Understory light regimes following silvicultural treatments in central hardwood forests in Kentucky, USA

Treesearch

Stephen F. Grayson; David S. Buckley; Jason G. Henning; Callie J. Schweitzer; Kurt W. Gottschalk; David L. Loftis

2012-01-01

Manipulation of the light regime is a primary goal of many silvicultural treatments, but the specific light conditions created remain poorly documented for many forest types and geographic locations. To help quantify effects of silvicultural treatments on light conditions, measurements of basal area, canopy cover, and photosynthetically active radiation (PAR), measured...

Validity and Reliability of Nintendo Wii Fit Balance Scores

PubMed Central

Wikstrom, Erik A.

2012-01-01

Context: Interactive gaming systems have the potential to help rehabilitate patients with musculoskeletal conditions. The Nintendo Wii Balance Board, which is part of the Wii Fit game, could be an effective tool to monitor progress during rehabilitation because the board and game can provide objective measures of balance. However, the validity and reliability of Wii Fit balance scores remain unknown. Objective: To determine the concurrent validity of balance scores produced by the Wii Fit game and the intrasession and intersession reliability of Wii Fit balance scores. Design: Descriptive laboratory study. Setting: Sports medicine research laboratory. Patients or Other Participants: Forty-five recreationally active participants (age  =  27.0 ± 9.8 years, height  =  170.9 ± 9.2 cm, mass  =  72.4 ± 11.8 kg) with a heterogeneous history of lower extremity injury. Intervention(s): Participants completed a single-limb–stance task on a force plate and the Star Excursion Balance Test (SEBT) during the first test session. Twelve Wii Fit balance activities were completed during 2 test sessions separated by 1 week. Main Outcome Measure(s): Postural sway in the anteroposterior (AP) and mediolateral (ML) directions and the AP, ML, and resultant center-of-pressure (COP) excursions were calculated from the single-limb stance. The normalized reach distance was recorded for the anterior, posteromedial, and posterolateral directions of the SEBT. Wii Fit balance scores that the game software generated also were recorded. Results: All 96 of the calculated correlation coefficients among Wii Fit activity outcomes and established balance outcomes were interpreted as poor (r < 0.50). Intrasession reliability for Wii Fit balance activity scores ranged from good (intraclass correlation coefficient [ICC]  =  0.80) to poor (ICC  =  0.39), with 8 activities having poor intrasession reliability. Similarly, 11 of the 12 Wii Fit balance activity scores demonstrated poor intersession reliability, with scores ranging from fair (ICC  =  0.74) to poor (ICC  =  0.29). Conclusions: Wii Fit balance activity scores had poor concurrent validity relative to COP outcomes and SEBT reach distances. In addition, the included Wii Fit balance activity scores generally had poor intrasession and intersession reliability. PMID:22892412

Selective Neuronal Activation by Cochlear Implant Stimulation in Auditory Cortex of Awake Primate

PubMed Central

Johnson, Luke A.; Della Santina, Charles C.

2016-01-01

Despite the success of cochlear implants (CIs) in human populations, most users perform poorly in noisy environments and music and tonal language perception. How CI devices engage the brain at the single neuron level has remained largely unknown, in particular in the primate brain. By comparing neuronal responses with acoustic and CI stimulation in marmoset monkeys unilaterally implanted with a CI electrode array, we discovered that CI stimulation was surprisingly ineffective at activating many neurons in auditory cortex, particularly in the hemisphere ipsilateral to the CI. Further analyses revealed that the CI-nonresponsive neurons were narrowly tuned to frequency and sound level when probed with acoustic stimuli; such neurons likely play a role in perceptual behaviors requiring fine frequency and level discrimination, tasks that CI users find especially challenging. These findings suggest potential deficits in central auditory processing of CI stimulation and provide important insights into factors responsible for poor CI user performance in a wide range of perceptual tasks. SIGNIFICANCE STATEMENT The cochlear implant (CI) is the most successful neural prosthetic device to date and has restored hearing in hundreds of thousands of deaf individuals worldwide. However, despite its huge successes, CI users still face many perceptual limitations, and the brain mechanisms involved in hearing through CI devices remain poorly understood. By directly comparing single-neuron responses to acoustic and CI stimulation in auditory cortex of awake marmoset monkeys, we discovered that neurons unresponsive to CI stimulation were sharply tuned to frequency and sound level. Our results point out a major deficit in central auditory processing of CI stimulation and provide important insights into mechanisms underlying the poor CI user performance in a wide range of perceptual tasks. PMID:27927962

An Evaluation of Passive and Active Approaches to Improve Tuberculosis Notifications in Afghanistan

PubMed Central

Sanaie, A.; Nasrat, A.; Seddiq, M. K.; Mahmoodi, S. D.; Stevens, R. H.; Creswell, J.

2016-01-01

Background In Afghanistan, improving TB case detection remains challenging. In 2014, only half of the estimated incident TB cases were notified, and notifications have decreased since peaking in 2007. Active case finding has been increasingly considered to improve TB case notifications. While access to health services has improved in Afghanistan, it remains poor and many people seeking health services won’t receive proper care. Methods From October 2011 through December 2012 we conducted three separate case finding strategies in six provinces of Afghanistan and measured impact on TB case notification. Systematically screening cough among attendees at 47 health facilities, active household contact investigation of smear-positive index TB patients, and active screening at 15 camps for internally displaced people were conducted. We collected both intervention yield and official quarterly notification data. Additional TB notifications were calculated by comparing numbers of cases notified during the intervention with those notified before the intervention, then adjusting for secular trends in notification. Results We screened 2,022,127 people for TB symptoms during the intervention, tested 59,838 with smear microscopy and detected 5,046 people with smear-positive TB. Most cases (81.7%, 4,125) were identified in health facilities while nearly 20% were found through active case finding. A 56% increase in smear-positive TB notifications was observed between the baseline and intervention periods among the 47 health facilities, where cases detected by all three strategies were notified. Discussion While most people with TB are likely to be identified through health facility screening, there are many people who remain without a proper diagnosis if outreach is not attempted. This is especially true in places like Afghanistan where access to general services is poor. Targeted active case finding can improve the number of people who are detected and treated for TB and can push towards the targets of the Stop TB Global Plan and End TB Strategy. PMID:27701446

An Evaluation of Passive and Active Approaches to Improve Tuberculosis Notifications in Afghanistan.

PubMed

Sanaie, A; Mergenthaler, C; Nasrat, A; Seddiq, M K; Mahmoodi, S D; Stevens, R H; Creswell, J

2016-01-01

In Afghanistan, improving TB case detection remains challenging. In 2014, only half of the estimated incident TB cases were notified, and notifications have decreased since peaking in 2007. Active case finding has been increasingly considered to improve TB case notifications. While access to health services has improved in Afghanistan, it remains poor and many people seeking health services won't receive proper care. From October 2011 through December 2012 we conducted three separate case finding strategies in six provinces of Afghanistan and measured impact on TB case notification. Systematically screening cough among attendees at 47 health facilities, active household contact investigation of smear-positive index TB patients, and active screening at 15 camps for internally displaced people were conducted. We collected both intervention yield and official quarterly notification data. Additional TB notifications were calculated by comparing numbers of cases notified during the intervention with those notified before the intervention, then adjusting for secular trends in notification. We screened 2,022,127 people for TB symptoms during the intervention, tested 59,838 with smear microscopy and detected 5,046 people with smear-positive TB. Most cases (81.7%, 4,125) were identified in health facilities while nearly 20% were found through active case finding. A 56% increase in smear-positive TB notifications was observed between the baseline and intervention periods among the 47 health facilities, where cases detected by all three strategies were notified. While most people with TB are likely to be identified through health facility screening, there are many people who remain without a proper diagnosis if outreach is not attempted. This is especially true in places like Afghanistan where access to general services is poor. Targeted active case finding can improve the number of people who are detected and treated for TB and can push towards the targets of the Stop TB Global Plan and End TB Strategy.

Lateral gene transfer in a heavy metal-contaminated-groundwater microbial community

DOE PAGES

Hemme, Christopher L.; Green, Stefan J.; Rishishwar, Lavanya; ...

2016-04-05

Here, unraveling the drivers controlling the response and adaptation of biological communities to environmental change, especially anthropogenic activities, is a central but poorly understood issue in ecology and evolution. Comparative genomics studies suggest that lateral gene transfer (LGT) is a major force driving microbial genome evolution, but its role in the evolution of microbial communities remains elusive.

Naïve CD8 T cell activation by liver bone marrow-derived cells leads to a "neglected" IL-2low Bimhigh phenotype, poor CTL function and cell death.

PubMed

Holz, Lauren E; Benseler, Volker; Vo, Michelle; McGuffog, Claire; Van Rooijen, Nico; McCaughan, Geoffrey W; Bowen, David G; Bertolino, Patrick

2012-10-01

The occurrence of primary CD8 T cell activation within the liver, unique among the non-lymphoid organs, is now well accepted. However, the outcome of intrahepatic T cell activation remains controversial. We have previously reported that activation initiated by hepatocytes results in a tolerogenic phenotype characterized by low expression of CD25 and IL-2, poor cytotoxic T lymphocyte (CTL) function, and excessive expression of the pro-apoptotic protein Bim. To investigate whether this phenotype was due to activation in the absence of co-stimulation, we generated bone marrow (bm) radiation chimeras in which adoptively transferred naïve transgenic CD8 T cells were activated in the presence of co-stimulation by liver bm-derived cells. Despite expressing pro-inflammatory cytokines, high levels of CD25 and CD54, donor T cells activated by liver bm-derived cells did not produce detectable IL-2 and displayed poor CTL function, suggesting incomplete acquisition of effector function. Simultaneously, these cells expressed high levels of Bim and died by neglect. Transfer of Bim-deficient T cells resulted in increased T cell numbers. These results imply that expression of CD25 and CD54 is co-stimulation dependent and distinguishes T cell activated by hepatocytes and liver bm-derived cells. In contrast, low expression of IL-2, poor CTL function and excess Bim production represent a more universal phenotype defining T cells undergoing primary activation by both types of hepatic antigen presenting cells (APC). These results have important implications for transplantation, in which all liver antigen presenting cells contribute to activation of T cells specific for the allograft. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The Infernal Business of Contract Cheating: Understanding the Business Processes and Models of Academic Custom Writing Sites

ERIC Educational Resources Information Center

Ellis, Cath; Zucker, Ian Michael; Randall, David

2018-01-01

While there is growing awareness of the existence and activities of Academic Custom Writing websites, which form a small part of the contract cheating industry, how they work remains poorly understood. Very little research has been done on these sites, probably because it has been assumed that it is impossible to see behind their firewalls and…

Physical inactivity post-stroke: a 3-year longitudinal study.

PubMed

Kunkel, Dorit; Fitton, Carolyn; Burnett, Malcolm; Ashburn, Ann

2015-01-01

To explore change in activity levels post-stroke. We measured activity levels using the activPAL™ in hospital and at 1, 2 and 3 years' post-stroke onset. Of the 74 participants (mean age 76 (SD 11), 39 men), 61 were assessed in hospital: 94% of time was spent in sitting/lying, 4% standing and 2% walking. Activity levels improved over time (complete cases n = 15); time spent sitting/lying decreased (p = 0.001); time spent standing, walking and number of steps increased (p = 0.001, p = 0.028 and p = 0.03, respectively). At year 3, 18% of time was spent in standing and 9% walking. Time spent upright correlated significantly with Barthel (r = 0.69 on admission, r = 0.68 on discharge, both p < 0.01) and functional ambulation category scores (r = 0.55 on admission, 0.63 on discharge, both p < 0.05); correlations remained significant at all assessment points. Depression (in hospital), left hemisphere infarction (Years 1-2), visual neglect (Year 2), poor mobility and balance (Years 1-3) correlated with poorer activity levels. People with stroke were inactive for the majority of time. Time spent upright improved significantly by 1 year post-stroke; improvements slowed down thereafter. Poor activity levels correlated with physical and psychological measures. Larger studies are indicated to identify predictors of activity levels. Implications for Rehabilitation Activity levels (measured using activPAL™ activity monitor), increased significantly by 1 year post-stroke but improvements slowed down at 2 and 3 years. People with stroke were inactive for the majority of their day in hospital and in the community. Poor activity levels correlated with physical and psychological measures. Larger studies are indicated to identify the most important predictors of activity levels.

Emerging roles for hemostatic dysfunction in malaria pathogenesis.

PubMed

O'Sullivan, Jamie M; Preston, Roger J S; O'Regan, Niamh; O'Donnell, James S

2016-05-12

Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance. © 2016 by The American Society of Hematology.

Singing with yourself: evidence for an inverse modeling account of poor-pitch singing.

PubMed

Pfordresher, Peter Q; Mantell, James T

2014-05-01

Singing is a ubiquitous and culturally significant activity that humans engage in from an early age. Nevertheless, some individuals - termed poor-pitch singers - are unable to match target pitches within a musical semitone while singing. In the experiments reported here, we tested whether poor-pitch singing deficits would be reduced when individuals imitate recordings of themselves as opposed to recordings of other individuals. This prediction was based on the hypothesis that poor-pitch singers have not developed an abstract "inverse model" of the auditory-vocal system and instead must rely on sensorimotor associations that they have experienced directly, which is true for sequences an individual has already produced. In three experiments, participants, both accurate and poor-pitch singers, were better able to imitate sung recordings of themselves than sung recordings of other singers. However, this self-advantage was enhanced for poor-pitch singers. These effects were not a byproduct of self-recognition (Experiment 1), vocal timbre (Experiment 2), or the absolute pitch of target recordings (i.e., the advantage remains when recordings are transposed, Experiment 3). Results support the conceptualization of poor-pitch singing as an imitative deficit resulting from a deficient inverse model of the auditory-vocal system with respect to pitch. Copyright © 2014 Elsevier Inc. All rights reserved.

Measurement of host-to-activator transfer efficiency in nano-crystalline Y{sub 2}O{sub 3}:Eu{sup 3+} under VUV excitation

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

Waite, Christopher; Mann, Rusty; Diaz, Anthony L., E-mail: DiazA@cwu.edu

2013-02-15

We have conducted a systematic study of the excitation and reflectance spectra of nano-crystalline Y{sub 2}O{sub 3}:Eu prepared by combustion synthesis. Excitation through the host lattice becomes relatively more efficient as the firing temperature of the precursor is increased, while reflectance properties remain essentially unchanged. Using these data, host-to-activator transfer efficiencies were calculated for excitation at the band edge of Y{sub 2}O{sub 3}, and evaluated using a competition kinetics model. From this analysis we conclude that the relatively low luminous efficiency of these materials is due more to poor bulk crystallinity than to surface loss effects. - Graphical abstract: Themore » low luminous efficiency of nano-crystalline Y{sub 2}O{sub 3}:Eu{sup 3+} prepared by combustion synthesis is due to poor bulk crystallinity rather than surface loss effects. Highlights: Black-Right-Pointing-Pointer We report on the optical properties of Y{sub 2}O{sub 3}:Eu{sup 3+} prepared by combustion synthesis. Black-Right-Pointing-Pointer Host-to-activator transfer efficiencies under VUV excitation were calculated. Black-Right-Pointing-Pointer The low luminous efficiency of these materials is due to poor bulk crystallinity.« less

Tracking Vaccination Teams During Polio Campaigns in Northern Nigeria by Use of Geographic Information System Technology: 2013-2015.

PubMed

Touray, Kebba; Mkanda, Pascal; Tegegn, Sisay G; Nsubuga, Peter; Erbeto, Tesfaye B; Banda, Richard; Etsano, Andrew; Shuaib, Faisal; Vaz, Rui G

2016-05-01

Nigeria is among the 3 countries in which polio remains endemic. The country made significant efforts to reduce polio transmission but remains challenged by poor-quality campaigns and poor team performance in some areas. This article demonstrates the application of geographic information system technology to track vaccination teams to monitor settlement coverage, reduce the number of missed settlements, and improve team performance. In each local government area where tracking was conducted, global positioning system-enabled Android phones were given to each team on a daily basis and were used to record team tracks. These tracks were uploaded to a dashboard to show the level of coverage and identify areas missed by the teams. From 2012 to June 2015, tracking covered 119 immunization days. A total of 1149 tracking activities were conducted. Of these, 681 (59%) were implemented in Kano state. There was an improvement in the geographic coverage of settlements and an overall reduction in the number of missed settlements. The tracking of vaccination teams provided significant feedback during polio campaigns and enabled supervisors to evaluate performance of vaccination teams. The reports supported other polio program activities, such as review of microplans and the deployment of other interventions, for increasing population immunity in northern Nigeria. © 2016 World Health Organization; licensee Oxford Journals.

Structure of the novel monomeric glyoxalase I from Zea mays

PubMed Central

Turra, Gino L.; Agostini, Romina B.; Fauguel, Carolina M.; Presello, Daniel A.; Andreo, Carlos S.; González, Javier M.; Campos-Bermudez, Valeria A.

2015-01-01

The glyoxalase system is ubiquitous among all forms of life owing to its central role in relieving the cell from the accumulation of methylglyoxal, a toxic metabolic byproduct. In higher plants, this system is upregulated under diverse metabolic stress conditions, such as in the defence response to infection by pathogenic microorganisms. Despite their proven fundamental role in metabolic stresses, plant glyoxalases have been poorly studied. In this work, glyoxalase I from Zea mays has been characterized both biochemically and structurally, thus reporting the first atomic model of a glyoxalase I available from plants. The results indicate that this enzyme comprises a single polypeptide with two structurally similar domains, giving rise to two lateral concavities, one of which harbours a functional nickel(II)-binding active site. The putative function of the remaining cryptic active site remains to be determined. PMID:26457425

Structure of the novel monomeric glyoxalase I from Zea mays.

PubMed

Turra, Gino L; Agostini, Romina B; Fauguel, Carolina M; Presello, Daniel A; Andreo, Carlos S; González, Javier M; Campos-Bermudez, Valeria A

2015-10-01

The glyoxalase system is ubiquitous among all forms of life owing to its central role in relieving the cell from the accumulation of methylglyoxal, a toxic metabolic byproduct. In higher plants, this system is upregulated under diverse metabolic stress conditions, such as in the defence response to infection by pathogenic microorganisms. Despite their proven fundamental role in metabolic stresses, plant glyoxalases have been poorly studied. In this work, glyoxalase I from Zea mays has been characterized both biochemically and structurally, thus reporting the first atomic model of a glyoxalase I available from plants. The results indicate that this enzyme comprises a single polypeptide with two structurally similar domains, giving rise to two lateral concavities, one of which harbours a functional nickel(II)-binding active site. The putative function of the remaining cryptic active site remains to be determined.

Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict

PubMed Central

Zavala, Baltazar; Damera, Srikanth; Dong, Jian Wilson; Lungu, Codrin; Brown, Peter; Zaghloul, Kareem A.

2017-01-01

Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict. PMID:26494798

Phosphoinositide 3-Kinase p110δ Mediates Estrogen- and FSH-Stimulated Ovarian Follicle Growth

PubMed Central

Li, Qian; He, Hui; Zhang, Yin-Li; Li, Xiao-Meng; Guo, Xuejiang; Huo, Ran; Bi, Ye; Li, Jing

2013-01-01

In the mammalian ovary, primordial follicles are generated early in life and remain dormant for prolonged periods. Their growth resumes via primordial follicle activation, and they continue to grow until the preovulatory stage under the regulation of hormones and growth factors, such as estrogen, FSH, and IGF-1. Both FSH and IGF-1 activate the phosphatidylinositol-3 kinase (PI3K)/Akt (acute transforming retrovirus thymoma protein kinase) signaling pathway in granulosa cells (GCs), yet it remains inconclusive whether the PI3K pathway is crucial for follicle growth. In this study, we investigated the p110δ isoform (encoded by the Pik3cd gene) of PI3K catalytic subunit expression in the mouse ovary and its function in fertility. Pik3cd-null females were subfertile, exhibited fewer growing follicles and more atretic antral follicles in the ovary, and responded poorly to exogenous gonadotropins compared with controls. Ovary transplantation showed that Pik3cd-null ovaries responded poorly to FSH stimulation in vitro; this confirmed that the follicle growth defect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growth and GC proliferation in preantral follicles was impaired in Pik3cd-null ovaries. FSH and E2 substantially activated the PI3K/Akt pathway in GCs of control mice but not in those of Pik3cd-null mice. However, primordial follicle activation and oocyte meiotic maturation were not affected by Pik3cd knockout. Taken together, our findings indicate that the p110δ isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian GCs; however, it is not required for primordial follicle activation and oocyte development. PMID:23820902

Serial functional imaging poststroke reveals visual cortex reorganization.

PubMed

Brodtmann, Amy; Puce, Aina; Darby, David; Donnan, Geoffrey

2009-02-01

Visual cortical reorganization following injury remains poorly understood. The authors performed serial functional magnetic resonance imaging (fMRI) on patients with visual cortex infarction to evaluate early and late striate, ventral, and dorsal extrastriate cortical activation. Patients were studied with fMRI within 10 days and at 6 months. The authors used a high-level visual activation task designed to activate the ventral extrastriate cortex. These data were compared to those of age-appropriate healthy control participants. The results from 24 healthy control individuals (mean age 65.7 +/- SE 3.6 years, range 32-89) were compared to those from 5 stroke patients (mean age 73.8 +/- SE 7 years, range 49-86). Patients had infarcts involving the striate and ventral extrastriate cortex. Patient activation patterns were markedly different to controls. Bilateral striate and ventral extrastriate activation was reduced at both sessions, but dorsal extrastriate activated voxel counts remained comparable to controls. Conversely, mean percent magnetic resonance signal change increased in dorsal sites. These data provide strong evidence of bilateral poststroke functional depression of striate and ventral extrastriate cortices. Possible utilization or surrogacy of the dorsal visual system was demonstrated following stroke. This activity could provide a target for novel visual rehabilitation therapies.

Isotopic signals of summer denitrification in a northern hardwood forested catchment

Treesearch

Sarah K. Wexler; Christine L. Goodale; Kevin J. McGuire; Scott W. Bailey; Peter M. Groffman

2014-01-01

Despite decades of measurements, the nitrogen balance of temperate forest catchments remains poorly understood. Atmospheric nitrogen deposition often greatly exceeds streamwater nitrogen losses; the fate of the remaining nitrogen is highly uncertain. Gaseous losses of nitrogen to denitrification are especially poorly documented and are often ignored. Here, we provide...

Individualized controlled ovarian stimulation in expected poor-responders: an update.

PubMed

Haahr, Thor; Esteves, Sandro C; Humaidan, Peter

2018-03-09

Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies.

Nanostructured lipid carriers: versatile oral delivery vehicle

PubMed Central

Poonia, Neelam; Kharb, Rajeev; Lather, Viney; Pandita, Deepti

2016-01-01

Oral delivery is the most accepted and economical route for drug administration and leads to substantial reduction in dosing frequency. However, this route still remains a challenge for the pharmaceutical industry due to poorly soluble and permeable drugs leading to poor oral bioavailability. Incorporating bioactives into nanostructured lipid carriers (NLCs) has helped in boosting their therapeutic functionality and prolonged release from these carrier systems thus providing improved pharmacokinetic parameters. The present review provides an overview of noteworthy studies reporting impending benefits of NLCs in oral delivery and highlights recent advancements for developing engineered NLCs either by conjugating polymers over their surface or modifying their charge to overcome the mucosal barrier of GI tract for active transport across intestinal membrane. PMID:28031979

Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain

PubMed Central

Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.

2015-01-01

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050

Factors associated with numbers of remaining teeth among type 2 diabetes: a cross-sectional study.

PubMed

Huang, Jui-Chu; Peng, Yun-Shing; Fan, Jun-Yu; Jane, Sui-Whi; Tu, Liang-Tse; Chang, Chang-Cheng; Chen, Mei-Yen

2013-07-01

To explore the factors associated with the numbers of remaining teeth among type 2 diabetes community residents. Promoting oral health is an important nursing role for patients with diabetes, especially in disadvantaged areas. However, limited research has been carried out on the relationship between numbers of remaining teeth, diabetes-related biomarkers and personal oral hygiene among diabetic rural residents. A cross-sectional, descriptive design with a simple random sample was used. This study was part of a longitudinal cohort study of health promotion for preventing diabetic foot among rural community diabetic residents. It was carried out in 18 western coastal and inland districts of Chiayi County in central Taiwan. In total, 703 participants were enrolled in this study. The findings indicated that a high percentage of the participants (26%) had no remaining natural teeth. Nearly three quarters (74%) had fewer than 20 natural teeth. After controlling for the potential confounding factors, multivariate analysis demonstrated that the factors determining numbers of remaining teeth were age (p < 0.001), education (p < 0.001), using dental floss (p = 0.003), ankle brachial pressure index (p = 0.028), waist circumference (p = 0.024) and HbA1C (p = 0.033). Except for some unmodifiable factors, the factors most significantly associated with numbers of remaining teeth were less tooth-brushing with dental floss, abnormal ankle brachial pressure and poor glycemic control. This study highlights the importance of nursing intervention in oral hygiene for patients with type 2 diabetes. It is necessary to initiate oral health promotion activities when diabetes is first diagnosed, especially for older diabetic residents of rural or coastal areas who are poorly educated. © 2013 John Wiley & Sons Ltd.

The solar dynamo

NASA Technical Reports Server (NTRS)

Hathaway, David H.

1994-01-01

The solar dynamo is the process by which the Sun's magnetic field is generated through the interaction of the field with convection and rotation. In this, it is kin to planetary dynamos and other stellar dynamos. Although the precise mechanism by which the Sun generates its field remains poorly understood in spite of decades of theoretical and observational work, recent advances suggest that solutions to this solar dynamo problem may be forthcoming. The two basic processes involved in dynamo activity are demonstrated and the Sun's activity effects are presented in this document, along with a historical perspective regarding solar dynamos and the efforts to understand and measure them.

What are the characteristics of 'sexually ready' adolescents? Exploring the sexual readiness of youth in urban poor Accra.

PubMed

Biney, Adriana A E; Dodoo, F Nii-Amoo

2016-01-05

Adolescent sexual activity, especially among the urban poor, remains a challenge. Despite numerous interventions and programs to address the negative consequences arising from early and frequent sexual activity among youth in sub-Saharan Africa, including Ghana, only slight progress has been made. A plausible explanation is that our understanding of what adolescents think about sex and about their own sexuality is poor. In that sense, examining how adolescents in urban poor communities think about their sexual readiness, and identifying characteristics associated with that sexual self-concept dimension, should deepen our understanding of this topical issue. A total of 196 male and female adolescents, ages 12 to 19, were surveyed in the 2011 RIPS Urban Health and Poverty Project in Accra, Ghana. The youth responded to three statements which determined their levels of sexual readiness. Other background characteristics were also obtained enabling the assessment of the correlates of their preparedness to engage in sex. The data were analyzed using ordered logistic regression models. Overall, the majority of respondents did not consider themselves ready for sex. Multivariate analyses indicated that sexual experience, exposure to pornographic movies, gender, ethnicity and household wealth were significantly linked to their readiness for sex. Sexual readiness is related to sexual activity as well as other characteristics of the adolescents, suggesting the need to consider these factors in the design of programs and interventions to curb early sex. The subject of sexual readiness has to be investigated further to ensure adolescents do not identify with any negative effects of this sexual self-view.

Reducing violence in poor urban areas of Honduras by building community resilience through community-based interventions.

PubMed

Hansen-Nord, Nete Sloth; Kjaerulf, Finn; Almendarez, Juan; Rodas, Victor Morales; Castro, Julio

2016-11-01

To examine the impact of a 3 year community-based violence prevention intervention on risk of violence and social capital in two poor urban communities in Honduras in 2011-2014. A quasi-experimental design pre and post implementation of the intervention was conducted based on data from two randomly selected samples using the same structured questionnaire in 2011 and in 2014. Community members had a 42 % lower risk of violence in 2014 compared to 2011. There was a positive relation between participation in the intervention and structural social capital, and participants had more than twice the likelihood of engaging in citizenship activities compared to the general population. The intervention contributed to decreasing violence and increasing community resilience in two urban areas in Honduras. Citizenship activities and active community participation in the violence prevention agenda rather than social trust and cohesion characteristics was affected by the intervention. This research introduces important lessons learned to future researchers aiming to retrieve very sensitive data in a similarly violent setting, and provides strong research opportunities within areas, which to this date remain undiscovered.

[Autologous bone marrow transplantation in intestinal carcinoma].

PubMed

Sebesta, C; Tiefengraber, E; Kier, P; Ruckser, R; Habertheuer, K H; Schmid, A; Hinterberger, W

1995-01-01

Although adjuvant chemotherapy has made some progress in the treatment of colorectal cancer, chemotherapy of metastatic disease remains disappointing. Autologous bone marrow or stem cell transplantation following supralethal chemotherapy is presently not of major significance in tumors of the intestine. The registry of the EBMT (European Cooperative Group for Blood and Marrow Transplantation) contains at March 1993 a total of 2085 cases of autotransplants for solid tumors, of which only 19 were performed for disseminated gastrointestinal cancer (15 gastric, 4 colon). It remains to be shown, whether the presently poor results can be improved upon inclusion of lymphokine-activated killer cells (LAK-cells) by use of cytokine combinations or by the use of tumor infiltrating lymphocytes (TIL) post transplantation.

Mapping Proteome-wide Targets of Glyphosate in Mice.

PubMed

Ford, Breanna; Bateman, Leslie A; Gutierrez-Palominos, Leilani; Park, Robin; Nomura, Daniel K

2017-02-16

Glyphosate, the active ingredient in the herbicide Roundup, is one of the most widely used pesticides in agriculture and home garden use. Whether glyphosate causes any mammalian toxicity remains highly controversial. While many studies have associated glyphosate with numerous adverse health effects, the mechanisms underlying glyphosate toxicity in mammals remain poorly understood. Here, we used activity-based protein profiling to map glyphosate targets in mice. We show that glyphosate at high doses can be metabolized in vivo to reactive metabolites such as glyoxylate and react with cysteines across many proteins in mouse liver. We show that glyoxylate inhibits liver fatty acid oxidation enzymes and glyphosate treatment in mice increases the levels of triglycerides and cholesteryl esters, likely resulting from diversion of fatty acids away from oxidation and toward other lipid pathways. Our study highlights the utility of using chemoproteomics to identify novel toxicological mechanisms of environmental chemicals such as glyphosate. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nitric oxide mediates local activity-dependent excitatory synapse development.

PubMed

Nikonenko, Irina; Nