contribute to intervention development efforts. Copyright © 2017 Elsevier B.V. All rights reserved.

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy

PubMed Central

Dees, Ellen; Miller, Paul M.; Moynihan, Katherine L.; Pooley, Ryan D.; Hunt, R. Pierre; Galindo, Cristi L.; Rottman, Jeffrey N.; Bader, David M.

2012-01-01

SUMMARY CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs. PMID:22563055

EEG activity as an objective measure of cognitive load during effortful listening: A study on pediatric subjects with bilateral, asymmetric sensorineural hearing loss.

PubMed

Marsella, Pasquale; Scorpecci, Alessandro; Cartocci, Giulia; Giannantonio, Sara; Maglione, Anton Giulio; Venuti, Isotta; Brizi, Ambra; Babiloni, Fabio

2017-08-01

Deaf subjects with hearing aids or cochlear implants generally find it challenging to understand speech in noisy environments where a great deal of listening effort and cognitive load are invested. In prelingually deaf children, such difficulties may have detrimental consequences on the learning process and, later in life, on academic performance. Despite the importance of such a topic, currently, there is no validated test for the assessment of cognitive load during audiological tasks. Recently, alpha and theta EEG rhythm variations in the parietal and frontal areas, respectively, have been used as indicators of cognitive load in adult subjects. The aim of the present study was to investigate, by means of EEG, the cognitive load of pediatric subjects affected by asymmetric sensorineural hearing loss as they were engaged in a speech-in-noise identification task. Seven children (4F and 3M, age range = 8-16 years) affected by asymmetric sensorineural hearing loss (i.e. profound degree on one side, mild-to-severe degree on the other side) and using a hearing aid only in their better ear, were included in the study. All of them underwent EEG recording during a speech-in-noise identification task: the experimental conditions were quiet, binaural noise, noise to the better hearing ear and noise to the poorer hearing ear. The subjects' Speech Recognition Thresholds (SRT) were also measured in each test condition. The primary outcome measures were: frontal EEG Power Spectral Density (PSD) in the theta band and parietal EEG PSD in the alpha band, as assessed before stimulus (word) onset. No statistically significant differences were noted among frontal theta power levels in the four test conditions. However, parietal alpha power levels were significantly higher in the "binaural noise" and in the "noise to worse hearing ear" conditions than in the "quiet" and "noise to better hearing ear" conditions (p < 0.001). SRT scores were consistent with task difficulty, but did not correlate with alpha and theta power level variations. This is the first time that EEG has been applied to children with sensorineural hearing loss with the purpose of studying the cognitive load during effortful listening. Significantly higher parietal alpha power levels in two of three noisy conditions, compared to the quiet condition, are consistent with increased cognitive load. Specifically, considering the time window of the analysis (pre-stimulus), parietal alpha power levels may be a measure of cognitive functions such as sustained attention and selective inhibition. In this respect, the significantly lower parietal alpha power levels in the most challenging listening condition (i.e. noise to the better ear) may be attributed to loss of attention and to the subsequent fatigue and "withdrawal" from the task at hand. Copyright © 2017 Elsevier B.V. All rights reserved.

Stationary bubbles and their tunneling channels toward trivial geometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Pisin; Yeom, Dong-han; Domènech, Guillem

2016-04-01

In the path integral approach, one has to sum over all histories that start from the same initial condition in order to obtain the final condition as a superposition of histories. Applying this into black hole dynamics, we consider stable and unstable stationary bubbles as a reasonable and regular initial condition. We find examples where the bubble can either form a black hole or tunnel toward a trivial geometry, i.e., with no singularity nor event horizon. We investigate the dynamics and tunneling channels of true vacuum bubbles for various tensions. In particular, in line with the idea of superposition ofmore » geometries, we build a classically stable stationary thin-shell solution in a Minkowski background where its fate is probabilistically given by non-perturbative effects. Since there exists a tunneling channel toward a trivial geometry in the entire path integral, the entire information is encoded in the wave function. This demonstrates that the unitarity is preserved and there is no loss of information when viewed from the entire wave function of the universe, whereas a semi-classical observer, who can see only a definitive geometry, would find an effective loss of information. This may provide a resolution to the information loss dilemma.« less

Stationary bubbles and their tunneling channels toward trivial geometry

DOE PAGES

Chen, Pisin; Domènech, Guillem; Sasaki, Misao; ...

2016-04-07

In the path integral approach, one has to sum over all histories that start from the same initial condition in order to obtain the final condition as a superposition of histories. Applying this into black hole dynamics, we consider stable and unstable stationary bubbles as a reasonable and regular initial condition. We find examples where the bubble can either form a black hole or tunnel toward a trivial geometry, i.e., with no singularity nor event horizon. We investigate the dynamics and tunneling channels of true vacuum bubbles for various tensions. In particular, in line with the idea of superposition ofmore » geometries, we build a classically stable stationary thin-shell solution in a Minkowski background where its fate is probabilistically given by non-perturbative effects. Since there exists a tunneling channel toward a trivial geometry in the entire path integral, the entire information is encoded in the wave function. This demonstrates that the unitarity is preserved and there is no loss of information when viewed from the entire wave function of the universe, whereas a semi-classical observer, who can see only a definitive geometry, would find an effective loss of information. Ultimately, this may provide a resolution to the information loss dilemma.« less

Apoptosis of Limb Innervating Motor Neurons and Erosion of Motor Pool Identity Upon Lineage Specific Dicer Inactivation

PubMed Central

Chen, Jun-An; Wichterle, Hynek

2012-01-01

Diversification of mammalian spinal motor neurons into hundreds of subtypes is critical for the maintenance of body posture and coordination of complex movements. Motor neuron differentiation is controlled by extrinsic signals that regulate intrinsic genetic programs specifying and consolidating motor neuron subtype identity. While transcription factors have been recognized as principal regulators of the intrinsic program, the role of posttranscriptional regulations has not been systematically tested. MicroRNAs produced by Dicer mediated cleavage of RNA hairpins contribute to gene regulation by posttranscriptional silencing. Here we used Olig2-cre conditional deletion of Dicer gene in motor neuron progenitors to examine effects of miRNA biogenesis disruption on postmitotic spinal motor neurons. We report that despite the initial increase in the number of motor neuron progenitors, disruption of Dicer function results in a loss of many limb- and sympathetic ganglia-innervating spinal motor neurons. Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties. PMID:22629237

Genetic Landscape of Auditory Dysfunction.

PubMed

Bowl, Michael R; Brown, S D M

2018-05-02

Over the past 25 years, human and mouse genetics research together has identified several hundred genes essential for mammalian hearing, leading to a greater understanding of the molecular mechanisms underlying auditory function. However, from the number of still as yet uncloned human deafness loci and the findings of large-scale mouse mutant screens, it is clear we are still far from identifying all of the genes critical for auditory function. In particular, while we have made great progress in understanding the genetic bases of congenital and early-onset hearing loss, we have only just begun to elaborate upon the genetic landscape of age-related hearing loss. With an aging population and a growing literature suggesting links between age-related hearing loss and neuropsychiatric conditions, such as dementia and depression, understanding the genetics and subsequently the molecular mechanisms underlying this very prevalent condition is of paramount importance. Increased knowledge of genes and molecular pathways required for hearing will ultimately provide the foundation upon which novel therapeutic approaches can be built. Here we discuss the current status of deafness genetics research and the ongoing efforts being undertaken for discovery of novel genes essential for hearing.

Test-specific control conditions for functional analyses.

PubMed

Fahmie, Tara A; Iwata, Brian A; Querim, Angie C; Harper, Jill M

2013-01-01

Most functional analyses of problem behavior include a common condition (play or noncontingent reinforcement) as a control for both positive and negative reinforcement. However, test-specific conditions that control for each potential source of reinforcement may be beneficial occasionally. We compared responding during alone, ignore, play, and differential reinforcement of other behavior (DRO) control conditions for individuals whose problem behavior was maintained by positive or negative reinforcement. Results showed that all of the conditions were effective controls for problem behavior maintained by positive reinforcement; however, the DRO condition was consistently ineffective as a control for problem behavior maintained by negative reinforcement. Implications for the design of functional analyses and future research are discussed. © Society for the Experimental Analysis of Behavior.

High-Throughput Identification of Loss-of-Function Mutations for Anti-Interferon Activity in the Influenza A Virus NS Segment

PubMed Central

Wu, Nicholas C.; Young, Arthur P.; Al-Mawsawi, Laith Q.; Olson, C. Anders; Feng, Jun; Qi, Hangfei; Luan, Harding H.; Li, Xinmin; Wu, Ting-Ting

2014-01-01

ABSTRACT Viral proteins often display several functions which require multiple assays to dissect their genetic basis. Here, we describe a systematic approach to screen for loss-of-function mutations that confer a fitness disadvantage under a specified growth condition. Our methodology was achieved by genetically monitoring a mutant library under two growth conditions, with and without interferon, by deep sequencing. We employed a molecular tagging technique to distinguish true mutations from sequencing error. This approach enabled us to identify mutations that were negatively selected against, in addition to those that were positively selected for. Using this technique, we identified loss-of-function mutations in the influenza A virus NS segment that were sensitive to type I interferon in a high-throughput fashion. Mechanistic characterization further showed that a single substitution, D92Y, resulted in the inability of NS to inhibit RIG-I ubiquitination. The approach described in this study can be applied under any specified condition for any virus that can be genetically manipulated. IMPORTANCE Traditional genetics focuses on a single genotype-phenotype relationship, whereas high-throughput genetics permits phenotypic characterization of numerous mutants in parallel. High-throughput genetics often involves monitoring of a mutant library with deep sequencing. However, deep sequencing suffers from a high error rate (∼0.1 to 1%), which is usually higher than the occurrence frequency for individual point mutations within a mutant library. Therefore, only mutations that confer a fitness advantage can be identified with confidence due to an enrichment in the occurrence frequency. In contrast, it is impossible to identify deleterious mutations using most next-generation sequencing techniques. In this study, we have applied a molecular tagging technique to distinguish true mutations from sequencing errors. It enabled us to identify mutations that underwent negative selection, in addition to mutations that experienced positive selection. This study provides a proof of concept by screening for loss-of-function mutations on the influenza A virus NS segment that are involved in its anti-interferon activity. PMID:24965464

Neural tube closure depends on expression of Grainyhead-like 3 in multiple tissues.

PubMed

De Castro, Sandra C P; Hirst, Caroline S; Savery, Dawn; Rolo, Ana; Lickert, Heiko; Andersen, Bogi; Copp, Andrew J; Greene, Nicholas D E

2018-03-15

Failure of neural tube closure leads to neural tube defects (NTDs), common congenital abnormalities in humans. Among the genes whose loss of function causes NTDs in mice, Grainyhead-like3 (Grhl3) is essential for spinal neural tube closure, with null mutants exhibiting fully penetrant spina bifida. During spinal neurulation Grhl3 is initially expressed in the surface (non-neural) ectoderm, subsequently in the neuroepithelial component of the neural folds and at the node-streak border, and finally in the hindgut endoderm. Here, we show that endoderm-specific knockout of Grhl3 causes late-arising spinal NTDs, preceded by increased ventral curvature of the caudal region which was shown previously to suppress closure of the spinal neural folds. This finding supports the hypothesis that diminished Grhl3 expression in the hindgut is the cause of spinal NTDs in the curly tail, carrying a hypomorphic Grhl3 allele. Complete loss of Grhl3 function produces a more severe phenotype in which closure fails earlier in neurulation, before the stage of onset of expression in the hindgut of wild-type embryos. This implicates additional tissues and NTD mechanisms in Grhl3 null embryos. Conditional knockout of Grhl3 in the neural plate and node-streak border has minimal effect on closure, suggesting that abnormal function of surface ectoderm, where Grhl3 transcripts are first detected, is primarily responsible for early failure of spinal neurulation in Grhl3 null embryos. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Decision-making after continuous wins or losses in a randomized guessing task: implications for how the prior selection results affect subsequent decision-making

PubMed Central

2014-01-01

Background Human decision-making is often affected by prior selections and their outcomes, even in situations where decisions are independent and outcomes are unpredictable. Methods In this study, we created a task that simulated real-life non-strategic gambling to examine the effect of prior outcomes on subsequent decisions in a group of male college students. Results Behavioral performance showed that participants needed more time to react after continuous losses (LOSS) than continuous wins (WIN) and discontinuous outcomes (CONTROL). In addition, participants were more likely to repeat their selections in both WIN and LOSS conditions. Functional MRI data revealed that decisions in WINs were associated with increased activation in the mesolimbic pathway, but decreased activation in the inferior frontal gyrus relative to LOSS. Increased prefrontal cortical activation was observed during LOSS relative to WIN and CONTROL conditions. Conclusion Taken together, the behavioral and neuroimaging findings suggest that participants tended to repeat previous selections during LOSS trials, a pattern resembling the gambler’s fallacy. However, during WIN trials, participants tended to follow their previous lucky decisions, like the ‘hot hand’ fallacy. PMID:24708897

Determinants of Propranolol's Selective Effect on Loss Aversion.

PubMed

Sokol-Hessner, Peter; Lackovic, Sandra F; Tobe, Russell H; Camerer, Colin F; Leventhal, Bennett L; Phelps, Elizabeth A

2015-07-01

Research on emotion and decision making has suggested that arousal mediates risky decisions, but several distinct and often confounded processes drive such choices. We used econometric modeling to separate and quantify the unique contributions of loss aversion, risk attitudes, and choice consistency to risky decision making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention's pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e., as a function of initial loss aversion and body mass index), and did not affect risk attitudes or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of emotion and risky decision making. © The Author(s) 2015.

CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes

PubMed Central

Teng, Beina; Schroder, Patricia; Müller-Deile, Janina; Schenk, Heiko; Staggs, Lynne; Tossidou, Irini; Dikic, Ivan; Haller, Hermann

2016-01-01

Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. Podocytes are important for glomerular filtration barrier function and maintenance of size selectivity in protein filtration in the kidney. Podocyte damage is the basis of many glomerular diseases characterized by loss of interdigitating foot processes and decreased expression of components of the slit diaphragm. Nephrin, a podocyte-specific protein, is the main component of the slit diaphragm. Loss of nephrin is observed in human and rodent models of diabetic kidney disease. The long isoform of CIN85 (RukL) is a binding partner of nephrin that mediates nephrin endocytosis via ubiquitination in podocytes. Here we demonstrate that the loss of nephrin expression and the onset of proteinuria in diabetic mice correlate with an increased accumulation of ubiquitinated proteins and expression of CIN85/RukL in podocytes. CIN85/RukL deficiency preserved nephrin surface expression on the slit diaphragm and reduced proteinuria in diabetic mice, whereas overexpression of CIN85 in zebrafish induced severe edema and disruption of the filtration barrier. Thus, CIN85/RukL is involved in endocytosis of nephrin in podocytes under diabetic conditions, causing podocyte depletion and promoting proteinuria. CIN85/RukL expression therefore shows potential to be a novel target for antiproteinuric therapy in diabetes. PMID:27531950

Memory enhancing drugs and Alzheimer's disease: enhancing the self or preventing the loss of it?

PubMed

Dekkers, Wim; Rikkert, Marcel Olde

2007-06-01

In this paper we analyse some ethical and philosophical questions related to the development of memory enhancing drugs (MEDs) and anti-dementia drugs. The world of memory enhancement is coloured by utopian thinking and by the desire for quicker, sharper, and more reliable memories. Dementia is characterized by decline, fragility, vulnerability, a loss of the most important cognitive functions and even a loss of self. While MEDs are being developed for self-improvement, in Alzheimer's Disease (AD) the self is being lost. Despite this it is precisely those patients with AD and other forms of dementia that provide the subjects for scientific research on memory improvement. Biomedical research in the field of MEDs and anti-dementia drugs appears to provide a strong impetus for rethinking what we mean by 'memory', 'enhancement', 'therapy', and 'self'. We conclude (1) that the enhancement of memory is still in its infancy, (2) that current MEDs and anti-dementia drugs are at best partially and minimally effective under specific conditions, (3) that 'memory' and 'enhancement' are ambiguous terms, (4) that there is no clear-cut distinction between enhancement and therapy, and (5) that the research into MEDs and anti-dementia drugs encourages a reductionistic view of the human mind and of the self.

Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

PubMed Central

Kramer, Edgar R; Aron, Liviu; Ramakers, Geert M. J; Seitz, Sabine; Zhuang, Xiaoxi; Beyer, Klaus; Smidt, Marten P; Klein, Rüdiger

2007-01-01

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD. PMID:17298183

Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1.

PubMed

Seitz, Tina; Stalmann, Robert; Dalila, Nawar; Chen, Jiayin; Pojar, Sherin; Dos Santos Pereira, Joao N; Krätzner, Ralph; Brockmöller, Jürgen; Tzvetkov, Mladen V

2015-01-01

The organic cation transporter OCT1 (SLC22A1) mediates the uptake of vitamin B1, cationic drugs, and xenobiotics into hepatocytes. Nine percent of Caucasians lack or have very low OCT1 activity due to loss-of-function polymorphisms in OCT1 gene. Here we analyzed the global genetic variability in OCT1 to estimate the therapeutic relevance of OCT1 polymorphisms in populations beyond Caucasians and to identify evolutionary patterns of the common loss of OCT1 activity in humans. We applied massively parallel sequencing to screen for coding polymorphisms in 1,079 unrelated individuals from 53 populations worldwide. The obtained data was combined with the existing 1000 Genomes data comprising an additional 1,092 individuals from 14 populations. The identified OCT1 variants were characterized in vitro regarding their cellular localization and their ability to transport 10 known OCT1 substrates. Both the population genetics data and transport data were used in tandem to generate a world map of loss of OCT1 activity. We identified 16 amino acid substitutions potentially causing loss of OCT1 function and analyzed them together with five amino acid substitutions that were not expected to affect OCT1 function. The variants constituted 16 major alleles and 14 sub-alleles. Six major alleles showed improper subcellular localization leading to substrate-wide loss in activity. Five major alleles showed correct subcellular localization, but substrate-specific loss of activity. Striking differences were observed in the frequency of loss of OCT1 activity worldwide. While most East Asian and Oceanian individuals had completely functional OCT1, 80 % of native South American Indians lacked functional OCT1 alleles. In East Asia and Oceania the average nucleotide diversity of the loss-of-function variants was much lower than that of the variants that do not affect OCT1 function (ratio of 0.03) and was significantly lower than the theoretically expected heterozygosity (Tajima's D = -1.64, P < 0.01). Comprehensive genetic analyses showed strong global variations in the frequency of loss of OCT1 activity with selection pressure for maintaining OCT1 activity in East Asia and Oceania. These results not only enable pharmacogenetically-based optimization of drug treatment worldwide, but may help elucidate the functional role of human OCT1.

Malnutrition in postacute geriatric care: Basic ESPEN diagnosis and etiology based diagnoses analyzed by length of stay, in-hospital mortality, and functional rehabilitation indexes.

PubMed

Sánchez-Rodríguez, Dolores; Marco, Ester; Annweiler, Cédric; Ronquillo-Moreno, Natalia; Tortosa, Andrea; Vázquez-Ibar, Olga; Escalada, Ferran; Duran, Xavier; Muniesa, Josep M

2017-11-01

To determine the relationships between malnutrition and nutrition-related conditions according to the European Society of Clinical Nutrition and Metabolism (ESPEN) consensus and guidelines and clinical outcomes in postacute rehabilitation. Of 102 eligible inpatients, 95 (84.5 years old, 63.2% women) fulfilled inclusion criteria: aged ≥70 years, body mass index <30kg/m 2 , admission for rehabilitation. Mini-Nutritional Assessment-Short Form (MNA-SF≤11) identified patients "at risk" and ESPEN basic and etiology based definitions were applied. Nutrition-related conditions (sarcopenia, frailty, overweight/obesity, micronutrient abnormalities) were determined. We assessed the relationship between these conditions and the clinical and rehabilitation outcomes (relative functional gain, rehabilitation efficiency) during hospitalization. All patients were "at risk" by MNA-SF criteria and 31 reported unintentional weight loss >5% in the last year or 2-3kg in the last 6 months. Nineteen fulfilled the ESPEN basic definition, of which 10 had disease-related malnutrition with inflammation and 9 without inflammation, and 20 had cachexia. Sarcopenia (n=44), frailty (n=94), overweight/obesity (n=59), and micronutrient abnormalities (n=70) were frequent. Unintentional weight loss impaired all functional outcomes and increased length of stay [OR=6.04 (2.87-9.22); p<0.001]. In multivariate analysis, relationships between rehabilitation impact indices and the ESPEN basic and etiology-based definitions observed in univariate analysis persisted only (and marginally) for relative functional gain [OR=13.24 (0.96-181.95); p=0.005]. Infrequent in-hospital mortality prevented meaningful analysis of this outcome. ESPEN basic and etiology-based definitions and nutrition related disorders were determined in postacute care. Malnutrition was associated with poor rehabilitation outcomes, mainly due to unintentional weight loss. Copyright © 2017 Elsevier B.V. All rights reserved.

On the Relative Relevance of Subject-Specific Geometries and Degeneration-Specific Mechanical Properties for the Study of Cell Death in Human Intervertebral Disk Models

PubMed Central

Malandrino, Andrea; Pozo, José M.; Castro-Mateos, Isaac; Frangi, Alejandro F.; van Rijsbergen, Marc M.; Ito, Keita; Wilke, Hans-Joachim; Dao, Tien Tuan; Ho Ba Tho, Marie-Christine; Noailly, Jérôme

2015-01-01

Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro-mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration-dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration. PMID:25717471

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function

PubMed Central

Sharma, Aarti; Lyashchenko, Alexander K.; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z.; Shneider, Neil A.

2016-01-01

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. PMID:26842965

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

PubMed

Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

2016-02-04

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

Quantification of flash flood economic risk using ultra-detailed stage-damage functions and 2-D hydraulic models

NASA Astrophysics Data System (ADS)

Garrote, J.; Alvarenga, F. M.; Díez-Herrero, A.

2016-10-01

The village of Pajares de Pedraza (Segovia, Spain) is located in the floodplain of the Cega River, a left bank tributary of the Douro River. Repeated flash flood events occur in this small village because of its upstream catchment area, mountainous character and impermeable lithology, which reduce concentration time to just a few hours. River overbank flow has frequently caused flooding and property damage to homes and rural properties, most notably in 1927, 1991, 1996, 2001, 2013 and 2014. Consequently, a detailed analysis was carried out to quantify the economic risk of flash floods in peri-urban and rural areas. Magnitudes and exceedance probabilities were obtained from a flood frequency analysis of maximum discharges. To determine the extent and characteristics of the flooded area, we performed 2D hydraulic modeling (Iber 2.0 software) based on LIDAR (1 m) topography and considering three different scenarios associated with the initial construction (1997) and subsequent extension (2013) of a linear defense structure (rockfill dike or levee) to protect the population. Specific stage-damage functions were expressly developed using in situ data collection for exposed elements, with special emphasis on urban-type categories. The average number of elements and their unit value were established. The relationship between water depth and the height at which electric outlets, furniture, household goods, etc. were located was analyzed; due to its effect on the form of the function. Other nonspecific magnitude-damage functions were used in order to compare both economic estimates. The results indicate that the use of non-specific magnitude-damage functions leads to a significant overestimation of economic losses, partly linked to the use of general economic cost data. Furthermore, a detailed classification and financial assessment of exposed assets is the most important step to ensure a correct estimate of financial losses. In both cases, this should include a consideration of the socio-economic and cultural conditions prevailing in the area, as well as the types of flood that affect it.

Quantile Regression for Analyzing Heterogeneity in Ultra-high Dimension

PubMed Central

Wang, Lan; Wu, Yichao

2012-01-01

Ultra-high dimensional data often display heterogeneity due to either heteroscedastic variance or other forms of non-location-scale covariate effects. To accommodate heterogeneity, we advocate a more general interpretation of sparsity which assumes that only a small number of covariates influence the conditional distribution of the response variable given all candidate covariates; however, the sets of relevant covariates may differ when we consider different segments of the conditional distribution. In this framework, we investigate the methodology and theory of nonconvex penalized quantile regression in ultra-high dimension. The proposed approach has two distinctive features: (1) it enables us to explore the entire conditional distribution of the response variable given the ultra-high dimensional covariates and provides a more realistic picture of the sparsity pattern; (2) it requires substantially weaker conditions compared with alternative methods in the literature; thus, it greatly alleviates the difficulty of model checking in the ultra-high dimension. In theoretic development, it is challenging to deal with both the nonsmooth loss function and the nonconvex penalty function in ultra-high dimensional parameter space. We introduce a novel sufficient optimality condition which relies on a convex differencing representation of the penalized loss function and the subdifferential calculus. Exploring this optimality condition enables us to establish the oracle property for sparse quantile regression in the ultra-high dimension under relaxed conditions. The proposed method greatly enhances existing tools for ultra-high dimensional data analysis. Monte Carlo simulations demonstrate the usefulness of the proposed procedure. The real data example we analyzed demonstrates that the new approach reveals substantially more information compared with alternative methods. PMID:23082036

MOLD SPECIFIC QUANTITATIVE PCR FOR RAPID IDENTIFICATION AND ENUMERATION

EPA Science Inventory

There is growing awareness that indoor molds/fungi may be connected to such conditions as asthma, allergies, hemorrhaging, chronic rhinosinusitis, memory loss, and a symptom complex called sick-building-syndrome. In addition, molds cause frequently fatal nosocomical infections. ...

IP3R-mediated Ca2+ release regulates protein metabolism in Drosophila neuroendocrine cells: implications for development under nutrient stress.

PubMed

Megha; Hasan, Gaiti

2017-04-15

Successful completion of animal development is fundamentally reliant on nutritional cues. Surviving periods of nutritional insufficiency requires adaptations that are coordinated, in part, by neural circuits. As neuropeptides secreted by neuroendocrine (NE) cells modulate neural circuits, we investigated NE cell function during development under nutrient stress. Starved Drosophila larvae exhibited reduced pupariation if either insulin signaling or IP 3 /Ca 2+ signaling were downregulated in NE cells. Moreover, an IP 3 R (inositol 1,4,5-trisphosphate receptor) loss-of-function mutant displayed reduced protein synthesis, which was rescued by overexpression of either InR (insulin receptor) or IP 3 R in NE cells of the mutant, suggesting that the two signaling pathways might be functionally compensatory. Furthermore, cultured IP 3 R mutant NE cells, but not neurons, exhibited reduced protein translation. Thus cell-specific regulation of protein synthesis by IP 3 R in NE cells influences protein metabolism. We propose that this regulation helps developing animals survive in poor nutritional conditions. © 2017. Published by The Company of Biologists Ltd.

MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes.

PubMed

Ardestani, Amin; Paroni, Federico; Azizi, Zahra; Kaur, Supreet; Khobragade, Vrushali; Yuan, Ting; Frogne, Thomas; Tao, Wufan; Oberholzer, Jose; Pattou, Francois; Conte, Julie Kerr; Maedler, Kathrin

2014-04-01

Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction are urgently needed. Here, we identified mammalian sterile 20-like kinase-1 (MST1) as a critical regulator of apoptotic beta cell death and function. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes.

3D Cultivation Techniques for Primary Human Hepatocytes

PubMed Central

Bachmann, Anastasia; Moll, Matthias; Gottwald, Eric; Nies, Cordula; Zantl, Roman; Wagner, Helga; Burkhardt, Britta; Sánchez, Juan J. Martínez; Ladurner, Ruth; Thasler, Wolfgang; Damm, Georg; Nussler, Andreas K.

2015-01-01

One of the main challenges in drug development is the prediction of in vivo toxicity based on in vitro data. The standard cultivation system for primary human hepatocytes is based on monolayer cultures, even if it is known that these conditions result in a loss of hepatocyte morphology and of liver-specific functions, such as drug-metabolizing enzymes and transporters. As it has been demonstrated that hepatocytes embedded between two sheets of collagen maintain their function, various hydrogels and scaffolds for the 3D cultivation of hepatocytes have been developed. To further improve or maintain hepatic functions, 3D cultivation has been combined with perfusion. In this manuscript, we discuss the benefits and drawbacks of different 3D microfluidic devices. For most systems that are currently available, the main issues are the requirement of large cell numbers, the low throughput, and expensive equipment, which render these devices unattractive for research and the drug-developing industry. A higher acceptance of these devices could be achieved by their simplification and their compatibility with high-throughput, as both aspects are of major importance for a user-friendly device. PMID:27600213

Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome

PubMed Central

Carbonneau, Élise; Royer, Marie-Michelle; Richard, Caroline; Couture, Patrick; Desroches, Sophie; Lemieux, Simone; Lamarche, Benoît

2017-01-01

The objective of this study was to investigate the impact of the Mediterranean diet (MedDiet) consumed before and after weight loss on eating behavioral traits as measured by the Three-Factor Eating Questionnaire (TFEQ) in men with metabolic syndrome (MetS). In this fixed sequence study, 19 men with MetS (National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria), aged between 24 and 62 years, first consumed a five-week standardized North American control diet followed by a five-week MedDiet, both under weight-maintaining controlled-feeding conditions. This was followed by a 20-week caloric restriction weight loss period in free-living conditions, without specific recommendations towards adhering to the principles of the MedDiet. Participants were finally subjected to a final five-week MedDiet phase under isoenergetic controlled-feeding conditions. The MedDiet before weight loss had no impact on eating behavioral traits. Body weight reduction by caloric restriction (−10.2% of initial weight) was associated with increased cognitive restraint (p < 0.0001) and with reduced disinhibition (p = 0.02) and susceptibility to hunger (p = 0.01). Feeding the MedDiet for five weeks under isoenergetic conditions after the weight loss phase had no further impact on eating behavioral traits. Results of this controlled-feeding study suggest that consumption of the MedDiet per se has no effect on eating behavioral traits as measured by TFEQ, unless it is combined with significant weight loss. PMID:28335489

[Treatment with nutrition and fluids in patients with non-curable cancer].

PubMed

Nordøy, Tone; Thoresen, Lene; Kvikstad, Anne; Svensen, Rune

2006-02-23

Patients with non-curable cancer represent a large and heterogeneous group in which malnutrition and weight loss is a frequent finding. This article is based on relevant literature and our own clinical experience. For every patient a thorough examination of possible underlying causes should be explored and corrected as soon as possible (secondary cachexia). However, in many patients primary cachexia is the cause, a catabolic condition where muscle protein and lipids are degraded and even aggressive nutrition will not reverse the process. This condition is very different from starvation. Metoclopramide, corticosteroids and gestagens can relieve symptoms as anorexia, chronic nausea and asthenia which frequently occur in patients with cachexia. Treatments that may maintain or increase muscle function and modulate inflammatory processes are new approaches, such as eicosapentaneoic acid, adenosine triphosphate, specific amino acids and nonsteroidal antiinflammatory drugs. Nutrition is an integrated part of supportive therapy to all cancer patients, unless expected survival is short. At this time in life, nutrition will not influence survival and focus should be on symptom control.

Disordered Cold Regulated15 Proteins Protect Chloroplast Membranes during Freezing through Binding and Folding, But Do Not Stabilize Chloroplast Enzymes in Vivo1[W][OPEN

PubMed Central

Thalhammer, Anja; Bryant, Gary; Sulpice, Ronan; Hincha, Dirk K.

2014-01-01

Freezing can severely damage plants, limiting geographical distribution of natural populations and leading to major agronomical losses. Plants native to cold climates acquire increased freezing tolerance during exposure to low nonfreezing temperatures in a process termed cold acclimation. This involves many adaptative responses, including global changes in metabolite content and gene expression, and the accumulation of cold-regulated (COR) proteins, whose functions are largely unknown. Here we report that the chloroplast proteins COR15A and COR15B are necessary for full cold acclimation in Arabidopsis (Arabidopsis thaliana). They protect cell membranes, as indicated by electrolyte leakage and chlorophyll fluorescence measurements. Recombinant COR15 proteins stabilize lactate dehydrogenase during freezing in vitro. However, a transgenic approach shows that they have no influence on the stability of selected plastidic enzymes in vivo, although cold acclimation results in increased enzyme stability. This indicates that enzymes are stabilized by other mechanisms. Recombinant COR15 proteins are disordered in water, but fold into amphipathic α-helices at high osmolyte concentrations in the presence of membranes, a condition mimicking molecular crowding induced by dehydration during freezing. X-ray scattering experiments indicate protein-membrane interactions specifically under such crowding conditions. The COR15-membrane interactions lead to liposome stabilization during freezing. Collectively, our data demonstrate the requirement for COR15 accumulation for full cold acclimation of Arabidopsis. The function of these intrinsically disordered proteins is the stabilization of chloroplast membranes during freezing through a folding and binding mechanism, but not the stabilization of chloroplastic enzymes. This indicates a high functional specificity of these disordered plant proteins. PMID:25096979

T-Box Genes in the Kidney and Urinary Tract.

PubMed

Kispert, A

2017-01-01

T-box (Tbx) genes encode an ancient group of transcription factors that play important roles in patterning, specification, proliferation, and differentiation programs in vertebrate organogenesis. This is testified by severe organ malformation syndromes in mice homozygous for engineered null alleles of specific T-box genes and by the large number of human inherited organ-specific diseases that have been linked to mutations in these genes. One of the organ systems that has not been associated with loss of specific T-box gene function in human disease for long is the excretory system. However, this has changed with the finding that mutations in TBX18, a member of a vertebrate-specific subgroup within the Tbx1-subfamily of T-box transcription factor genes, cause congenital anomalies of the kidney and urinary tract, predominantly hydroureter and ureteropelvic junction obstruction. Gene expression analyses, loss-of-function studies, and lineage tracing in the mouse suggest a primary role for this transcription factor in specifying the ureteric mesenchyme in the common anlage of the kidney, the ureter, and the bladder. We review the function of Tbx18 in ureterogenesis and discuss the body of evidence that Tbx18 and other members of the T-box gene family, namely, Tbx1, Tbx2, Tbx3, and Tbx20, play additional roles in development and homeostasis of other components of the excretory system in vertebrates. © 2017 Elsevier Inc. All rights reserved.

Segregated and integrated coding of reward and punishment in the cingulate cortex.

PubMed

Fujiwara, Juri; Tobler, Philippe N; Taira, Masato; Iijima, Toshio; Tsutsui, Ken-Ichiro

2009-06-01

Reward and punishment have opposite affective value but are both processed by the cingulate cortex. However, it is unclear whether the positive and negative affective values of monetary reward and punishment are processed by separate or common subregions of the cingulate cortex. We performed a functional magnetic resonance imaging study using a free-choice task and compared cingulate activations for different levels of monetary gain and loss. Gain-specific activation (increasing activation for increasing gain, but no activation change in relation to loss) occurred mainly in the anterior part of the anterior cingulate and in the posterior cingulate cortex. Conversely, loss-specific activation (increasing activation for increasing loss, but no activation change in relation to gain) occurred between these areas, in the middle and posterior part of the anterior cingulate. Integrated coding of gain and loss (increasing activation throughout the full range, from biggest loss to biggest gain) occurred in the dorsal part of the anterior cingulate, at the border with the medial prefrontal cortex. Finally, unspecific activation increases to both gains and losses (increasing activation to increasing gains and increasing losses, possibly reflecting attention) occurred in dorsal and middle regions of the cingulate cortex. Together, these results suggest separate and common coding of monetary reward and punishment in distinct subregions of the cingulate cortex. Further meta-analysis suggested that the presently found reward- and punishment-specific areas overlapped with those processing positive and negative emotions, respectively.

Follicular Fluid redox involvement for ovarian follicle growth.

PubMed

Freitas, Cláudia; Neto, Ana Catarina; Matos, Liliana; Silva, Elisabete; Ribeiro, Ângela; Silva-Carvalho, João Luís; Almeida, Henrique

2017-07-12

As the human ovarian follicle enlarges in the course of a regular cycle or following controlled ovarian stimulation, the changes in its structure reveal the oocyte environment composed of cumulus oophorus cells and the follicular fluid (FF).In contrast to the dynamic nature of cells, the fluid compartment appears as a reservoir rich in biomolecules. In some aspects, it is similar to the plasma, but it also exhibits differences that likely relate to its specific localization around the oocyte. The chemical composition indicates that the follicular fluid is able to detect and buffer excessive amounts of reactive oxygen species, employing a variety of antioxidants, some of them components of the intracellular milieu.An important part is played by albumin through specific cysteine residues. But the fluid contains other molecules whose cysteine residues may be involved in sensing and buffering the local oxidative conditions. How these molecules are recruited and regulated to intervene such process is unknown but it is a critical issue in reproduction.In fact, important proteins in the FF, that regulate follicle growth and oocyte quality, exhibit cysteine residues at specific points, whose untoward oxidation would result in functional loss. Therefore, preservation of controlled oxidative conditions in the FF is a requirement for the fine-tuned oocyte maturation process. In contrast, its disturbance enhances the susceptibility to the establishment of reproductive disorders that would require the intervention of reproductive medicine technology.

Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

PubMed Central

Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Gurney, Mark E.; O’Donnell, James M.

2017-01-01

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. PMID:28054669

pH feedback and phenotypic diversity within bacterial functional groups of the human gut.

PubMed

Kettle, Helen; Donnelly, Ruairi; Flint, Harry J; Marion, Glenn

2014-02-07

Microbial diversity in the human colon is very high with apparently large functional redundancy such that within each bacterial functional group there are many coexisting strains. Modelling this mathematically is problematic since strains within a functional group are often competing for the same limited number of resources and therefore competitive exclusion theory predicts a loss of diversity over time. Here we investigate, through computer simulation, a fluctuation dependent mechanism for the promotion of diversity. A variable pH environment caused by acidic by-products of bacterial growth on a fluctuating substrate coupled with small differences in acid tolerance between strains promotes diversity under both equilibrium and far-from-equilibrium conditions. Under equilibrium conditions pH fluctuations and relative nonlinearity in pH limitation among strains combine to prevent complete competitive exclusion. Under far-from-equilibrium conditions, loss of diversity through extinctions is made more difficult because pH cycling leads to fluctuations in the competitive ranking of strains, thereby helping to equalise fitness. We assume a trade-off between acid tolerance and maximum growth rate so that our microbial system consists of strains ranging from specialists to generalists. By altering the magnitude of the effect of the system on its pH environment (e.g. the buffering capacity of the colon) and the pattern of incoming resource we explore the conditions that promote diversity. © 2013 Elsevier Ltd. Published by Elsevier Ltd. All rights reserved.

Loss of G2 subunit of vacuolar-type proton transporting ATPase leads to G1 subunit upregulation in the brain

PubMed Central

Kawamura, Nobuyuki; Sun-Wada, Ge-Hong; Wada, Yoh

2015-01-01

Vacuolar-type ATPase (V-ATPase) is a primary proton pump with versatile functions in various tissues. In nerve cells, V-ATPase is required for accumulation of neurotransmitters into secretory vesicles and subsequent release at the synapse. Neurons express a specific isoform (G2) of the G subunit of V-ATPase constituting the catalytic sector of the enzyme complex. Using gene targeting, we generated a mouse lacking functional G2 (G2 null), which showed no apparent disorders in architecture and behavior. In the G2-null mouse brain, a G1 subunit isoform, which is ubiquitously expressed in neuronal and non-neuronal tissues, accumulated more abundantly than in wild-type animals. This G1 upregulation was not accompanied by an increase in mRNA. These results indicate that loss of function of neuron-specific G2 isoform was compensated by an increase in levels of the G1 isoform without apparent upregulation of the G1 mRNA. PMID:26353914

Effects of category-specific costs on neural systems for perceptual decision-making.

PubMed

Fleming, Stephen M; Whiteley, Louise; Hulme, Oliver J; Sahani, Maneesh; Dolan, Raymond J

2010-06-01

Perceptual judgments are often biased by prospective losses, leading to changes in decision criteria. Little is known about how and where sensory evidence and cost information interact in the brain to influence perceptual categorization. Here we show that prospective losses systematically bias the perception of noisy face-house images. Asymmetries in category-specific cost were associated with enhanced blood-oxygen-level-dependent signal in a frontoparietal network. We observed selective activation of parahippocampal gyrus for changes in category-specific cost in keeping with the hypothesis that loss functions enact a particular task set that is communicated to visual regions. Across subjects, greater shifts in decision criteria were associated with greater activation of the anterior cingulate cortex (ACC). Our results support a hypothesis that costs bias an intermediate representation between perception and action, expressed via general effects on frontal cortex, and selective effects on extrastriate cortex. These findings indicate that asymmetric costs may affect a neural implementation of perceptual decision making in a similar manner to changes in category expectation, constituting a step toward accounting for how prospective losses are flexibly integrated with sensory evidence in the brain.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or ‘classical’ congenital myopathy

PubMed Central

Zaharieva, Irina T.; Thor, Michael G.; Oates, Emily C.; van Karnebeek, Clara; Hendson, Glenda; Blom, Eveline; Witting, Nanna; Rasmussen, Magnhild; Gabbett, Michael T.; Ravenscroft, Gianina; Sframeli, Maria; Suetterlin, Karen; Sarkozy, Anna; D’Argenzio, Luigi; Hartley, Louise; Matthews, Emma; Pitt, Matthew; Vissing, John; Ballegaard, Martin; Krarup, Christian; Slørdahl, Andreas; Halvorsen, Hanne; Ye, Xin Cynthia; Zhang, Lin-Hua; Løkken, Nicoline; Werlauff, Ulla; Abdelsayed, Mena; Davis, Mark R.; Feng, Lucy; Phadke, Rahul; Sewry, Caroline A.; Morgan, Jennifer E.; Laing, Nigel G.; Vallance, Hilary; Ruben, Peter; Hanna, Michael G.; Lewis, Suzanne; Kamsteeg, Erik-Jan; Männikkö, Roope

2016-01-01

Abstract See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Na v 1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero - or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Na v 1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Na v 1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy. PMID:26700687

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.

PubMed

Zaharieva, Irina T; Thor, Michael G; Oates, Emily C; van Karnebeek, Clara; Hendson, Glenda; Blom, Eveline; Witting, Nanna; Rasmussen, Magnhild; Gabbett, Michael T; Ravenscroft, Gianina; Sframeli, Maria; Suetterlin, Karen; Sarkozy, Anna; D'Argenzio, Luigi; Hartley, Louise; Matthews, Emma; Pitt, Matthew; Vissing, John; Ballegaard, Martin; Krarup, Christian; Slørdahl, Andreas; Halvorsen, Hanne; Ye, Xin Cynthia; Zhang, Lin-Hua; Løkken, Nicoline; Werlauff, Ulla; Abdelsayed, Mena; Davis, Mark R; Feng, Lucy; Phadke, Rahul; Sewry, Caroline A; Morgan, Jennifer E; Laing, Nigel G; Vallance, Hilary; Ruben, Peter; Hanna, Michael G; Lewis, Suzanne; Kamsteeg, Erik-Jan; Männikkö, Roope; Muntoni, Francesco

2016-03-01

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Aging and cancer: are sirtuins the link?

PubMed

Rodriguez, Ramon M; Fraga, Mario F

2010-06-01

Classically, aging has been defined as a general degeneration process that leads to the loss of corporal function. The loss of function caused by degeneration limits the maximum lifespan of all organisms and is linked to disease and cancer. Nevertheless, the molecular mechanisms behind aging and their connection to cancer are not well understood. NAD-dependent protein deacetylase enzymes, sirtuins, are emerging as a novel molecular link between aging and cancer due to their specific role in cell cycle regulation, antistress response and cell survival. This article reviews the contribution of sirtuins and environmental factors to ontogenic development, senescence and cancer.

Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia.

PubMed

Harper, David G; Stopa, Edward G; Kuo-Leblanc, Victoria; McKee, Ann C; Asayama, Kentaro; Volicer, Ladislav; Kowall, Neil; Satlin, Andrew

2008-06-01

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain-behaviour relationships in the human.

Decomposition Dynamics and Changes in Chemical Composition of Wheat Straw Residue under Anaerobic and Aerobic Conditions

PubMed Central

Gao, Hongjian; Chen, Xi; Wei, Junling; Zhang, Yajie; Zhang, Ligan; Chang, Jiang; Thompson, Michael L.

2016-01-01

Soil aeration is a crucial factor that regulates crop residue decomposition, and the chemical composition of decomposing crop residues may change the forms and availability of soil nutrients, such as N and P. However, to date, differences in the chemical composition of crop straw residues after incorporation into soil and during its decomposition under anaerobic vs. aerobic conditions have not been well documented. The objective of the present study was to assess changes in the C-containing functional groups of wheat straw residue during its decomposition in anaerobic and aerobic environments. A 12-month incubation experiment was carried out to investigate the temporal variations of mass, carbon, and nitrogen loss, as well as changes in the chemical composition of wheat (Triticum aestivum L) straw residues under anaerobic and aerobic conditions by measuring C-containing functional groups using solid state nuclear magnetic resonance (NMR) spectroscopy. The residual mass, carbon content, and nitrogen content of the straw residue sharply declined during the initial 3 months, and then slowly decreased during the last incubation period from 3 to 12 months. The decomposition rate constant (k) for mass loss under aerobic conditions (0.022 d-1) was higher than that under anaerobic conditions (0.014 d-1). The residual mass percentage of cellulose and hemicellulose in the wheat straw gradually declined, whereas that of lignin gradually increased during the entire 12-month incubation period. The NMR spectra of C-containing functional groups in the decomposing straw under both aerobic and anaerobic conditions were similar at the beginning of the incubation as well as at 1 month, 6 months, and 12 months. The main alterations in C-containing functional groups during the decomposition of wheat straw were a decrease in the relative abundances of O-alkyl C and an increase in the relative abundances of alkyl C, aromatic C and COO/N-C = O functional groups. The NMR signals of alkyl C and aromatic C in decomposing wheat straw residues under anaerobic condition were higher than those under aerobic conditions. The higher mass percentages of lignin and the higher signals of aromatic C and alkyl C functional groups in decomposing wheat residues under anaerobic conditions than under aerobic conditions were due to the slower decomposition rates of aryl C and alkyl C in wheat straw residues under anaerobic conditions. PMID:27380023

Viscoelastic properties of uncured resin composites: Dynamic oscillatory shear test and fractional derivative model.

PubMed

Petrovic, Ljubomir M; Zorica, Dusan M; Stojanac, Igor Lj; Krstonosic, Veljko S; Hadnadjev, Miroslav S; Janev, Marko B; Premovic, Milica T; Atanackovic, Teodor M

2015-08-01

In this study we analyze viscoelastic properties of three flowable (Wave, Wave MV, Wave HV) and one universal hybrid resin (Ice) composites, prior to setting. We developed a mathematical model containing fractional derivatives in order to describe their properties. Isothermal experimental study was conducted on a rheometer with parallel plates. In dynamic oscillatory shear test, storage and loss modulus, as well as the complex viscosity where determined. We assumed four different fractional viscoelastic models, each belonging to one particular class, derivable from distributed-order fractional constitutive equation. The restrictions following from the Second law of thermodynamics are imposed on each model. The optimal parameters corresponding to each model are obtained by minimizing the error function that takes into account storage and loss modulus, thus obtaining the best fit to the experimental data. In the frequency range considered, we obtained that for Wave HV and Wave MV there exist a critical frequency for which loss and storage modulus curves intersect, defining a boundary between two different types of behavior: one in which storage modulus is larger than loss modulus and the other in which the situation is opposite. Loss and storage modulus curves for Ice and Wave do not show this type of behavior, having either elastic, or viscous effects dominating in entire frequency range considered. The developed models may be used to predict behavior of four tested composites in different flow conditions (different deformation speed), thus helping to estimate optimal handling characteristics for specific clinical applications. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Land degradation at the Stara Planina ski resort.

PubMed

Ristić, Ratko; Kašanin-Grubin, Milica; Radić, Boris; Nikić, Zoran; Vasiljević, Nevena

2012-03-01

The environmental impacts of ski resorts in the Balkan region are great and can lead to landscape degradation and loss of land functionality. In this study, we present an example of the negative effects of human activities at the Stara Planina ski resort in southeastern Serbia. The objective of this study is detailed analysis of the characteristics of environmental impacts at the Stara Planina. The management of the ski area and ski slope development caused severe degradation of topsoil and native vegetation. The morphological characteristics of the area, lithological properties of the exposed material and climate conditions resulted in various geomorphic impacts, including rills, deep gullies, solifluctions and debris from rock weathering. Significant changes in land usage altered hydrological conditions, resulting in more frequent torrential floods in the downstream sections of the Zubska River and increased the sediment yield. Environmental impacts were analyzed in the immediate and wider zones of the ski resort in accordance with the specific topography and visual exposure. The restoration and erosion control measures have stopped degradation processes and helped to rehabilitate the appearance and functions of the landscape. The results show the importance of considering lithological (the type and characteristics of minerals present) and hydrological (precipitation, water storage capacity of soil, runoff) factors under the conditions of significant changes in land usage. The results of this investigation can contribute to the improvement of planning processes and the implementation of development projects in ski areas.

Ultrafast Power Processor for Smart Grid Power Module Development

DOE Office of Scientific and Technical Information (OSTI.GOV)

MAITRA, ARINDAM; LITWIN, RAY; lai, Jason

This project’s goal was to increase the switching speed and decrease the losses of the power semiconductor devices and power switch modules necessary to enable Smart Grid energy flow and control equipment such as the Ultra-Fast Power Processor. The primary focus of this project involves exploiting the new silicon-based Super-GTO (SGTO) technology and build on prototype modules already being developed. The prototype super gate-turn-off thyristor (SGTO) has been tested fully under continuously conducting and double-pulse hard-switching conditions for conduction and switching characteristics evaluation. The conduction voltage drop measurement results indicate that SGTO has excellent conduction characteristics despite inconsistency among somemore » prototype devices. Tests were conducted with two conditions: (1) fixed gate voltage and varying anode current condition, and (2) fixed anode current and varying gate voltage condition. The conduction voltage drop is relatively a constant under different gate voltage condition. In terms of voltage drop as a function of the load current, there is a fixed voltage drop about 0.5V under zero current condition, and then the voltage drop is linearly increased with the current. For a 5-kV voltage blocking device that may operate under 2.5-kV condition, the projected voltage drop is less than 2.5 V under 50-A condition, or 0.1%. If the device is adopted in a converter operating under soft-switching condition, then the converter can achieve an ultrahigh efficiency, typically above 99%. The two-pulse switching test results indicate that SGTO switching speed is very fast. The switching loss is relatively low as compared to that of the insulated-gate-bipolar-transistors (IGBTs). A special phenomenon needs to be noted is such a fast switching speed for the high-voltage switching tends to create an unexpected Cdv/dt current, which reduces the turn-on loss because the dv/dt is negative and increases the turn-off loss because the dv/dt is positive. As a result, the turn-on loss at low current is quite low, and the turn-off loss at low current is relatively high. The phenomenon was verified with junction capacitance measurement along with the dv/dt calculation. Under 2-kV test condition, the turn-on and turn-off losses at 25-A is about 3 and 9 mJ, respectively. As compared to a 4.5-kV, 60-A rated IGBT, which has turn-on and turn-off losses about 25 and 20 mJ under similar test condition, the SGTO shows significant switching loss reduction. The switching loss depends on the switching frequency, but under hard-switching condition, the SGTO is favored to the IGBT device. The only concern is during low current turn-on condition, there is a voltage bump that can translate to significant power loss and associated heat. The reason for such a current bump is not known from this study. It is necessary that the device manufacturer perform though test and provide the answer so the user can properly apply SGTO in pulse-width-modulated (PWM) converter and inverter applications.« less

Olfactory epithelium: Cells, clinical disorders, and insights from an adult stem cell niche

PubMed Central

Choi, Rhea

2018-01-01

Disorders causing a loss of the sense of smell remain a therapeutic challenge. Basic research has, however, greatly expanded our knowledge of the organization and function of the olfactory system. This review describes advances in our understanding of the cellular components of the peripheral olfactory system, specifically the olfactory epithelium in the nose. The article discusses recent findings regarding the mechanisms involved in regeneration and cellular renewal from basal stem cells in the adult olfactory epithelium, considering the strategies involved in embryonic olfactory development and insights from research on other stem cell niches. In the context of clinical conditions causing anosmia, the current view of adult olfactory neurogenesis, tissue homeostasis, and failures in these processes is considered, along with current and future treatment strategies. Level of Evidence NA PMID:29492466

Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors

PubMed Central

Cho, Kyoung-in; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha C. L.; Peachey, Neal S.; Ferreira, Paulo A.

2013-01-01

Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+-apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders. PMID:23818861

Gamified working memory training in overweight individuals reduces food intake but not body weight.

PubMed

Dassen, Fania C M; Houben, Katrijn; Van Breukelen, Gerard J P; Jansen, Anita

2018-05-01

Working Memory (WM) plays a crucial role in successful self-regulation of behavior, including weight regulation. Improving WM might therefore be a promising strategy to support weight loss. In the present study, overweight individuals with a desire to lose weight (N = 91) received an online lifestyle intervention, in conjunction with either 25 sessions of gamified WM training (experimental condition) or a sham training (control). Primary outcomes were Body Mass Index (BMI) and food intake at posttest. Secondary outcomes were executive functioning, self-control, eating style, eating psychopathology and healthy eating. Data were analyzed with mixed regression analyses with condition as between-subjects factor (experimental versus control) and time as within-subjects factor (baseline, posttest, FU1 after one month and FU2 after six months). Results revealed that the experimental condition increased their WM span more than control from pretest to posttest, and these gains were retained at FU1, though lost at FU2. No transfer effects of WM training to other executive functioning measures were found. During the bogus taste test at posttest, participants in the experimental condition consumed significantly less than participants in the control condition. However, both conditions showed a small reduction in BMI, improved eating style, reduced eating disorder pathology, and reported more self-control and a healthier eating pattern. In conclusion, the current results provide some evidence that WM training can improve eating behavior at the short term. However, the WM gains were short-lived, and the added value of WM training as an intervention to promote weight loss could not be established. Future studies should test the added value of WM training booster sessions to promote weight loss over a prolonged period of time. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of resting state condition on reliability, trait specificity, and network connectivity of brain function measured with arterial spin labeled perfusion MRI.

PubMed

Li, Zhengjun; Vidorreta, Marta; Katchmar, Natalie; Alsop, David C; Wolf, Daniel H; Detre, John A

2018-06-01

Resting state fMRI (rs-fMRI) provides imaging biomarkers of task-independent brain function that can be associated with clinical variables or modulated by interventions such as behavioral training or pharmacological manipulations. These biomarkers include time-averaged regional brain function as manifested by regional cerebral blood flow (CBF) measured using arterial spin labeled (ASL) perfusion MRI and correlated temporal fluctuations of function across brain networks with either ASL or blood oxygenation level dependent (BOLD) fMRI. Resting-state studies are typically carried out using just one of several prescribed state conditions such as eyes closed (EC), eyes open (EO), or visual fixation on a cross-hair (FIX), which may affect the reliability and specificity of rs-fMRI. In this study, we collected test-retest ASL MRI data during 4 resting-state task conditions: EC, EO, FIX and PVT (low-frequency psychomotor vigilance task), and examined the effects of these task conditions on reliability and reproducibility as well as trait specificity of regional brain function. We also acquired resting-state BOLD fMRI under FIX and compared the network connectivity reliabilities between the four ASL conditions and the BOLD FIX condition. For resting-state ASL data, EC provided the highest CBF reliability, reproducibility, trait specificity, and network connectivity reliability, followed by EO, while FIX was lowest on all of these measures. PVT demonstrated lower CBF reliability, reproducibility and trait specificity than EO and EC. Overall network connectivity reliability was comparable between ASL and BOLD. Our findings confirm ASL CBF as a reliable, stable, and consistent measure of resting-state regional brain function and support the use of EC or EO over FIX and PVT as the resting-state condition. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Streamflow gain and loss of selected streams in northern Arkansas

USGS Publications Warehouse

Freiwald, David A.

1987-01-01

This map shows streamflow gain and loss measurements (seepage runs) on the Crooked, Osage, and Spavinaw Creeks, and Illinois, Kings, Mulberry, Spring, and Strawberry Rivers during the low-flow conditions from September 1982 to October 1984. Data indicated that streamflow gains and losses resulted from differences in lithology of the predominately carbonate rocks and from the presence of faults. The Kings and Strawberry Rivers and Osage Creek were gaining streams throughout their length, however wastewater discharges precluded an accurate determination on Osage Creek. Crooked and Spavinaw Creeks and the Illinois, Spring, and Mulberry Rivers generally were gaining streams throughout most of their lengths although short losing reaches were identified. The largest gains in streamflow generally occurred were Mississippian formation predominated near the streams. Faults that intersected the stream channels primarily were responsible for streamflow losses. The specific conductance of water increased in the stream reaches that had the most significant streamflow gains. The specific conductance of water in tributaries was generally higher than that in larger streams. (Author 's abstract)

Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent

PubMed Central

Carter, Emma J.; Barnes, David; Hoppe, Hans-Jürgen; Hughes, Jennifer; Cobbold, Stephen; Harper, James; Morreau, Hans; Surakhy, Mirvat; Hassan, A. Bassim

2016-01-01

Two important protein-protein interactions establish E-cadherin (Cdh1) in the adhesion complex; homophilic binding via the extra-cellular (EC1) domain and cytoplasmic tail binding to β-catenin. Here, we evaluate whether E-cadherin binding can inhibit β-catenin when there is loss of Adenomatous polyposis coli (APC) from the β-catenin destruction complex. Combined conditional loss of Cdh1 and Apc were generated in the intestine, intestinal adenoma and adenoma organoids. Combined intestinal disruption (Cdh1fl/flApcfl/flVil-CreERT2) resulted in lethality, breakdown of the intestinal barrier, increased Wnt target gene expression and increased nuclear β-catenin localization, suggesting that E-cadherin inhibits β-catenin. Combination with an intestinal stem cell Cre (Lgr5CreERT2) resulted in ApcΔ/Δ recombination and adenoma, but intact Cdh1fl/fl alleles. Cultured ApcΔ/ΔCdh1fl/fl adenoma cells infected with adenovirus-Cre induced Cdh1fl/fl recombination (Cdh1Δ/Δ), disruption of organoid morphology, nuclear β-catenin localization, and cells with an epithelial-mesenchymal phenotype. Complementation with adenovirus expressing wild-type Cdh1 (Cdh1-WT) rescued adhesion and β-catenin membrane localization, yet an EC1 specific double mutant defective in homophilic adhesion (Cdh1-MutW2A, S78W) did not. These data suggest that E-cadherin inhibits β-catenin in the context of disruption of the APC-destruction complex, and that this function is also EC1 domain dependent. Both binding functions of E-cadherin may be required for its tumour suppressor activity. PMID:27566565

Spatio-temporal patterns of major bacterial groups in alpine waters.

PubMed

Freimann, Remo; Bürgmann, Helmut; Findlay, Stuart E G; Robinson, Christopher T

2014-01-01

Glacial alpine landscapes are undergoing rapid transformation due to changes in climate. The loss of glacial ice mass has directly influenced hydrologic characteristics of alpine floodplains. Consequently, hyporheic sediment conditions are likely to change in the future as surface waters fed by glacial water (kryal) become groundwater dominated (krenal). Such environmental shifts may subsequently change bacterial community structure and thus potential ecosystem functioning. We quantitatively investigated the structure of major bacterial groups in glacial and groundwater-fed streams in three alpine floodplains during different hydrologic periods. Our results show the importance of several physico-chemical variables that reflect local geological characteristics as well as water source in structuring bacterial groups. For instance, Alpha-, Betaproteobacteria and Cytophaga-Flavobacteria were influenced by pH, conductivity and temperature as well as by inorganic and organic carbon compounds, whereas phosphorous compounds and nitrate showed specific influence on single bacterial groups. These results can be used to predict future bacterial group shifts, and potential ecosystem functioning, in alpine landscapes under environmental transformation.

Motor Deficits and Decreased Striatal Dopamine Receptor 2 Binding Activity in the Striatum-Specific Dyt1 Conditional Knockout Mice

PubMed Central

Yokoi, Fumiaki; Dang, Mai Tu; Li, Jianyong; Standaert, David G.; Li, Yuqing

2011-01-01

DYT1 early-onset generalized dystonia is a hyperkinetic movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Recently, significant progress has been made in studying pathophysiology of DYT1 dystonia using targeted mouse models. Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 knock-down (KD) mice exhibit motor deficits and alterations of striatal dopamine metabolisms, while Dyt1 knockout (KO) and Dyt1 ΔGAG homozygous KI mice show abnormal nuclear envelopes and neonatal lethality. However, it has not been clear whether motor deficits and striatal abnormality are caused by Dyt1 mutation in the striatum itself or the end results of abnormal signals from other brain regions. To identify the brain region that contributes to these phenotypes, we made a striatum-specific Dyt1 conditional knockout (Dyt1 sKO) mouse. Dyt1 sKO mice exhibited motor deficits and reduced striatal dopamine receptor 2 (D2R) binding activity, whereas they did not exhibit significant alteration of striatal monoamine contents. Furthermore, we also found normal nuclear envelope structure in striatal medium spiny neurons (MSNs) of an adult Dyt1 sKO mouse and cerebral cortical neurons in cerebral cortex-specific Dyt1 conditional knockout (Dyt1 cKO) mice. The results suggest that the loss of striatal torsinA alone is sufficient to produce motor deficits, and that this effect may be mediated, at least in part, through changes in D2R function in the basal ganglia circuit. PMID:21931745

Antipsychotic dose modulates behavioral and neural responses to feedback during reinforcement learning in schizophrenia.

PubMed

Insel, Catherine; Reinen, Jenna; Weber, Jochen; Wager, Tor D; Jarskog, L Fredrik; Shohamy, Daphna; Smith, Edward E

2014-03-01

Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

Channel Transmission Loss Studies During Ephemeral Flow Events: ER-5-3 Channel and Cambric Ditch, Nevada Test Site, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.J. Miller; S.A. Mizell; R.H. French

2005-10-01

Transmission losses along ephemeral channels are an important, yet poorly understood, aspect of rainfall-runoff prediction. Losses occur as flow infiltrates channel bed, banks, and floodplains. Estimating transmission losses in arid environments is difficult because of the variability of surficial geomorphic characteristics and infiltration capacities of soils and near-surface low-permeability geologic layers (e.g., calcrete). Transmission losses in ephemeral channels are nonlinear functions of discharge and time (Lane, 1972), and vary spatially along the channel reach and with soil antecedent moisture conditions (Sharma and Murthy, 1994). Rainfall-runoff models used to estimate peak discharge and runoff volume for flood hazard assessment are notmore » designed specifically for ephemeral channels, where transmission loss can be significant because of the available storage volume in channel soils. Accuracy of the flow routing and rainfall-runoff models is dependent on the transmission loss estimate. Transmission loss rate is the most uncertain parameter in flow routing through ephemeral channels. This research, sponsored by the U.S. Department of Energy, National Nuclear Security Administration (DOE/NNSA) and conducted at the Nevada Test Site (NTS), is designed to improve understanding of the impact of transmission loss on ephemeral flood modeling and compare various methodologies for predicting runoff from rainfall events. Various applications of this research to DOE projects include more site-specific accuracy in runoff prediction; possible reduction in size of flood mitigation structures at the NTS; and a better understanding of expected infiltration from runoff losses into landfill covers. Two channel transmission loss field experiments were performed on the NTS between 2001 and 2003: the first was conducted in the ER-5-3 channel (Miller et al., 2003), between March and June 2001, and the second was conducted in the Cambric Ditch (Mizell et al., 2005), between April and July 2003. Both studies used water discharged from unrelated drilling activities during well development and aquifer pump tests. Discharge measurements at several flumes located along the channels were used to directly measure transmission losses. Flume locations were chosen in relation to geomorphic surface types and ages, vegetative cover and types, subsurface indurated layers (calcrete), channel slopes, etc. Transmission losses were quantified using three different analysis methods. Method 1 uses Lane's Method (Lane, 1983) for estimating flood magnitude in ephemeral channels. Method 2 uses heat as a subsurface tracer for infiltration. Numerical modeling, using HYDRUS-2D (Simunek et al., 1999), a finite-element-based flow and transport code, was applied to estimate infiltration from soil temperature data. Method 3 uses hydraulic gradient and water content in a Darcy's Law approach (Freeze and Cherry, 1979) to calculate one-dimensional flow rates. Heat dissipation and water content data were collected for this analysis.« less

Conception on the cell mechanisms of bone tissue loss under spase flight conditions

NASA Astrophysics Data System (ADS)

Rodionova, Natalia; Oganov, Victor; Kabitskaya, Olga

Basing on the analysis of available literature and the results of our own electron microscopic and radioautographic researches the data are presented about the morpho-functional peculiarities and succession of cellular interactions in adaptive remodeling of bone structures under normal conditions and after exposure of animals (rats, monkeys, mice) to microgravity (SLS-2, Bion-11, BionM-1). The probable cellular mechanisms of the development of osteopenia and osteoporosis are considered. Our conception on remodeling proposes the following sequence in the development of cellular interactions after decrease of the mechanical loading: a primary response of osteocytes (mechanosensory cells) to the mechanical stimulus; osteocytic remodeling (osteolysis); transmission of the mechanical signals through a system of canals and processes to functionally active osteoblasts and surface osteocytes as well as to the bone-marrow stromal cells and to those lying on bone surfaces. As a response to the mechanical stimulus (microgravity) the system of stromal cell-preosteoblast-osteoblast shows a delay in proliferation, differentiation and specific functioning of the osteogenetic cells, some of the osteoblasts undergo apoptosis. Then the osteoclastic reaction occurs (attraction of monocytes and formation of osteoclasts and bone matrix resorption in the loci of apoptosis of osteoblasts and osteocytes). The macrophagal reaction is followed by osteoblastogenesis, which appears to be a rehabilitating process. However, during prolonged absence of mechanical stimuli (microgravity, long-time immobilization) the adaptive activization of osteoblastogenesis doesn’t occur (as it is the case during the physiological remodeling of bone tissue) or it occurs to a smaller degree. The loading deficit leads to an adaptive differentiation of stromal cells to fibroblastic cells and adipocytes in these remodeling loci. These cell reactions are considered as adaptive-compensatory, but they don’t result in rehabilitation of the resorbed bone tissue. This sequence of events is considered as a mechanism of bone tissue loss which underlies the development of osteopenia and osteoporosis under the mechanical loading deficit.

Effects of hearing loss on speech recognition under distracting conditions and working memory in the elderly.

PubMed

Na, Wondo; Kim, Gibbeum; Kim, Gungu; Han, Woojae; Kim, Jinsook

2017-01-01

The current study aimed to evaluate hearing-related changes in terms of speech-in-noise processing, fast-rate speech processing, and working memory; and to identify which of these three factors is significantly affected by age-related hearing loss. One hundred subjects aged 65-84 years participated in the study. They were classified into four groups ranging from normal hearing to moderate-to-severe hearing loss. All the participants were tested for speech perception in quiet and noisy conditions and for speech perception with time alteration in quiet conditions. Forward- and backward-digit span tests were also conducted to measure the participants' working memory. 1) As the level of background noise increased, speech perception scores systematically decreased in all the groups. This pattern was more noticeable in the three hearing-impaired groups than in the normal hearing group. 2) As the speech rate increased faster, speech perception scores decreased. A significant interaction was found between speed of speech and hearing loss. In particular, 30% of compressed sentences revealed a clear differentiation between moderate hearing loss and moderate-to-severe hearing loss. 3) Although all the groups showed a longer span on the forward-digit span test than the backward-digit span test, there was no significant difference as a function of hearing loss. The degree of hearing loss strongly affects the speech recognition of babble-masked and time-compressed speech in the elderly but does not affect the working memory. We expect these results to be applied to appropriate rehabilitation strategies for hearing-impaired elderly who experience difficulty in communication.

Cyclic hydrostatic pressure promotes a stable cartilage phenotype and enhances the functional development of cartilaginous grafts engineered using multipotent stromal cells isolated from bone marrow and infrapatellar fat pad.

PubMed

Carroll, S F; Buckley, C T; Kelly, D J

2014-06-27

The objective of this study was to investigate how joint specific biomechanical loading influences the functional development and phenotypic stability of cartilage grafts engineered in vitro using stem/progenitor cells isolated from different source tissues. Porcine bone marrow derived multipotent stromal cells (BMSCs) and infrapatellar fat pad derived multipotent stromal cells (FPSCs) were seeded in agarose hydrogels and cultured in chondrogenic medium, while simultaneously subjected to 10MPa of cyclic hydrostatic pressure (HP). To mimic the endochondral phenotype observed in vivo with cartilaginous tissues engineered using BMSCs, the culture media was additionally supplemented with hypertrophic factors, while the loss of phenotype observed in vivo with FPSCs was induced by withdrawing transforming growth factor (TGF)-β3 from the media. The application of HP was found to enhance the functional development of cartilaginous tissues engineered using both BMSCs and FPSCs. In addition, HP was found to suppress calcification of tissues engineered using BMSCs cultured in chondrogenic conditions and acted to maintain a chondrogenic phenotype in cartilaginous grafts engineered using FPSCs. The results of this study point to the importance of in vivo specific mechanical cues for determining the terminal phenotype of chondrogenically primed multipotent stromal cells. Furthermore, demonstrating that stem or progenitor cells will appropriately differentiate in response to such biophysical cues might also be considered as an additional functional assay for evaluating their therapeutic potential. Copyright © 2013 Elsevier Ltd. All rights reserved.

Audio-visual speech processing in age-related hearing loss: Stronger integration and increased frontal lobe recruitment.

PubMed

Rosemann, Stephanie; Thiel, Christiane M

2018-07-15

Hearing loss is associated with difficulties in understanding speech, especially under adverse listening conditions. In these situations, seeing the speaker improves speech intelligibility in hearing-impaired participants. On the neuronal level, previous research has shown cross-modal plastic reorganization in the auditory cortex following hearing loss leading to altered processing of auditory, visual and audio-visual information. However, how reduced auditory input effects audio-visual speech perception in hearing-impaired subjects is largely unknown. We here investigated the impact of mild to moderate age-related hearing loss on processing audio-visual speech using functional magnetic resonance imaging. Normal-hearing and hearing-impaired participants performed two audio-visual speech integration tasks: a sentence detection task inside the scanner and the McGurk illusion outside the scanner. Both tasks consisted of congruent and incongruent audio-visual conditions, as well as auditory-only and visual-only conditions. We found a significantly stronger McGurk illusion in the hearing-impaired participants, which indicates stronger audio-visual integration. Neurally, hearing loss was associated with an increased recruitment of frontal brain areas when processing incongruent audio-visual, auditory and also visual speech stimuli, which may reflect the increased effort to perform the task. Hearing loss modulated both the audio-visual integration strength measured with the McGurk illusion and brain activation in frontal areas in the sentence task, showing stronger integration and higher brain activation with increasing hearing loss. Incongruent compared to congruent audio-visual speech revealed an opposite brain activation pattern in left ventral postcentral gyrus in both groups, with higher activation in hearing-impaired participants in the incongruent condition. Our results indicate that already mild to moderate hearing loss impacts audio-visual speech processing accompanied by changes in brain activation particularly involving frontal areas. These changes are modulated by the extent of hearing loss. Copyright © 2018 Elsevier Inc. All rights reserved.

Homogenizing and diversifying effects of intensive agricultural land-use on plant species beta diversity in Central Europe - A call to adapt our conservation measures

Treesearch

Constanze Buhk; Martin Alt; Manuel J. Steinbauer; Carl Beierkuhnlein; Steve Warren; Anke Jentsch

2017-01-01

The prevention of biodiversity loss in agricultural landscapes to protect ecosystem stability and functions is of major importance to stabilize overall diversity. Intense agriculture leads to a loss in species richness and homogenization of species pools, but the processes behind are poorly understood due to a lack of systematic case studies: The specific...

Proteomic analysis of S-nitrosylated and S-glutathionylated proteins in wheat seedlings with different dehydration tolerances.

PubMed

Gietler, Marta; Nykiel, Małgorzata; Orzechowski, Sławomir; Fettke, Joerg; Zagdańska, Barbara

2016-11-01

A loss of dehydration tolerance in wheat seedlings on the fifth day following imbibition is associated with a disturbance in cellular redox homeostasis, as documented by a shift of the reduced/oxidized glutathione ratio to a more oxidized state and a significant increase in the ratio of protein thiols to the total thiol group content. Therefore, the identification and characterization of redox-sensitive proteins are important steps toward understanding the molecular mechanisms of the loss of dehydration tolerance. In the present study, proteins that were differentially expressed between fully turgid (control), dehydrated tolerant (four-day-old) and dehydrated sensitive (six-day-old) wheat seedlings were analysed. Protein spots having at least a significant (p < 0.05) two-fold change in protein abundance were selected by Delta2D as differentially expressed, identified by MALDI-TOF and LC-MS/MS, and classified according to their function. The observed changes in the proteomic patterns of the differentially S-nitrosylated and S-glutathionylated proteins were highly specific in dehydration-tolerant and -sensitive wheat seedlings. The metabolic function of these proteins indicates that dehydration tolerance is mainly related to nucleic acids, protein metabolism, and energy metabolism. It has been proven that leaf-specific thionins BTH6 and DB4, chloroplastic 50S ribosomal protein L16, phospholipase A1-II delta, and chloroplastic thioredoxin M2 are both S-nitrosylated and S-glutathionylated upon water deficiency. Our results revealed the existence of interplay between S-nitrosylation and S-glutathionylation, two redox-regulated protein posttranslational modifications that could enhance plant defence mechanisms and/or facilitate the acclimation of plants to unfavourable environmental conditions. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Genetic Perturbation of the Maize Methylome[W

PubMed Central

Li, Qing; Hermanson, Peter J.; Zaunbrecher, Virginia M.; Song, Jawon; Wendt, Jennifer; Rosenbaum, Heidi; Madzima, Thelma F.; Sloan, Amy E.; Huang, Ji; Burgess, Daniel L.; Richmond, Todd A.; McGinnis, Karen M.; Meeley, Robert B.; Danilevskaya, Olga N.; Vaughn, Matthew W.; Kaeppler, Shawn M.; Jeddeloh, Jeffrey A.

2014-01-01

DNA methylation can play important roles in the regulation of transposable elements and genes. A collection of mutant alleles for 11 maize (Zea mays) genes predicted to play roles in controlling DNA methylation were isolated through forward- or reverse-genetic approaches. Low-coverage whole-genome bisulfite sequencing and high-coverage sequence-capture bisulfite sequencing were applied to mutant lines to determine context- and locus-specific effects of these mutations on DNA methylation profiles. Plants containing mutant alleles for components of the RNA-directed DNA methylation pathway exhibit loss of CHH methylation at many loci as well as CG and CHG methylation at a small number of loci. Plants containing loss-of-function alleles for chromomethylase (CMT) genes exhibit strong genome-wide reductions in CHG methylation and some locus-specific loss of CHH methylation. In an attempt to identify stocks with stronger reductions in DNA methylation levels than provided by single gene mutations, we performed crosses to create double mutants for the maize CMT3 orthologs, Zmet2 and Zmet5, and for the maize DDM1 orthologs, Chr101 and Chr106. While loss-of-function alleles are viable as single gene mutants, the double mutants were not recovered, suggesting that severe perturbations of the maize methylome may have stronger deleterious phenotypic effects than in Arabidopsis thaliana. PMID:25527708

How Much Binding Affinity Can be Gained by Filling a Cavity?

PubMed Central

Kawasaki, Yuko; Chufan, Eduardo E.; Lafont, Virginie; Hidaka, Koushi; Kiso, Yoshiaki; Amzel, L. Mario; Freire, Ernesto

2011-01-01

Binding affinity optimization is critical during drug development. Here we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this paper, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5-fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25-fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself (CH(CH3)2). It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization. PMID:20028396

From cyclone tracks to the costs of European winter storms: A probabilistic loss assessment model

NASA Astrophysics Data System (ADS)

Renggli, Dominik; Corti, Thierry; Reese, Stefan; Wueest, Marc; Viktor, Elisabeth; Zimmerli, Peter

2014-05-01

The quantitative assessment of the potential losses of European winter storms is essential for the economic viability of a global reinsurance company. For this purpose, reinsurance companies generally use probabilistic loss assessment models. This work presents an innovative approach to develop physically meaningful probabilistic events for Swiss Re's new European winter storm loss model. The meteorological hazard component of the new model is based on cyclone and windstorm tracks identified in the 20th Century Reanalysis data. The knowledge of the evolution of winter storms both in time and space allows the physically meaningful perturbation of properties of historical events (e.g. track, intensity). The perturbation includes a random element but also takes the local climatology and the evolution of the historical event into account. The low-resolution wind footprints taken from 20th Century Reanalysis are processed by a statistical-dynamical downscaling to generate high-resolution footprints of the historical and probabilistic winter storm events. Downscaling transfer functions are generated using ENSEMBLES regional climate model data. The result is a set of reliable probabilistic events representing thousands of years. The event set is then combined with country- and risk-specific vulnerability functions and detailed market- or client-specific exposure information to compute (re-)insurance risk premiums.

Influence of field penetration ratios and filamentation on end-effect related hysteretic loss reductions for superconducting strips

NASA Astrophysics Data System (ADS)

Dong, K.; Sumption, M.; Collings, E. W.; Majoros, M.; Yu, H.; Hu, M.

2017-12-01

There are a few key conductor-specific factors which influence the power loss of superconductors; these include critical current, geometry, and normal metal resistivity. This paper focuses on the influence of sample geometry on the power loss of superconducting strips and the effect of filamentation and sample length as a function of the field penetration state of the superconductor. We start with the analytical equations for infinite slabs and strips and then consider the influence of end effects for both unstriated and striated conductor. The loss is then calculated and compared as a function of applied field for striated and unstriated conductors. These results are much more general than they might seem at first glance, since they will be important building blocks for analytic loss calculations for twisted geometries for coated conductors, including helical (Conductor on Round Core, CORC), and twisted (e.g., twist stack cables) geometries. We show that for relatively low field penetration, end effects and reduced field penetration both reduce loss. In addition, for filamentary samples the relevant ratio of length scales becomes the filament width to sample length, thus modifying the loss ratios.

Balance deficiencies in women with fibromyalgia assessed using computerised dynamic posturography: a cross-sectional study in Spain

PubMed Central

Pérez-de-Heredia-Torres, Marta; Huertas-Hoyas, Elisabet; Martínez-Piédrola, Rosa; Palacios-Ceña, Domingo; Alegre-Ayala, Jorge; Santamaría-Vázquez, Montserrat; Fernández-de-las-Peñas, César

2017-01-01

Objectives Our aims were (1) to compare the sensory organisation of balance control and balance strategies between women with fibromyalgia (FM) and healthy women; (2) to investigate which sensory component, that is, vestibular, visual or somato-sensory, is the most affected in FM and (3) to determine the associations between the functional independence measure (FIM) and balance responses in FM. Design Cross-sectional observational study. Setting Urban regional hospital and university (Universidad Rey Juan Carlos, Madrid, Spain). Participants Twenty women with FM and 20 matched healthy women. Primary/secondary outcome measures The sensory organisation test (SOT) was used to determine postural sway and balance during six different conditions with subjects in a standing position. The FIM was used to determine the level of functional independence in daily life activities (ADL). Between-group differences were analysed with analysis of covariance, and the Spearman's test was used for correlations. Results Significant differences between-groups and between-conditions were found for all SOT conditions (all, p<0.001): women with FM showed lower scores being the vestibular score the most affected. Different correlations between SOT conditions and some specific ADL were observed in the FM group: bathing activity and balance condition 6 (rs=0.541; p<0.001), bed transfers activity and conditions 2 (rs=0.491; p<0.001) and 3 (rs=0.510; p<0.001), positioning strategy six and dressing the upper (rs=0.530; p<0.001) or lower (rs=0.562; p<0.001) body, and toileting (rs=0.521; p<0.001): the greater the loss of balance, the greater the interference on some daily life activities. Conclusions Women with FM exhibited balance deficiencies and used different strategies for maintaining their balance in standing, which was associated with a negative impact on functional independence. PMID:28765133

Multilayer Piezoelectric Stack Actuator Characterization

NASA Technical Reports Server (NTRS)

Sherrit, Stewart; Jones, Christopher M.; Aldrich, Jack B.; Blodget, Chad; Bao, Xioaqi; Badescu, Mircea; Bar-Cohen, Yoseph

2008-01-01

Future NASA missions are increasingly seeking to use actuators for precision positioning to accuracies of the order of fractions of a nanometer. For this purpose, multilayer piezoelectric stacks are being considered as actuators for driving these precision mechanisms. In this study, sets of commercial PZT stacks were tested in various AC and DC conditions at both nominal and extreme temperatures and voltages. AC signal testing included impedance, capacitance and dielectric loss factor of each actuator as a function of the small-signal driving sinusoidal frequency, and the ambient temperature. DC signal testing includes leakage current and displacement as a function of the applied DC voltage. The applied DC voltage was increased to over eight times the manufacturers' specifications to investigate the correlation between leakage current and breakdown voltage. Resonance characterization as a function of temperature was done over a temperature range of -180C to +200C which generally exceeded the manufacturers' specifications. In order to study the lifetime performance of these stacks, five actuators from one manufacturer were driven by a 60volt, 2 kHz sine-wave for ten billion cycles. The tests were performed using a Lab-View controlled automated data acquisition system that monitored the waveform of the stack electrical current and voltage. The measurements included the displacement, impedance, capacitance and leakage current and the analysis of the experimental results will be presented.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

PubMed Central

Pennucci, Roberta; Talpo, Francesca; Astro, Veronica; Montinaro, Valentina; Morè, Lorenzo; Cursi, Marco; Castoldi, Valerio; Chiaretti, Sara; Bianchi, Veronica; Marenna, Silvia; Cambiaghi, Marco; Tonoli, Diletta; Leocani, Letizia; Biella, Gerardo; D'Adamo, Patrizia; de Curtis, Ivan

2016-01-01

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons. PMID:26582364

Cerebellar Influence on Motor Cortex Plasticity: Behavioral Implications for Parkinson’s Disease

PubMed Central

Kishore, Asha; Meunier, Sabine; Popa, Traian

2014-01-01

Normal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration, and normal functioning of these networks. Strong topography-specific connections among the basal ganglia, cerebellum, and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other’s plastic responses and functions. The defective striatal signaling in Parkinson’s disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of co-ordination among the basal ganglia, cerebellar, and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD. The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimentary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD. PMID:24834063

Retinotopic maps and foveal suppression in the visual cortex of amblyopic adults.

PubMed

Conner, Ian P; Odom, J Vernon; Schwartz, Terry L; Mendola, Janine D

2007-08-15

Amblyopia is a developmental visual disorder associated with loss of monocular acuity and sensitivity as well as profound alterations in binocular integration. Abnormal connections in visual cortex are known to underlie this loss, but the extent to which these abnormalities are regionally or retinotopically specific has not been fully determined. This functional magnetic resonance imaging (fMRI) study compared the retinotopic maps in visual cortex produced by each individual eye in 19 adults (7 esotropic strabismics, 6 anisometropes and 6 controls). In our standard viewing condition, the non-tested eye viewed a dichoptic homogeneous mid-level grey stimulus, thereby permitting some degree of binocular interaction. Regions-of-interest analysis was performed for extrafoveal V1, extrafoveal V2 and the foveal representation at the occipital pole. In general, the blood oxygenation level-dependent (BOLD) signal was reduced for the amblyopic eye. At the occipital pole, population receptive fields were shifted to represent more parafoveal locations for the amblyopic eye, compared with the fellow eye, in some subjects. Interestingly, occluding the fellow eye caused an expanded foveal representation for the amblyopic eye in one early-onset strabismic subject with binocular suppression, indicating real-time cortical remapping. In addition, a few subjects actually showed increased activity in parietal and temporal cortex when viewing with the amblyopic eye. We conclude that, even in a heterogeneous population, abnormal early visual experience commonly leads to regionally specific cortical adaptations.

Long-term acclimatization of hydraulic properties, xylem conduit size, wall strength and cavitation resistance in Phaseolus vulgaris in response to different environmental effects.

PubMed

Holste, Ellen K; Jerke, Megan J; Matzner, Steven L

2006-05-01

Phaseolus vulgaris grown under various environmental conditions was used to assess long-term acclimatization of xylem structural characteristics and hydraulic properties. Conduit diameter tended to be reduced and 'wood' density (of 'woody' stems) increased under low moisture ('dry'), increased soil porosity ('porous soil') and low phosphorus ('low P') treatments. Dry and low P had the largest percentage of small vessels. Dry, low light ('shade') and porous soil treatments decreased P50 (50% loss in conductivity) by 0.15-0.25 MPa (greater cavitation resistance) compared with 'controls'. By contrast, low P increased P50 by 0.30 MPa (less cavitation resistance) compared with porous soil (the control for low P). Changes in cavitation resistance were independent of conduit diameter. By contrast, changes in cavitation resistance were correlated with wood density for the control, dry and porous soil treatments, but did not appear to be a function of wood density for the shade and low P treatments. In a separate experiment comparing control and porous soil plants, stem hydraulic conductivity (kh), specific conductivity (ks), leaf specific conductivity (LSC), total pot water loss, plant biomass and leaf area were all greater for control plants compared to porous soil plants. Porous soil plants, however, demonstrated higher midday stomatal conductance to water vapour (gs), apparently because they experienced proportionally less midday xylem cavitation.

Challenges in forest reclamation of marginal lands: a balance between site conditions and seedling quality

NASA Astrophysics Data System (ADS)

Landhäusser, Simon

2017-04-01

Forest loss and degradation is occurring worldwide, but at the same time efforts in forest restoration are ever increasing. While approaches to restoration often follow specific stakeholder objectives, regional climates and the degree of site degradation also play an important role in the prioritization of restoration efforts. Often the restoration of degraded lands can satisfy only few measurable objectives; however, to design and restore resistant and resilient ecosystems that can adapt to changing conditions, there is a need for new and adaptive management approaches. Mining and other resource extraction industries are affecting more and more forested areas worldwide. A priority in the reclamation and certification of forest lands disturbed by industrial activity is their expeditious redevelopment to functioning forests. To rehabilitate these heavily disturbed areas back to forest ecosystems, planting of trees remains one of the most effective strategies for the redevelopment of a continuous tree canopy on a site. It is well understood that access to good quality seedling stock is essential to achieve establishment success and early growth of seedlings. However, most reclamation areas have challenging initial site conditions and these conditions are often not a single factor but a combination of factors that can be additive or synergistic. Therefore successful forest restoration on degraded lands needs to consider multiple objectives and approaches to minimize trade-offs in achieving these objectives. To meet these demands, new methods for the production and evaluation of seedling stock types are needed to ensure that that seedlings are fit to grow on a wide range of site conditions or are particularly designed to grow in very specific conditions. Generally, defining seedling quality is difficult as it is species specific and results have been mixed; likely influenced by site conditions, further reiterating the need to carefully evaluate sites allowing appropriate seedling qualities to be identified. In this presentation, I will show results from a range of studies that explored the role of seedling characteristics in response to challenging site conditions and explore the need for a balance between the recognition and improvement of limiting site conditions and the availability of quality seedling stock in forest restoration.

Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals.

PubMed

Charpentier, Caroline J; De Martino, Benedetto; Sim, Alena L; Sharot, Tali; Roiser, Jonathan P

2016-04-01

Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of 'neural loss aversion', both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. © The Author (2015). Published by Oxford University Press.

Loss of Smad4 in Sertoli and Leydig Cells Leads to Testicular Dysgenesis and Hemorrhagic Tumor Formation in Mice1

PubMed Central

Archambeault, Denise R.; Yao, Humphrey Hung-Chang

2014-01-01

ABSTRACT As the central component of canonical TGFbeta superfamily signaling, SMAD4 is a critical regulator of organ development, patterning, tumorigenesis, and many other biological processes. Because numerous TGFbeta superfamily ligands are expressed in developing testes, there may exist specific requirements for SMAD4 in individual testicular cell types. Previously, we reported that expansion of the fetal testis cords requires expression of SMAD4 by the Sertoli cell lineage. To further uncover the role of Smad4 in murine testes, we produced conditional knockout mice lacking Smad4 in either Leydig cells or in both Sertoli and Leydig cells simultaneously. Loss of Smad4 concomitantly in Sertoli and Leydig cells led to underdevelopment of the testis cords during fetal life and mild testicular dysgenesis in young adulthood (decreased testis size, partially dysgenic seminiferous tubules, and low sperm production). When the Sertoli/Leydig cell Smad4 conditional knockout mice aged (56- to 62-wk old), the testis phenotypes became exacerbated with the appearance of hemorrhagic tumors, Leydig cell adenomas, and a complete loss of spermatogenesis. In contrast, loss of Smad4 in Leydig cells alone did not appreciably alter fetal and adult testis development. Our findings support a cell type-specific requirement of Smad4 in testis development and suppression of testicular tumors. PMID:24501173

Recruitment of Mediator Complex by Cell Type and Stage-Specific Factors Required for Tissue-Specific TAF Dependent Gene Activation in an Adult Stem Cell Lineage.

PubMed

Lu, Chenggang; Fuller, Margaret T

2015-12-01

Onset of terminal differentiation in adult stem cell lineages is commonly marked by robust activation of new transcriptional programs required to make the appropriate differentiated cell type(s). In the Drosophila male germ line stem cell lineage, the switch from proliferating spermatogonia to spermatocyte is accompanied by one of the most dramatic transcriptional changes in the fly, as over 1000 new transcripts turn on in preparation for meiosis and spermatid differentiation. Here we show that function of the coactivator complex Mediator is required for activation of hundreds of new transcripts in the spermatocyte program. Mediator appears to act in a sequential hierarchy, with the testis activating Complex (tMAC), a cell type specific form of the Mip/dREAM general repressor, required to recruit Mediator subunits to the chromatin, and Mediator function required to recruit the testis TAFs (tTAFs), spermatocyte specific homologs of subunits of TFIID. Mediator, tMAC and the tTAFs co-regulate expression of a major set of spermatid differentiation genes. The Mediator subunit Med22 binds the tMAC component Topi when the two are coexpressed in S2 cells, suggesting direct recruitment. Loss of Med22 function in spermatocytes causes meiosis I maturation arrest male infertility, similar to loss of function of the tMAC subunits or the tTAFs. Our results illuminate how cell type specific versions of the Mip/dREAM complex and the general transcription machinery cooperate to drive selective gene activation during differentiation in stem cell lineages.

incurvata13, a Novel Allele of AUXIN RESISTANT6, Reveals a Specific Role for Auxin and the SCF Complex in Arabidopsis Embryogenesis, Vascular Specification, and Leaf Flatness1[W][OA

PubMed Central

Esteve-Bruna, David; Pérez-Pérez, José Manuel; Ponce, María Rosa; Micol, José Luis

2013-01-01

Auxin plays a pivotal role in plant development by modulating the activity of SCF ubiquitin ligase complexes. Here, we positionally cloned Arabidopsis (Arabidopsis thaliana) incurvata13 (icu13), a mutation that causes leaf hyponasty and reduces leaf venation pattern complexity and auxin responsiveness. We found that icu13 is a novel recessive allele of AUXIN RESISTANT6 (AXR6), which encodes CULLIN1, an invariable component of the SCF complex. Consistent with a role for auxin in vascular specification, the vascular defects in the icu13 mutant were accompanied by reduced expression of auxin transport and auxin perception markers in provascular cells. This observation is consistent with the expression pattern of AXR6, which we found to be restricted to vascular precursors and hydathodes in wild-type leaf primordia. AXR1, RELATED TO UBIQUITIN1-CONJUGATING ENZYME1, CONSTITUTIVE PHOTOMORPHOGENIC9 SIGNALOSOME5A, and CULLIN-ASSOCIATED NEDD8-DISSOCIATED1 participate in the covalent modification of CULLIN1 by RELATED TO UBIQUITIN. Hypomorphic alleles of these genes also display simple venation patterns, and their double mutant combinations with icu13 exhibited a synergistic, rootless phenotype reminiscent of that caused by loss of function of MONOPTEROS (MP), which forms an auxin-signaling module with BODENLOS (BDL). The phenotypes of double mutant combinations of icu13 with either a gain-of-function allele of BDL or a loss-of-function allele of MP were synergistic. In addition, a BDL:green fluorescent protein fusion protein accumulated in icu13, and BDL loss of function or MP overexpression suppressed the phenotype of icu13. Our results demonstrate that the MP-BDL module is required not only for root specification in embryogenesis and vascular postembryonic development but also for leaf flatness. PMID:23319550

Sleep and athletic performance: the effects of sleep loss on exercise performance, and physiological and cognitive responses to exercise.

PubMed

Fullagar, Hugh H K; Skorski, Sabrina; Duffield, Rob; Hammes, Daniel; Coutts, Aaron J; Meyer, Tim

2015-02-01

Although its true function remains unclear, sleep is considered critical to human physiological and cognitive function. Equally, since sleep loss is a common occurrence prior to competition in athletes, this could significantly impact upon their athletic performance. Much of the previous research has reported that exercise performance is negatively affected following sleep loss; however, conflicting findings mean that the extent, influence, and mechanisms of sleep loss affecting exercise performance remain uncertain. For instance, research indicates some maximal physical efforts and gross motor performances can be maintained. In comparison, the few published studies investigating the effect of sleep loss on performance in athletes report a reduction in sport-specific performance. The effects of sleep loss on physiological responses to exercise also remain equivocal; however, it appears a reduction in sleep quality and quantity could result in an autonomic nervous system imbalance, simulating symptoms of the overtraining syndrome. Additionally, increases in pro-inflammatory cytokines following sleep loss could promote immune system dysfunction. Of further concern, numerous studies investigating the effects of sleep loss on cognitive function report slower and less accurate cognitive performance. Based on this context, this review aims to evaluate the importance and prevalence of sleep in athletes and summarises the effects of sleep loss (restriction and deprivation) on exercise performance, and physiological and cognitive responses to exercise. Given the equivocal understanding of sleep and athletic performance outcomes, further research and consideration is required to obtain a greater knowledge of the interaction between sleep and performance.

Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour.

PubMed

Doe, Christine M; Relkovic, Dinko; Garfield, Alastair S; Dalley, Jeffrey W; Theobald, David E H; Humby, Trevor; Wilkinson, Lawrence S; Isles, Anthony R

2009-06-15

The Prader-Willi syndrome (PWS) genetic interval contains several brain-expressed small nucleolar (sno)RNA species that are subject to genomic imprinting. In vitro studies have shown that one of these snoRNA molecules, h/mbii-52, negatively regulates editing and alternative splicing of the serotonin 2C receptor (5htr2c) pre-RNA. However, the functional consequences of loss of h/mbii-52 and subsequent increased post-transcriptional modification of 5htr2c are unknown. 5HT2CRs are important in controlling aspects of cognition and the cessation of feeding, and disruption of their function may underlie some of the psychiatric and feeding abnormalities seen in PWS. In a mouse model for PWS lacking expression of mbii-52 (PWS-IC+/-), we show an increase in editing, but not alternative splicing, of the 5htr2c pre-RNA. This change in post-transcriptional modification is associated with alterations in a number of 5HT2CR-related behaviours, including impulsive responding, locomotor activity and reactivity to palatable foodstuffs. In a non-5HT2CR-related behaviour, marble burying, loss of mbii-52 was without effect. The specificity of the behavioural effects to changes in 5HT2CR function was further confirmed using drug challenges. These data illustrate, for the first time, the physiological consequences of altered RNA editing of 5htr2c linked to mbii-52 loss that may underlie specific aspects of the complex PWS phenotype and point to an important functional role for this imprinted snoRNA.

Enhanced neural responsiveness to reward associated with obesity in the absence of food-related stimuli.

PubMed

Opel, Nils; Redlich, Ronny; Grotegerd, Dominik; Dohm, Katharina; Haupenthal, Cordula; Heindel, Walter; Kugel, Harald; Arolt, Volker; Dannlowski, Udo

2015-06-01

Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food-related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward-associated functional aberrations in obesity are specific for food-related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance-related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food-related stimuli during a monetary reward condition. Twenty-nine healthy obese subjects (body mass index >30) and 29 healthy, age-, and sex-matched control subjects of normal weight underwent functional MRI during a frequently used card guessing paradigm. A Group × Condition (win vs. loss) ANOVA was conducted to investigate differences between obese and normal-weight subjects. We found significant Group × Condition interaction effects in brain areas involved in emotion regulation and reward processing including the insula, the striatum, and the orbitofrontal cortex (OFC). This interaction was predominantly driven by a significant increase in blood oxygenation level dependent (BOLD) response in obese individuals while experiencing reward. Enhanced neural activation in obesity during reward processing seems to be apparent even in the absence of food-related stimuli and, thus, might point to generalized dysfunctions in reward-related brain circuits in obese individuals. © 2015 Wiley Periodicals, Inc.

Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain.

PubMed

Moechars, Diederik; Weston, Matthew C; Leo, Sandra; Callaerts-Vegh, Zsuzsanna; Goris, Ilse; Daneels, Guy; Buist, A; Cik, M; van der Spek, P; Kass, Stefan; Meert, Theo; D'Hooge, Rudi; Rosenmund, Christian; Hampson, R Mark

2006-11-15

Uptake of L-glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). Three transporters (VGLUT1-VGLUT3) are expressed in the mammalian CNS, with partial overlapping expression patterns, and VGLUT2 is the most abundantly expressed paralog in the thalamus, midbrain, and brainstem. Previous studies have shown that VGLUT1 is necessary for glutamatergic transmission in the hippocampus, but the role of VGLUT2 in excitatory transmission is unexplored in glutamatergic neurons and in vivo. We examined the electrophysiological and behavioral consequences of loss of either one or both alleles of VGLUT2. We show that targeted deletion of VGLUT2 in mice causes perinatal lethality and a 95% reduction in evoked glutamatergic responses in thalamic neurons, although hippocampal synapses function normally. Behavioral analysis of heterozygous VGLUT2 mice showed unchanged motor function, learning and memory, acute nociception, and inflammatory pain, but acquisition of neuropathic pain, maintenance of conditioned taste aversion, and defensive marble burying were all impaired. Reduction or loss of VGLUT2 in heterozygous and homozygous VGLUT2 knock-outs led to a graded reduction in the amplitude of the postsynaptic response to single-vesicle fusion in thalamic neurons, indicating that the vesicular VGLUT content is critically important for quantal size and demonstrating that VGLUT2-mediated reduction of excitatory drive affects specific forms of sensory processing.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

PubMed

Stomby, A; Simonyte, K; Mellberg, C; Ryberg, M; Stimson, R H; Larsson, C; Lindahl, B; Andrew, R; Walker, B R; Olsson, T

2015-05-01

Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue were studied. Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parker, B. F.; Hohloch, S.; Pankhurst, J. R.

Vanadium is the main competitor for uranium extraction from seawater, and V( iv ) comprises a minor but important portion of this. V( iv ) undergoes redox reactions with oximes and amidoxime ligands under seawater-relevant conditions, leading to V( v ) complexes and loss of oxime functional groups.

Changes in functional activity of bone tissue cells under space flight conditions.

NASA Astrophysics Data System (ADS)

Rodionova, Natalia; Nesterenko, Olga; Kabitskaya, Olga

The space flight conditions affect considerably the state of bone tissue, leading to the development of osteoporosis and osteopenia. Many aspects of reactions of bone tissue cells still remain unclear until now. With the use of electron microscopy we studied the samples gathered from the femoral bones metaphyses of rats flown on board the space laboratory (Spacelab - 2) during 2 weeks and samples from tibial bones of mice C57 Black ( Bion M-1). It was established, that under microgravity conditions there occur remodelling processes in a spongy bone related with a deficit of support load. In this work the main attention is focused on studying the ultrastructure of osteogenetic cells and osteoclasts. The degree of differentiation and functional state are evaluated according to the degree of development of organelles for specific biosynthesis: rough endoplasmic reticulum (RER), Golgy complex (GC), as well as the state of mitochondria and cell nucleus. As compared with a synchronous control, the population of osteogenetic cells from zones of bone reconstruction shows a decrease in the number of functionally active forms. We can judge of this from the reduction of a specific volume of RER, GC, mitochondria in osteoblasts. RER loses architectonics typical for osteoblasts and, as against the control, is represented by short narrow canaliculi distributed throughout the cytoplasm; some canals disintegrate. GC is slightly pronounced, mitochondria become smaller in size and acquire an optically dark matrix. These phenomena are supposed to be associated with the desorganization of microtubules and microfilaments in the cells under microgravity conditions. The population of osteogenetic cells shows a decrease in the number of differentiating osteoblasts and an increase in the number of little-differentiated stromal cells. In the population of osteoblasts, degrading and apoptotic cells are sometimes encountered. Such zones show a numerical increase of monocytic cells and osteoclasts. Among them are typical osteoclasts with 3 to 4 nuclei on a section, as well as the "giant" cells with 5 to 6 nuclei and a highly developed zone 2, in which organelles and structures are concentrated, providing for specific functions (primary and secondary lysosomes, heterophagous vacuoles, fibrous layer and "brush border"). The availability of these functionally active osteoclasts testify to the intensification of resorptive processes in remodelling zones. To confirm the obtained electronmicroscopic findings, the experiments were conducted on albino rats under model microgravity conditions ("tail suspension" method) with the use of radionuclides. The experiments with 3H-glycine demonstrated a lower isotope uptake in the osteogenetic cells compared with the control. The autoradiographic studies employing 3H-thymidine, showed that hind limbs unloading leads to a significant acceleration of osteoclast formation in zones of spongy bone reconstruction. Considering the obtained results, the cell mechanisms of osteoclast - osteoblast remodelling and bone tissue loss under the action of space flight factors are discussed.

Conditional Function of Autoaggregative Protein Cah and Common cah Mutations in Shiga Toxin-Producing Escherichia coli

PubMed Central

Brandl, Maria T.; Kudva, Indira T.; Katani, Robab; Moreau, Matthew R.; Kapur, Vivek

2017-01-01

ABSTRACT Cah is a calcium-binding autotransporter protein involved in autoaggregation and biofilm formation. Although cah is widespread in Shiga toxin-producing Escherichia coli (STEC), we detected mutations in cah at a frequency of 31.3% in this pathogen. In STEC O157:H7 supershedder strain SS17, a large deletion results in a smaller coding sequence, encoding a protein lacking the C-terminal 71 amino acids compared with Cah in STEC O157:H7 strain EDL933. We examined the function of Cah in biofilm formation and host colonization to better understand the selective pressures for cah mutations. EDL933-Cah played a conditional role in biofilm formation in vitro: it enhanced E. coli DH5α biofilm formation on glass surfaces under agitated culture conditions that prevented autoaggregation but inhibited biofilm formation under hydrostatic conditions that facilitated autoaggregation. This function appeared to be strain dependent since Cah-mediated biofilm formation was diminished when an EDL933 cah gene was expressed in SS17. Deletion of cah in EDL933 enhanced bacterial attachment to spinach leaves and altered the adherence pattern of EDL933 to bovine recto-anal junction squamous epithelial (RSE) cells. In contrast, in trans expression of EDL933 cah in SS17 increased its attachment to leaf surfaces, and in DH5α, it enhanced its adherence to RSE cells. Hence, the ecological function of Cah appears to be modulated by environmental conditions and other bacterial strain-specific properties. Considering the prevalence of cah in STEC and its role in attachment and biofilm formation, cah mutations might be selected in ecological niches in which inactivation of Cah would result in an increased fitness in STEC during colonization of plants or animal hosts. IMPORTANCE Shiga toxin-producing Escherichia coli (STEC) harbors genes encoding diverse adhesins, and many of these are known to play an important role in bacterial attachment and host colonization. We demonstrated here that the autotransporter protein Cah confers on E. coli DH5α cells a strong autoaggregative phenotype that is inversely correlated with its ability to form biofilms and plays a strain-specific role in plant and animal colonization by STEC. Although cah is widespread in the STEC population, we detected a mutation rate of 31.3% in cah, which is similar to that reported for rpoS and fimH. The formation of cell aggregates due to increased bacterium-to-bacterium interactions may be disadvantageous to bacterial populations under conditions that favor a planktonic state in STEC. Therefore, a loss-of-function mutation in cah is likely a selective trait in STEC when autoaggregative properties become detrimental to bacterial cells and may contribute to the adaptability of STEC to fluctuating environments. PMID:29054868

Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation.

PubMed

Choudhary, Mayur; Naczki, Christine; Chen, Wenhong; Barlow, Keith D; Case, L Douglas; Metheny-Barlow, Linda J

2015-05-23

Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and proliferative. The mechanisms by which tumors prevent proper association between mural cells and EC are not well understood. Since gap junctions (GJ) play an important role in cell-cell contact and communication, we investigated whether loss of GJ plays a role in tumor-induced mural cell dissociation. Mural cell regulation of endothelial proliferation was assessed by direct co-culture assays of fluorescently labeled cells quantified by flow cytometry or plate reader. Gap junction function was assessed by parachute assay. Connexin 43 (Cx43) protein in mural cells exposed to conditioned media from cancer cells was assessed by Western and confocal microscopy; mRNA levels were assessed by quantitative real-time PCR. Expression vectors or siRNA were utilized to overexpress or knock down Cx43. Tumor growth and angiogenesis was assessed in mouse hosts deficient for Cx43. Using parachute dye transfer assay, we demonstrate that media conditioned by MDA-MB-231 breast cancer cells diminishes GJ communication between mural cells (vascular smooth muscle cells, vSMC) and EC. Both protein and mRNA of the GJ component Connexin 43 (Cx43) are downregulated in mural cells by tumor-conditioned media; media from non-tumorigenic MCF10A cells had no effect. Loss of GJ communication by Cx43 siRNA knockdown, treatment with blocking peptide, or exposure to tumor-conditioned media diminishes the ability of mural cells to inhibit EC proliferation in co-culture assays, while overexpression of Cx43 in vSMC restores GJ and endothelial inhibition. Breast tumor cells implanted into mice heterozygous for Cx43 show no changes in tumor growth, but exhibit significantly increased tumor vascularization determined by CD31 staining, along with decreased mural cell support detected by NG2 staining. Our data indicate that i) functional Cx43 is required for mural cell-induced endothelial quiescence, and ii) downregulation of Cx43 GJ by tumors frees endothelium to respond to angiogenic cues. These data define a novel and important role for maintained Cx43 function in regulation of vessel quiescence, and suggest its loss may contribute to pathological tumor angiogenesis.

Gasification Characteristics of Coal/Biomass Mixed Fuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitchell, Reginald

2014-09-01

A research project was undertaken that had the overall objective of developing the models needed to accurately predict conversion rates of coal/biomass mixtures to synthesis gas under conditions relevant to a commercially-available coal gasification system configured to co-produce electric power as well as chemicals and liquid fuels. In our efforts to accomplish this goal, experiments were performed in an entrained flow reactor in order to produce coal and biomass chars at high heating rates and temperatures, typical of the heating rates and temperatures fuel particles experience in real systems. Mixed chars derived from coal/biomass mixtures containing up to 50% biomassmore » and the chars of the pure coal and biomass components were subjected to a matrix of reactivity tests in a pressurized thermogravimetric analyzer (TGA) in order to obtain data on mass loss rates as functions of gas temperature, pressure and composition as well as to obtain information on the variations in mass specific surface area during char conversion under kinetically-limited conditions. The experimental data were used as targets when determining the unknown parameters in the chemical reactivity and specific surface area models developed. These parameters included rate coefficients for the reactions in the reaction mechanism, enthalpies of formation and absolute entropies of adsorbed species formed on the carbonaceous surfaces, and pore structure coefficients in the model used to describe how the mass specific surface area of the char varies with conversion. So that the reactivity models can be used at high temperatures when mass transport processes impact char conversion rates, Thiele modulus – effectiveness factor relations were also derived for the reaction mechanisms developed. In addition, the reactivity model and a mode of conversion model were combined in a char-particle gasification model that includes the effects of chemical reaction and diffusion of reactive gases through particle pores and energy exchange between the particle and its environment. This char-particle gasification model is capable of predicting the average mass loss rates, sizes, apparent densities, specific surface areas, and temperatures of the char particles produced when co-firing coal and biomass to the type environments established in entrained flow gasifiers operating at high temperatures and elevated pressures.« less

Affective forecasting about hedonic loss and adaptation: Implications for damage awards.

PubMed

Greene, Edie; Sturm, Kristin A; Evelo, Andrew J

2016-06-01

In tort lawsuits, plaintiffs may seek damages for loss of enjoyment of life, so-called hedonic loss, which occurred as a result of an accident or injury. In 2 studies, we examined how people judge others' adaptation and hedonic loss after an injury. Laypeople's forecasts of hedonic loss are relevant to concerns about whether jurors appropriately compensate plaintiffs. Longitudinal data of subjective well-being (e.g., Binder & Coad, 2013) show that hedonic loss is domain-specific: Many physical impairments (e.g., strokes) inflict less hedonic loss than many persistent yet invisible ailments (e.g., mental illness and conditions that cause chronic pain). We used vignette methodology to determine whether laypeople (n = 68 community members and 65 students in Study 1; 87 community members and 93 students in Study 2) and rehabilitation professionals (n = 47 in Study 2) were aware of this fact. In Study 1, participants' ratings of hedonic loss subsequent to a physical injury and a comparably severe psychological impairment did not differ. In Study 2, ratings of short- and long-term hedonic loss stemming from paraplegia and chronic back pain showed that neither laypeople nor professionals understood that hedonic loss is domain-specific. These findings imply that observers may forecast a future for people who suffered serious physical injuries as grimmer than it is likely to be, and a future for people who experience chronic pain and psychological disorders as rosier than is likely. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

General contamination criteria for optical surfaces. [instrument performance losses in spaceborne conditions

NASA Technical Reports Server (NTRS)

Bremer, J. C.

1982-01-01

Physical models are developed for establishing criteria to decide on the acceptable contamination level of optical devices in space-borne conditions. Optical systems can be degraded in terms of decreased throughput, i.e., transmissivity or reflectivity, or increases in the total integrated scatter (TIS). Performance losses can be caused by particulate accretion, molecular film accretion, and impact cratering. A quantitative relationship is defined for film thickness and loss of throughput. Formulas are also developed for cases where induced surface defects are larger than the desired viewing wavelengths, or smaller or of the same order of the observed wavelengths. The techniques are used to quantify the degradation of a VUV solar coronagraph, a VUV stellar telescope, and a solar cell due to TIS. Applications are projected for estimating the contamination sensitivity of specific instruments, assessing the contamination hazard from known particulates, or to define clean room standards.

A study of the effect of message framing on oocyte donation.

PubMed

Purewal, S; van den Akker, O B A

2009-12-01

The aims of this study were to examine the effect of gain- and loss-framed messages on British and South East Asian women's intentions towards oocyte donation and to examine whether the components of the theory of planned behaviour influenced the relationship between framing and intentions. A total of 406 women participated in this study (mean age = 22, SD = 2.9). There were 211 participants in the gain condition and 195 in the loss condition. An analysis of covariance found a main effect for framing (F(1, 402) = 6.3; P < 0.01) after controlling for existing attitudes towards oocyte donation and pre-message intentions to donate. Specifically, participants in the gain-framed condition were significantly more likely to report higher post-message intentions to donate oocytes than participants in the loss condition. However, the framing effect was only observed with British populations and not with women from South East Asia. Further, structural equation modelling analyses revealed lower levels of 'perceived behavioural control' (beta = -0.420, P < 0.03) and positive attitudes towards 'the importance of genetic ties between parent and child' (beta = 0.70, P < 0.001) were direct predictors of post-message intentions in the gain (but not loss) frame condition. Findings obtained from this study indicate that oocyte donation campaigns should consider using gain-framed messages in recruitment appeals and message frames should be matched to the target populations' perceived level of behavioural control.

Macrocell path loss prediction using artificial intelligence techniques

NASA Astrophysics Data System (ADS)

Usman, Abraham U.; Okereke, Okpo U.; Omizegba, Elijah E.

2014-04-01

The prediction of propagation loss is a practical non-linear function approximation problem which linear regression or auto-regression models are limited in their ability to handle. However, some computational Intelligence techniques such as artificial neural networks (ANNs) and adaptive neuro-fuzzy inference systems (ANFISs) have been shown to have great ability to handle non-linear function approximation and prediction problems. In this study, the multiple layer perceptron neural network (MLP-NN), radial basis function neural network (RBF-NN) and an ANFIS network were trained using actual signal strength measurement taken at certain suburban areas of Bauchi metropolis, Nigeria. The trained networks were then used to predict propagation losses at the stated areas under differing conditions. The predictions were compared with the prediction accuracy of the popular Hata model. It was observed that ANFIS model gave a better fit in all cases having higher R2 values in each case and on average is more robust than MLP and RBF models as it generalises better to a different data.

Management factors affecting ammonia volatilization from land-applied cattle slurry in the Mid-Atlantic USA.

PubMed

Thompson, R B; Meisinger, J J

2002-01-01

Ammonia (NH3) volatilization commonly causes a substantial loss of crop-available N from surface-applied cattle slurry. Field studies were conducted with small wind tunnels to assess the effect of management factors on NH3 volatilization. Two studies compared NH3 volatilization from grass sward and bare soil. The average total NH3 loss was 1.5 times greater from slurry applied to grass sward. Two studies examined the effect of slurry dry matter (DM) content on NH3 loss under hot, summer conditions in Maryland, USA. Slurry DM contents were between 54 and 134 g kg(-1). Dry matter content did not affect total NH3 loss, but did influence the time course of NH3 loss. Higher DM content slurries had relatively higher rates of NH3 volatilization during the first 12 to 24 h, but lower rates thereafter. Under the hot conditions, the higher DM content slurries appeared to dry and crust more rapidly causing smaller rates of NH3 volatilization after 12 to 24 h, which offset the earlier positive effects of DM content on NH3 volatilization. Three studies compared immediate incorporation with different tillage implements. Total NH3 loss from unincorporated slurry was 45% of applied slurry NH4+-N, while losses following immediate incorporation with a moldboard plow, tandem-disk harrow, or chisel plow were, respectively, 0 to 3, 2 to 8, and 8 to 12%. These ground cover and DM content data can be used to improve predictions of NH3 loss under specific farming conditions. The immediate incorporation data demonstrate management practices that can reduce NH3 volatilization, which can improve slurry N utilization in crop-forage production.

Polar Bear Conservation Status in Relation to Projected Sea-ice Conditions

NASA Astrophysics Data System (ADS)

Regehr, E. V.

2015-12-01

The status of the world's 19 subpopulations of polar bears (Ursus maritimus) varies as a function of sea-ice conditions, ecology, management, and other factors. Previous methods to project the response of polar bears to loss of Arctic sea ice—the primary threat to the species—include expert opinion surveys, Bayesian Networks providing qualitative stressor assessments, and subpopulations-specific demographic analyses. Here, we evaluated the global conservation status of polar bears using a data-based sensitivity analysis. First, we estimated generation length for subpopulations with available data (n=11). Second, we developed standardized sea-ice metrics representing habitat availability. Third, we projected global population size under alternative assumptions for relationships between sea ice and subpopulation abundance. Estimated generation length (median = 11.4 years; 95%CI = 9.8 to 13.6) and sea-ice change (median = loss of 1.26 ice-covered days per year; 95%CI = 0.70 to 3.37) varied across subpopulations. Assuming a one-to-one proportional relationship between sea ice and abundance, the median percent change in global population size over three polar bear generations was -30% (95%CI = -35% to -25%). Assuming a linear relationship between sea ice and normalized estimates of subpopulation abundance, median percent change was -4% (95% CI = -62% to +50%) or -43% (95% CI = -76% to -20%), depending on how subpopulations were grouped and how inference was extended from relatively well-studied subpopulations (n=7) to those with little or no data. Our findings suggest the potential for large reductions in polar bear numbers over the next three polar bear generations if sea-ice loss due to climate change continues as forecasted.

Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia.

PubMed

Cording, Jimmi; Günther, Ramona; Vigolo, Emilia; Tscheik, Christian; Winkler, Lars; Schlattner, Isabella; Lorenz, Dorothea; Haseloff, Reiner F; Schmidt-Ott, Kai M; Wolburg, Hartwig; Blasig, Ingolf E

2015-11-01

Tight junctions (TJs) seal paracellular clefts in epithelia/endothelia and form tissue barriers for proper organ function. TJ-associated marvel proteins (TAMPs; tricellulin, occludin, marvelD3) are thought to be relevant to regulation. Under normal conditions, tricellulin tightens tricellular junctions against macromolecules. Traces of tricellulin occur in bicellular junctions. As pathological disturbances have not been analyzed, the structure and function of human tricellulin, including potentially redox-sensitive Cys sites, were investigated under reducing/oxidizing conditions at 3- and 2-cell contacts. Ischemia, hypoxia, and reductants redistributed tricellulin from 3- to 2-cell contacts. The extracellular loop 2 (ECL2; conserved Cys321, Cys335) trans-oligomerized between three opposing cells. Substitutions of these residues caused bicellular localization. Cys362 in transmembrane domain 4 contributed to bicellular heterophilic cis-interactions along the cell membrane with claudin-1 and marvelD3, while Cys395 in the cytosolic C-terminal tail promoted homophilic tricellullar cis-interactions. The Cys sites included in homo-/heterophilic bi-/tricellular cis-/trans-interactions contributed to cell barrier tightness for small/large molecules. Tricellulin forms TJs via trans- and cis-association in 3-cell contacts, as demonstrated electron and quantified fluorescence microscopically; it tightens 3- and 2-cell contacts. Tricellulin's ECL2 specifically seals 3-cell contacts redox dependently; a structural model is proposed. TAMP ECL2 and claudins' ECL1 share functionally and structurally similar features involved in homo-/heterophilic tightening of cell-cell contacts. Tricellulin is a specific redox sensor and sealing element at 3-cell contacts and may compensate as a redox mediator for occludin loss at 2-cell contacts in vivo and in vitro. Molecular interaction mechanisms were proposed that contribute to tricellulin's function. In conclusion, tricellulin is a junctional redox regulator for ischemia-related alterations.

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1.

PubMed

Galeone, Antonio; Han, Seung Yeop; Huang, Chengcheng; Hosomi, Akira; Suzuki, Tadashi; Jafar-Nejad, Hamed

2017-08-04

Mutations in the human N- glycanase 1 ( NGLY1 ) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N -glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during Drosophila development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an N -glycanase enzyme.

Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo.

PubMed

Flanagan, Dustin J; Barker, Nick; Nowell, Cameron; Clevers, Hans; Ernst, Matthias; Phesse, Toby J; Vincan, Elizabeth

2017-08-01

The gastric epithelium consists of tubular glandular units, each containing several differentiated cell types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation of signalling pathways that regulate homeostasis of the diseased organ. Therefore, it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and to identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions, including proliferation, differentiation and migration, and plays a crucial role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo Here, we show that the Wnt receptor frizzled 7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric-specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together, these data provide functional evidence of a crucial role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium. © 2017. Published by The Company of Biologists Ltd.

Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo

PubMed Central

2017-01-01

ABSTRACT The gastric epithelium consists of tubular glandular units, each containing several differentiated cell types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation of signalling pathways that regulate homeostasis of the diseased organ. Therefore, it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and to identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions, including proliferation, differentiation and migration, and plays a crucial role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo. Here, we show that the Wnt receptor frizzled 7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric-specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together, these data provide functional evidence of a crucial role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium. PMID:28600348

Mutant phenotypes for thousands of bacterial genes of unknown function

DOE PAGES

Price, Morgan N.; Wetmore, Kelly M.; Waters, R. Jordan; ...

2018-05-16

One-third of all protein-coding genes from bacterial genomes cannot be annotated with a function. Here, to investigate the functions of these genes, we present genome-wide mutant fitness data from 32 diverse bacteria across dozens of growth conditions. We identified mutant phenotypes for 11,779 protein-coding genes that had not been annotated with a specific function. Many genes could be associated with a specific condition because the gene affected fitness only in that condition, or with another gene in the same bacterium because they had similar mutant phenotypes. Of the poorly annotated genes, 2,316 had associations that have high confidence because theymore » are conserved in other bacteria. By combining these conserved associations with comparative genomics, we identified putative DNA repair proteins; in addition, we propose specific functions for poorly annotated enzymes and transporters and for uncharacterized protein families. Lastly, our study demonstrates the scalability of microbial genetics and its utility for improving gene annotations.« less

Mutant phenotypes for thousands of bacterial genes of unknown function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Morgan N.; Wetmore, Kelly M.; Waters, R. Jordan

One-third of all protein-coding genes from bacterial genomes cannot be annotated with a function. Here, to investigate the functions of these genes, we present genome-wide mutant fitness data from 32 diverse bacteria across dozens of growth conditions. We identified mutant phenotypes for 11,779 protein-coding genes that had not been annotated with a specific function. Many genes could be associated with a specific condition because the gene affected fitness only in that condition, or with another gene in the same bacterium because they had similar mutant phenotypes. Of the poorly annotated genes, 2,316 had associations that have high confidence because theymore » are conserved in other bacteria. By combining these conserved associations with comparative genomics, we identified putative DNA repair proteins; in addition, we propose specific functions for poorly annotated enzymes and transporters and for uncharacterized protein families. Lastly, our study demonstrates the scalability of microbial genetics and its utility for improving gene annotations.« less

Declining resilience of ecosystem functions under biodiversity loss.

PubMed

Oliver, Tom H; Isaac, Nick J B; August, Tom A; Woodcock, Ben A; Roy, David B; Bullock, James M

2015-12-08

The composition of species communities is changing rapidly through drivers such as habitat loss and climate change, with potentially serious consequences for the resilience of ecosystem functions on which humans depend. To assess such changes in resilience, we analyse trends in the frequency of species in Great Britain that provide key ecosystem functions--specifically decomposition, carbon sequestration, pollination, pest control and cultural values. For 4,424 species over four decades, there have been significant net declines among animal species that provide pollination, pest control and cultural values. Groups providing decomposition and carbon sequestration remain relatively stable, as fewer species are in decline and these are offset by large numbers of new arrivals into Great Britain. While there is general concern about degradation of a wide range of ecosystem functions, our results suggest actions should focus on particular functions for which there is evidence of substantial erosion of their resilience.

From Cyclone Tracks to the Costs of European Winter Storms: A Probabilistic Loss Assessment Model

NASA Astrophysics Data System (ADS)

Orwig, K.; Renggli, D.; Corti, T.; Reese, S.; Wueest, M.; Viktor, E.; Zimmerli, P.

2014-12-01

European winter storms cause billions of dollars of insured losses every year. Therefore, it is essential to understand potential impacts of future events, and the role reinsurance can play to mitigate the losses. The authors will present an overview on natural catastrophe risk assessment modeling in the reinsurance industry, and the development of a new innovative approach for modeling the risk associated with European winter storms.The new innovative approach includes the development of physically meaningful probabilistic (i.e. simulated) events for European winter storm loss assessment. The meteorological hazard component of the new model is based on cyclone and windstorm tracks identified in the 20thCentury Reanalysis data. The knowledge of the evolution of winter storms both in time and space allows the physically meaningful perturbation of historical event properties (e.g. track, intensity, etc.). The perturbation includes a random element but also takes the local climatology and the evolution of the historical event into account.The low-resolution wind footprints taken from the 20thCentury Reanalysis are processed by a statistical-dynamical downscaling to generate high-resolution footprints for both the simulated and historical events. Downscaling transfer functions are generated using ENSEMBLES regional climate model data. The result is a set of reliable probabilistic events representing thousands of years. The event set is then combined with country and site-specific vulnerability functions and detailed market- or client-specific information to compute annual expected losses.

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

PubMed Central

Borysov, Sergiy I.; Nepon-Sixt, Brook S.

2015-01-01

The N-terminal domain of the retinoblastoma (Rb) tumor suppressor protein (RbN) harbors in-frame exon deletions in partially penetrant hereditary retinoblastomas and is known to impair cell growth and tumorigenesis. However, how such RbN deletions contribute to Rb tumor- and growth-suppressive functions is unknown. Here we establish that RbN directly inhibits DNA replication initiation and elongation using a bipartite mechanism involving N-terminal exons lost in cancer. Specifically, Rb exon 7 is necessary and sufficient to target and inhibit the replicative CMG helicase, resulting in the accumulation of inactive CMGs on chromatin. An independent N-terminal loop domain, which forms a projection, specifically blocks DNA polymerase α (Pol-α) and Ctf4 recruitment without affecting DNA polymerases ε and δ or the CMG helicase. Individual disruption of exon 7 or the projection in RbN or Rb, as occurs in inherited cancers, partially impairs the ability of Rb/RbN to inhibit DNA replication and block G1-to-S cell cycle transit. However, their combined loss abolishes these functions of Rb. Thus, Rb growth-suppressive functions include its ability to block replicative complexes via bipartite, independent, and additive N-terminal domains. The partial loss of replication, CMG, or Pol-α control provides a potential molecular explanation for how N-terminal Rb loss-of-function deletions contribute to the etiology of partially penetrant retinoblastomas. PMID:26711265

Interpretation of monoclinic hafnia valence electron energy-loss spectra by time-dependent density functional theory

NASA Astrophysics Data System (ADS)

Hung, L.; Guedj, C.; Bernier, N.; Blaise, P.; Olevano, V.; Sottile, F.

2016-04-01

We present the valence electron energy-loss spectrum and the dielectric function of monoclinic hafnia (m -HfO2) obtained from time-dependent density-functional theory (TDDFT) predictions and compared to energy-filtered spectroscopic imaging measurements in a high-resolution transmission-electron microscope. Fermi's golden rule density-functional theory (DFT) calculations can capture the qualitative features of the energy-loss spectrum, but we find that TDDFT, which accounts for local-field effects, provides nearly quantitative agreement with experiment. Using the DFT density of states and TDDFT dielectric functions, we characterize the excitations that result in the m -HfO2 energy-loss spectrum. The sole plasmon occurs between 13 and 16 eV, although the peaks ˜28 and above 40 eV are also due to collective excitations. We furthermore elaborate on the first-principles techniques used, their accuracy, and remaining discrepancies among spectra. More specifically, we assess the influence of Hf semicore electrons (5 p and 4 f ) on the energy-loss spectrum, and find that the inclusion of transitions from the 4 f band damps the energy-loss intensity in the region above 13 eV. We study the impact of many-body effects in a DFT framework using the adiabatic local-density approximation (ALDA) exchange-correlation kernel, as well as from a many-body perspective using "scissors operators" matched to an ab initio G W calculation to account for self-energy corrections. These results demonstrate some cancellation of errors between self-energy and excitonic effects, even for excitations from the Hf 4 f shell. We also simulate the dispersion with increasing momentum transfer for plasmon and collective excitation peaks.

Variability and convergence in benthic communities in created salt marshes transitioning into mangrove habitats

EPA Science Inventory

Wetland creation, enhancement, and restoration activities are commonly implemented to compensate for wetland loss or degradation in coastal ecosystems. Although assessments of structural condition are commonly used to monitor habitat restoration effectiveness, functional equivale...

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

PubMed Central

2013-01-01

Background Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a. Methods We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models. Results Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression. Conclusions Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function. PMID:24274149

Agency Modulates the Lateral and Medial Prefrontal Cortex Responses in Belief-Based Decision Making

PubMed Central

Xue, Gui; He, Qinghua; Lu, Zhong-Lin; Levin, Irwin P.; Dong, Qi; Bechara, Antoine

2013-01-01

Many real-life decisions in complex and changing environments are guided by the decision maker’s beliefs, such as her perceived control over decision outcomes (i.e., agency), leading to phenomena like the “illusion of control”. However, the neural mechanisms underlying the “agency” effect on belief-based decisions are not well understood. Using functional imaging and a card guessing game, we revealed that the agency manipulation (i.e., either asking the subjects (SG) or the computer (CG) to guess the location of the winning card) not only affected the size of subjects’ bets, but also their “world model” regarding the outcome dependency. Functional imaging results revealed that the decision-related activation in the lateral and medial prefrontal cortex (PFC) was significantly modulated by agency and previous outcome. Specifically, these PFC regions showed stronger activation when subjects made decisions after losses than after wins under the CG condition, but the pattern was reversed under the SG condition. Furthermore, subjects with high external attribution of negative events were more affected by agency at the behavioral and neural levels. These results suggest that the prefrontal decision-making system can be modulated by abstract beliefs, and are thus vulnerable to factors such as false agency and attribution. PMID:23762332

A Functional Study of AUXILIN-LIKE1 and 2, Two Putative Clathrin Uncoating Factors in Arabidopsis[OPEN

PubMed Central

Adamowski, Maciek; Kania, Urszula

2018-01-01

Clathrin-mediated endocytosis (CME) is a cellular trafficking process in which cargoes and lipids are internalized from the plasma membrane into vesicles coated with clathrin and adaptor proteins. CME is essential for many developmental and physiological processes in plants, but its underlying mechanism is not well characterized compared with that in yeast and animal systems. Here, we searched for new factors involved in CME in Arabidopsis thaliana by performing tandem affinity purification of proteins that interact with clathrin light chain, a principal component of the clathrin coat. Among the confirmed interactors, we found two putative homologs of the clathrin-coat uncoating factor auxilin previously described in non-plant systems. Overexpression of AUXILIN-LIKE1 and AUXILIN-LIKE2 in Arabidopsis caused an arrest of seedling growth and development. This was concomitant with inhibited endocytosis due to blocking of clathrin recruitment after the initial step of adaptor protein binding to the plasma membrane. By contrast, auxilin-like1/2 loss-of-function lines did not present endocytosis-related developmental or cellular phenotypes under normal growth conditions. This work contributes to the ongoing characterization of the endocytotic machinery in plants and provides a robust tool for conditionally and specifically interfering with CME in Arabidopsis. PMID:29511054

Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice

PubMed Central

Kumar, Rakesh; Hunt, Clayton R.; Gupta, Arun; Nannepaga, Suraj; Pandita, Raj K.; Shay, Jerry W.; Bachoo, Robert; Ludwig, Thomas; Burns, Dennis K.; Pandita, Tej K.

2011-01-01

The brains of ataxia telangiectasia (AT) patients display an aberrant loss of Purkinje cells (PCs) that is postulated to contribute to the observed deficits in motor coordination as well as in learning and cognitive function. AT patients have mutations in the ataxia telangiectasia mutated (ATM) gene [Savitsky et al. (1995) Science 268:1749–1753]. However, in Atm-deficient mice, the neurological defects are limited, and the PCs are not deformed or lost as observed in AT patients [Barlow et al. (1996) Cell 86:159–171]. Here we report that PC-specific deletion of the mouse males absent on the first (mMof) gene (Cre−), which encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac) and influences ATM function, is critical for PC longevity. Mice deficient for PC-specific Mof display impaired motor coordination, ataxia, a backward-walking phenotype, and a reduced life span. Treatment of MofF/F/Pcp2-Cre+ mice with histone deacetylase inhibitors modestly prolongs PC survival and delays death. Therefore, Mof expression and H4K16 acetylation are essential for PC survival and function, and their absence leads to PC loss and cerebellar dysfunction similar to that observed in AT patients. PMID:21321203

Multi-subject Manifold Alignment of Functional Network Structures via Joint Diagonalization.

PubMed

Nenning, Karl-Heinz; Kollndorfer, Kathrin; Schöpf, Veronika; Prayer, Daniela; Langs, Georg

2015-01-01

Functional magnetic resonance imaging group studies rely on the ability to establish correspondence across individuals. This enables location specific comparison of functional brain characteristics. Registration is often based on morphology and does not take variability of functional localization into account. This can lead to a loss of specificity, or confounds when studying diseases. In this paper we propose multi-subject functional registration by manifold alignment via coupled joint diagonalization. The functional network structure of each subject is encoded in a diffusion map, where functional relationships are decoupled from spatial position. Two-step manifold alignment estimates initial correspondences between functionally equivalent regions. Then, coupled joint diagonalization establishes common eigenbases across all individuals, and refines the functional correspondences. We evaluate our approach on fMRI data acquired during a language paradigm. Experiments demonstrate the benefits in matching accuracy achieved by coupled joint diagonalization compared to previously proposed functional alignment approaches, or alignment based on structural correspondences.

Burden of major musculoskeletal conditions.

PubMed Central

Woolf, Anthony D.; Pfleger, Bruce

2003-01-01

Musculoskeletal conditions are a major burden on individuals, health systems, and social care systems, with indirect costs being predominant. This burden has been recognized by the United Nations and WHO, by endorsing the Bone and Joint Decade 2000-2010. This paper describes the burden of four major musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, osteoporosis, and low back pain. Osteoarthritis, which is characterized by loss of joint cartilage that leads to pain and loss of function primarily in the knees and hips, affects 9.6% of men and 18% of women aged > 60 years. Increases in life expectancy and ageing populations are expected to make osteoarthritis the fourth leading cause of disability by the year 2020. Joint replacement surgery, where available, provides effective relief. Rheumatoid arthritis is an inflammatory condition that usually affects multiple joints. It affects 0.3-1.0% of the general population and is more prevalent among women and in developed countries. Persistent inflammation leads to joint destruction, but the disease can be controlled with drugs. The incidence may be on the decline, but the increase in the number of older people in some regions makes it difficult to estimate future prevalence. Osteoporosis, which is characterized by low bone mass and microarchitectural deterioration, is a major risk factor for fractures of the hip, vertebrae, and distal forearm. Hip fracture is the most detrimental fracture, being associated with 20% mortality and 50% permanent loss in function. Low back pain is the most prevalent of musculoskeletal conditions; it affects nearly everyone at some point in time and about 4-33% of the population at any given point. Cultural factors greatly influence the prevalence and prognosis of low back pain. PMID:14710506

Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload

NASA Technical Reports Server (NTRS)

Evans-Flynn, Erin; Gregory, Kevin; Arsintescu, Lucia; Whitmire, Alexandra; Leveton, Lauren B.; Vessey, William

2015-01-01

Sleep loss, circadian desynchronization, and work overload occur to some extent for ground and flight crews, prior to and during spaceflight missions. Ground evidence indicates that such risk factors may lead to performance decrements and adverse health outcomes, which could potentially compromise mission objectives. Efforts are needed to identify the environmental and mission conditions that interfere with sleep and circadian alignment, as well as individual differences in vulnerability and resiliency to sleep loss and circadian desynchronization. Specifically, this report highlights a collection of new evidence to better characterize the risk and reveals new gaps in this risk.

Genome Editing of Monkey.

PubMed

Liu, Zhen; Cai, Yijun; Sun, Qiang

2017-01-01

Gene-modified monkey models would be particularly valuable in biomedical and neuroscience research. Virus-based transgenic and programmable nucleases-based site-specific gene editing methods (TALEN, CRISPR-cas9) enable the generation of gene-modified monkeys with gain or loss of function of specific genes. Here, we describe the generation of transgenic and knock-out (KO) monkeys with high efficiency by lentivirus and programmable nucleases.

Flood Risk Due to Hurricane Flooding

NASA Astrophysics Data System (ADS)

Olivera, Francisco; Hsu, Chih-Hung; Irish, Jennifer

2015-04-01

In this study, we evaluated the expected economic losses caused by hurricane inundation. We used surge response functions, which are physics-based dimensionless scaling laws that give surge elevation as a function of the hurricane's parameters (i.e., central pressure, radius, forward speed, approach angle and landfall location) at specified locations along the coast. These locations were close enough to avoid significant changes in surge elevations between consecutive points, and distant enough to minimize calculations. The probability of occurrence of a surge elevation value at a given location was estimated using a joint probability distribution of the hurricane parameters. The surge elevation, at the shoreline, was assumed to project horizontally inland within a polygon of influence. Individual parcel damage was calculated based on flood water depth and damage vs. depth curves available for different building types from the HAZUS computer application developed by the Federal Emergency Management Agency (FEMA). Parcel data, including property value and building type, were obtained from the county appraisal district offices. The expected economic losses were calculated as the sum of the products of the estimated parcel damages and their probability of occurrence for the different storms considered. Anticipated changes for future climate scenarios were considered by accounting for projected hurricane intensification, as indicated by sea surface temperature rise, and sea level rise, which modify the probability distribution of hurricane central pressure and change the baseline of the damage calculation, respectively. Maps of expected economic losses have been developed for Corpus Christi in Texas, Gulfport in Mississippi and Panama City in Florida. Specifically, for Port Aransas, in the Corpus Christi area, it was found that the expected economic losses were in the range of 1% to 4% of the property value for current climate conditions, of 1% to 8% for the 2030's and of 1% to 14% for the 2080's.

Determinants of propranolol’s selective effect on loss aversion

PubMed Central

Sokol-Hessner, Peter; Lackovic, Sandra F.; Tobe, Russell H.; Camerer, Colin F.; Leventhal, Bennett L.; Phelps, Elizabeth A.

2015-01-01

Research on emotion and decision-making has suggested that arousal mediates risky decisions (e.g., Bechara et al., 1997), but several distinct and often confounded processes drive such choices. Here, we used econometric modeling to separate and quantify the unique contributions of loss aversion, risk sensitivity and choice consistency to risky decision-making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention’s pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision-making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e. as a function of initial loss aversion and body-mass index), and did not affect risk sensitivity or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of both emotion and risky decision-making. PMID:26063441

Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

PubMed Central

Hunter, Chad S.; Stein, Roland W.

2017-01-01

The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e.g., insulin and transcription factors like MAFA, PDX1, and NKX6.1), as well as (2) de-differentiation, defined by regression to a progenitor or stem cell-like state. New technologies have allowed the field to compare islet cell characteristics from normal human donors to those under pathophysiological conditions by single cell RNA-Sequencing and through epigenetic analysis. This has revealed a remarkable level of heterogeneity among histologically defined “insulin-positive” β-cells. These results not only suggest that these β-cell subsets have different responses to insulin secretagogues, but that defining their unique gene expression and epigenetic modification profiles will offer opportunities to develop cellular therapeutics to enrich/maintain certain subsets for correcting pathological glucose levels. In this review, we will summarize the recent literature describing how β-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention. PMID:28424732

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice.

PubMed

Sundermeier, Thomas R; Sakami, Sanae; Sahu, Bhubanananda; Howell, Scott J; Gao, Songqi; Dong, Zhiqian; Golczak, Marcin; Maeda, Akiko; Palczewski, Krzysztof

2017-02-24

Age-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 ( Dgcr8 ), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Combinatorial Strategies for Improving Multiple-Stress Resistance in Industrially Relevant Escherichia coli Strains

PubMed Central

Herrgård, Markus J.

2014-01-01

High-cell-density fermentation for industrial production of chemicals can impose numerous stresses on cells due to high substrate, product, and by-product concentrations; high osmolarity; reactive oxygen species; and elevated temperatures. There is a need to develop platform strains of industrial microorganisms that are more tolerant toward these typical processing conditions. In this study, the growth of six industrially relevant strains of Escherichia coli was characterized under eight stress conditions representative of fed-batch fermentation, and strains W and BL21(DE3) were selected as platforms for transposon (Tn) mutagenesis due to favorable resistance characteristics. Selection experiments, followed by either targeted or genome-wide next-generation-sequencing-based Tn insertion site determination, were performed to identify mutants with improved growth properties under a subset of three stress conditions and two combinations of individual stresses. A subset of the identified loss-of-function mutants were selected for a combinatorial approach, where strains with combinations of two and three gene deletions were systematically constructed and tested for single and multistress resistance. These approaches allowed identification of (i) strain-background-specific stress resistance phenotypes, (ii) novel gene deletion mutants in E. coli that confer single and multistress resistance in a strain-background-dependent manner, and (iii) synergistic effects of multiple gene deletions that confer improved resistance over single deletions. The results of this study underscore the suboptimality and strain-specific variability of the genetic network regulating growth under stressful conditions and suggest that further exploration of the combinatorial gene deletion space in multiple strain backgrounds is needed for optimizing strains for microbial bioprocessing applications. PMID:25085490

Functional visualization and disruption of targeted genes using CRISPR/Cas9-mediated eGFP reporter integration in zebrafish.

PubMed

Ota, Satoshi; Taimatsu, Kiyohito; Yanagi, Kanoko; Namiki, Tomohiro; Ohga, Rie; Higashijima, Shin-Ichi; Kawahara, Atsuo

2016-10-11

The CRISPR/Cas9 complex, which is composed of a guide RNA (gRNA) and the Cas9 nuclease, is useful for carrying out genome modifications in various organisms. Recently, the CRISPR/Cas9-mediated locus-specific integration of a reporter, which contains the Mbait sequence targeted using Mbait-gRNA, the hsp70 promoter and the eGFP gene, has allowed the visualization of the target gene expression. However, it has not been ascertained whether the reporter integrations at both targeted alleles cause loss-of-function phenotypes in zebrafish. In this study, we have inserted the Mbait-hs-eGFP reporter into the pax2a gene because the disruption of pax2a causes the loss of the midbrain-hindbrain boundary (MHB) in zebrafish. In the heterozygous Tg[pax2a-hs:eGFP] embryos, MHB formed normally and the eGFP expression recapitulated the endogenous pax2a expression, including the MHB. We observed the loss of the MHB in homozygous Tg[pax2a-hs:eGFP] embryos. Furthermore, we succeeded in integrating the Mbait-hs-eGFP reporter into an uncharacterized gene epdr1. The eGFP expression in heterozygous Tg[epdr1-hs:eGFP] embryos overlapped the epdr1 expression, whereas the distribution of eGFP-positive cells was disorganized in the MHB of homozygous Tg[epdr1-hs:eGFP] embryos. We propose that the locus-specific integration of the Mbait-hs-eGFP reporter is a powerful method to investigate both gene expression profiles and loss-of-function phenotypes.

Functional visualization and disruption of targeted genes using CRISPR/Cas9-mediated eGFP reporter integration in zebrafish

PubMed Central

Ota, Satoshi; Taimatsu, Kiyohito; Yanagi, Kanoko; Namiki, Tomohiro; Ohga, Rie; Higashijima, Shin-ichi; Kawahara, Atsuo

2016-01-01

The CRISPR/Cas9 complex, which is composed of a guide RNA (gRNA) and the Cas9 nuclease, is useful for carrying out genome modifications in various organisms. Recently, the CRISPR/Cas9-mediated locus-specific integration of a reporter, which contains the Mbait sequence targeted using Mbait-gRNA, the hsp70 promoter and the eGFP gene, has allowed the visualization of the target gene expression. However, it has not been ascertained whether the reporter integrations at both targeted alleles cause loss-of-function phenotypes in zebrafish. In this study, we have inserted the Mbait-hs-eGFP reporter into the pax2a gene because the disruption of pax2a causes the loss of the midbrain-hindbrain boundary (MHB) in zebrafish. In the heterozygous Tg[pax2a-hs:eGFP] embryos, MHB formed normally and the eGFP expression recapitulated the endogenous pax2a expression, including the MHB. We observed the loss of the MHB in homozygous Tg[pax2a-hs:eGFP] embryos. Furthermore, we succeeded in integrating the Mbait-hs-eGFP reporter into an uncharacterized gene epdr1. The eGFP expression in heterozygous Tg[epdr1-hs:eGFP] embryos overlapped the epdr1 expression, whereas the distribution of eGFP-positive cells was disorganized in the MHB of homozygous Tg[epdr1-hs:eGFP] embryos. We propose that the locus-specific integration of the Mbait-hs-eGFP reporter is a powerful method to investigate both gene expression profiles and loss-of-function phenotypes. PMID:27725766

An implementation of the SNR high speed network communication protocol (Receiver part)

NASA Astrophysics Data System (ADS)

Wan, Wen-Jyh

1995-03-01

This thesis work is to implement the receiver pan of the SNR high speed network transport protocol. The approach was to use the Systems of Communicating Machines (SCM) as the formal definition of the protocol. Programs were developed on top of the Unix system using C programming language. The Unix system features that were adopted for this implementation were multitasking, signals, shared memory, semaphores, sockets, timers and process control. The problems encountered, and solved, were signal loss, shared memory conflicts, process synchronization, scheduling, data alignment and errors in the SCM specification itself. The result was a correctly functioning program which implemented the SNR protocol. The system was tested using different connection modes, lost packets, duplicate packets and large data transfers. The contributions of this thesis are: (1) implementation of the receiver part of the SNR high speed transport protocol; (2) testing and integration with the transmitter part of the SNR transport protocol on an FDDI data link layered network; (3) demonstration of the functions of the SNR transport protocol such as connection management, sequenced delivery, flow control and error recovery using selective repeat methods of retransmission; and (4) modifications to the SNR transport protocol specification such as corrections for incorrect predicate conditions, defining of additional packet types formats, solutions for signal lost and processes contention problems etc.

Combined strategies in the management of obesity.

PubMed

Dixon, John B; Dixon, Maureen E

2006-01-01

Obesity is a chronic relapsing disease requiring a similar long term approach to management as that of other chronic conditions. Management needs to be multifaceted aiming to achieve sustainable behavioural changes to physical activity and diet to alter the patient and family microenvironment to one favouring better weight control. A range of therapies including specific diets, calorie counting, meal replacements, very low calorie diets, pharmacotherapy, intragastric balloons and surgery can provide very useful additional benefit. Use of these should be guided by the extent of weight loss required to reduce BMI to an acceptable level with regard to the patient's ethnicity, risk and comorbid conditions. Patients need to set goals that are optimistic, but realistic, and understand the benefits of sustained modest weight loss and the likelihood of weight regain requiring repeat episodes of weight loss. Practitioners need to be informed about the efficacy of current therapies and their combinations to enhance choice of suitable methods for achieving the optimal weight loss required by the patient. They will also need to anticipate trigger points for renewed periods of weight loss in the event of weight regain, as relapse is likely but not a reason for abandoning the battle.

Effects of Category-Specific Costs on Neural Systems for Perceptual Decision-Making

PubMed Central

Whiteley, Louise; Hulme, Oliver J.; Sahani, Maneesh; Dolan, Raymond J.

2010-01-01

Perceptual judgments are often biased by prospective losses, leading to changes in decision criteria. Little is known about how and where sensory evidence and cost information interact in the brain to influence perceptual categorization. Here we show that prospective losses systematically bias the perception of noisy face-house images. Asymmetries in category-specific cost were associated with enhanced blood-oxygen-level-dependent signal in a frontoparietal network. We observed selective activation of parahippocampal gyrus for changes in category-specific cost in keeping with the hypothesis that loss functions enact a particular task set that is communicated to visual regions. Across subjects, greater shifts in decision criteria were associated with greater activation of the anterior cingulate cortex (ACC). Our results support a hypothesis that costs bias an intermediate representation between perception and action, expressed via general effects on frontal cortex, and selective effects on extrastriate cortex. These findings indicate that asymmetric costs may affect a neural implementation of perceptual decision making in a similar manner to changes in category expectation, constituting a step toward accounting for how prospective losses are flexibly integrated with sensory evidence in the brain. PMID:20357071

Experimental and Numerical Investigation of Losses in Low-Pressure Turbine Blade Rows

NASA Technical Reports Server (NTRS)

Dorney, Daniel J.; Lake, James P.; King, Paul I.; Ashpis, David E.

2000-01-01

Experimental data and numerical simulations of low-pressure turbines have shown that unsteady blade row interactions and separation can have a significant impact on the turbine efficiency. Measured turbine efficiencies at takeoff can be as much as two points higher than those at cruise conditions. Several recent studies have revealed that the performance of low-pressure turbine blades is a strong function of the Reynolds number. In the current investigation, experiments and simulations have been performed to study the behavior of a low-pressure turbine blade at several Reynolds numbers. Both the predicted and experimental results indicate increased cascade losses as the Reynolds number is reduced to the values associated with aircraft cruise conditions. In addition, both sets of data show that tripping the boundary layer helps reduce the losses at lower Reynolds numbers. Overall, the predicted aerodynamic and performance results exhibit fair agreement with experimental data.

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

PubMed

Ábrigo, Johanna; Elorza, Alvaro A; Riedel, Claudia A; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, Lisbell; Cabello-Verrugio, Claudio

2018-01-01

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

Paralysis and heart failure precede ion balance disruption in heat-stressed European green crabs.

PubMed

Jørgensen, Lisa B; Overgaard, Johannes; MacMillan, Heath A

2017-08-01

Acute exposure of ectotherms to critically high temperatures causes injury and death, and this mortality has been associated with a number of physiological perturbations including impaired oxygen transport, loss of ion and water homeostasis, and neuronal failure. It is difficult to discern which of these factors, if any, is the proximate cause of heat injury because, for example, loss of ion homeostasis can impair neuromuscular function (including cardiac function), and conversely impaired oxygen transport reduces ATP supply and can thus reduce ion transport capacity. In this study we investigated if heat stress causes a loss of ion homeostasis in marine crabs and examined if such loss is related to heart failure. We held crabs (Carcinus maenas) at temperatures just below their critical thermal maximum and measured extracellular (hemolymph) and intracellular (muscle) ion concentrations over time. Analysis of Arrhenius plots for heart rates during heating ramps revealed a breakpoint temperature below which heart rate increased with temperature, and above which heart rate declined until complete cardiac failure. As hypothesised, heat stress reduced the Nernst equilibrium potentials of both K + and Na + , likely causing a depolarization of the membrane potential. To examine whether this loss of ion balance was likely to cause disruption of neuromuscular function, we exposed crabs to the same temperatures, but this time measured ion concentrations at the individual-specific times of complete paralysis (from which the crabs never recovered), and at the time of cardiac failure. Loss of ion balance was observed only after both paralysis and complete heart failure had occurred; indicating that the loss of neuromuscular function is not caused by a loss of ion homeostasis. Instead we suggest that the observed loss of ion balance may be linked to tissue damage related to heat death. Copyright © 2016 Elsevier Ltd. All rights reserved.

Incipient Balancing Selection through Adaptive Loss of Aquaporins in Natural Saccharomyces cerevisiae Populations

PubMed Central

Will, Jessica L.; Kim, Hyun Seok; Clarke, Jessica; Painter, John C.; Fay, Justin C.; Gasch, Audrey P.

2010-01-01

A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw–tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function—providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments—contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection. PMID:20369021

HONSU, a protein phosphatase 2C, regulates seed dormancy by inhibiting ABA signaling in Arabidopsis.

PubMed

Kim, Woohyun; Lee, Yeon; Park, Jeongmoo; Lee, Nayoung; Choi, Giltsu

2013-04-01

Seed dormancy, a seed status that prohibits germination even in the presence of inductive germination signals, is a poorly understood process. To identify molecular components that regulate seed dormancy, we screened T-DNA insertion lines and identified a mutant designated honsu (hon). HON loss-of-function mutants display deep seed dormancy, whereas HON-overexpressing lines display shallow seed dormancy. HON encodes a seed-specific group A phosphatase 2C (PP2C) and is one of the major negative regulators of seed dormancy among group A PP2Cs. Like other PP2C family members, HON interacts with PYR1/RCAR11 in the presence of ABA. Our analysis indicates that HON inhibits ABA signaling and activates gibberellic acid signaling, and both of these conditions must be satisfied to promote the release of seed dormancy. However, HON mRNA levels are increased in mutants displaying deep seed dormancy or under conditions that deepen seed dormancy, and decreased in mutants displaying shallow seed dormancy or under conditions that promote the release of seed dormancy. Taken together, our results indicate that the expression of HON mRNA is homeostatically regulated by seed dormancy.

The role of nutrition in the prevention of sarcopenia.

PubMed

Volkert, Dorothee

2011-09-01

Nutrition is regarded as one important contributing factors in the complex etiology of sarcopenia. Associations between several nutritional factors and muscle mass, strength, function and physical performance were reported in a growing number of studies in recent years. Accordingly, the avoidance of weight loss is crucial to prevent the concomitant loss of muscle mass. Adequate amounts of high-quality protein are important for optimal stimulation of muscle protein synthesis. Vitamin D, antioxidants and ω 3-polyunsaturated fatty acids may also contribute to the preservation of muscle function. In order to ensure adequate intake in all elderly, nutritional problems like loss of appetite and weight loss should be recognized early by routine screening for malnutrition in the elderly. Underlying causes need to be identified and subsequently corrected. The importance of physical activity, specifically resistance training, is emphasized, not only in order to facilitate muscle protein anabolism but also to increase energy expenditure, appetite and food intake in elderly people at risk of malnutrition.

Plasma Cytokine Levels During Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Crucian, Brian E.; Zwart, Sara R.; Quiriarte, Heather A.; Smith, Scott M.; Sams, Clarence F.

2012-01-01

Determine the in-flight status of immunity, physiological stress, viral immunity/reactivation. Specific measurements include leukocyte distribution, T cell function, cytokine production profiles (mRNA, intracellular, secreted, plasma), virus-specific T cell number/function, latent herpesvirus reactivation, stress hormone levels. Determine the clinical risk related to immune dysregulation for exploration class spaceflight, as well as an appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures. Specific Study Objectives: Determine the nutritional status of astronauts before, during, and after spaceflight ensure adequate intake of energy, protein, and vitamins during missions. The Clinical Nutritional Status Assessment measures dietary intake, body composition, protein, bone, iron, mineral, vitamin, and antioxidant status (60 total analytes). Currently, it is a medical requirement for U.S. crewmembers on-board the ISS. The results of data analysis are used both to understand the connections between nutrition and human health during space flight, and to develop effective dietary strategies to reduce adverse health impacts (including bone loss, loss of important vitamins and minerals, and increased genetic damage from radiation).

Immune Reconstitution Inflammatory Syndrome (IRIS): What pathologists should know.

PubMed

Nelson, Ann Marie; Manabe, Yukari C; Lucas, Sebastian B

2017-07-01

Antiretroviral therapy has significantly improved the quality and length of life for those patients able to access effective and sustained treatment. The resulting restoration of the immune response is associated with a change in the clinical presentation of opportunistic infections, and the histologic reaction to pathogens. A complex combination of alterations in host response across the stages of HIV infection has been documented over the past 3 decades. The defects are seen in both acute and chronic phases of inflammation and involve innate and adaptive immunity. In advanced stages of HIV infection, the marked disruption of lymphoid tissue and loss of follicular dendritic cells limits the host's ability to process antigen and mount specific responses to pathogens. There are qualitative and quantitative defects in CD4 T cells due to HIV infection. The resulting indirect effects include loss of cytokine production, dysregulation of B-cell function, loss of cellular mediated immunity and "holes" in the immunologic repertoire that may not be restored with the use of antiretroviral therapy. Immune reconstitution allows the host to respond to and control infection, but a significant number of patients will have atypical inflammatory syndromes during the recovery period. We briefly discuss the impact of HIV infection on the immune system and give an overview of the spectrum of conditions attributed to the Immune Reconstitution Inflammatory syndrome (IRIS). Copyright © 2017 Elsevier Inc. All rights reserved.

Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models.

PubMed

Yokoi, Fumiaki; Dang, Mai T; Zhou, Tong; Li, Yuqing

2012-02-15

DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ε-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ε-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ε-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ε-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.

Metal Matrix Superconductor Composites for SMES-Driven, Ultra High Power BEP Applications: Part 2

NASA Astrophysics Data System (ADS)

Gross, Dan A.; Myrabo, Leik N.

2006-05-01

A 2.5 TJ superconducting magnetic energy storage (SMES) design presentation is continued from the preceding paper (Part 1) with electromagnetic and associated stress analysis. The application of interest is a rechargeable power-beaming infrastructure for manned microwave Lightcraft operations. It is demonstrated that while operational performance is within manageable parameter bounds, quench (loss of superconducting state) imposes enormous electrical stresses. Therefore, alternative multiple toroid modular configurations are identified, alleviating simultaneously all excessive stress conditions, operational and quench, in the structural, thermal and electromagnetic sense — at some reduction in specific energy, but presenting programmatic advantages for a lengthy technology development, demonstration and operation schedule. To this end several natural units, based on material properties and operating parameters are developed, in order to identify functional relationships and optimization paths more effectively.

Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland

PubMed Central

Godde, Nathan J.; Sheridan, Julie M.; Smith, Lorey K.; Pearson, Helen B.; Britt, Kara L.; Galea, Ryan C.; Yates, Laura L.; Visvader, Jane E.; Humbert, Patrick O.

2014-01-01

Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression. PMID:24852022

The long-term corrosion performance of Alloy 22 in heated brine solutions

DOE PAGES

Enos, D. G.; Bryan, C. R.

2015-02-13

Long-term corrosion experiments have been performed on Alloy 22 (UNS N06022), in a series of heated brines formulated to represent evaporatively concentrated ground water, to evaluate the long-term corrosion performance of the material. These solutions included 0.5 M NaCl, in addition to two simulated concentrated ground water solutions. Under conditions where Alloy 22 was anticipated to be passive, the corrosion rate was found to be vanishingly small (i.e., below the resolution of the weight-loss technique used to quantify corrosion in this study). However, under low pH conditions where Alloy 22 was anticipated to be active, or more specifically, where themore » chromium oxide passive film was not thermodynamically stable, the corrosion rate was appreciable. Furthermore, under such conditions the corrosion rate was observed to be a strong function of temperature, with an activation energy of 72.9±1.8 kJ/mol. Time of Flight-Secondary Ion Mass Spectroscopy analysis of the oxide layer revealed that, while sulfur was present within the oxide for all test conditions, no accumulation was observed at or near the metal/oxide interface. Furthermore, these observations confirm that inhibition of passive film formation via sulfur accumulation does not occur during the corrosion of Alloy 22.« less

Effects of sleep deprivation on cognition.

PubMed

Killgore, William D S

2010-01-01

Sleep deprivation is commonplace in modern society, but its far-reaching effects on cognitive performance are only beginning to be understood from a scientific perspective. While there is broad consensus that insufficient sleep leads to a general slowing of response speed and increased variability in performance, particularly for simple measures of alertness, attention and vigilance, there is much less agreement about the effects of sleep deprivation on many higher level cognitive capacities, including perception, memory and executive functions. Central to this debate has been the question of whether sleep deprivation affects nearly all cognitive capacities in a global manner through degraded alertness and attention, or whether sleep loss specifically impairs some aspects of cognition more than others. Neuroimaging evidence has implicated the prefrontal cortex as a brain region that may be particularly susceptible to the effects of sleep loss, but perplexingly, executive function tasks that putatively measure prefrontal functioning have yielded inconsistent findings within the context of sleep deprivation. Whereas many convergent and rule-based reasoning, decision making and planning tasks are relatively unaffected by sleep loss, more creative, divergent and innovative aspects of cognition do appear to be degraded by lack of sleep. Emerging evidence suggests that some aspects of higher level cognitive capacities remain degraded by sleep deprivation despite restoration of alertness and vigilance with stimulant countermeasures, suggesting that sleep loss may affect specific cognitive systems above and beyond the effects produced by global cognitive declines or impaired attentional processes. Finally, the role of emotion as a critical facet of cognition has received increasing attention in recent years and mounting evidence suggests that sleep deprivation may particularly affect cognitive systems that rely on emotional data. Thus, the extent to which sleep deprivation affects a particular cognitive process may depend on several factors, including the magnitude of global decline in general alertness and attention, the degree to which the specific cognitive function depends on emotion-processing networks, and the extent to which that cognitive process can draw upon associated cortical regions for compensatory support. Copyright © 2010 Elsevier B.V. All rights reserved.

Quantifying The Influence Of Time-Since-Creation On Benthic Secondary Production In Created Coastal Habitats

EPA Science Inventory

Wetland creation, enhancement, and restoration activities are commonly implemented to compensate for wetland loss or degradation in freshwater and coastal ecosystems. While assessments on structural condition are common in monitoring habitat restoration, functional equivalence i...

Nonparametric Conditional Estimation

DTIC Science & Technology

1987-02-01

the data because the statistician has complete control over the method. It is especially reasonable when there is a bone fide loss function to which...For example, the sample mean is m(Fn). Most calculations that statisticians perform on a set of data can be expressed as statistical functionals on...of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering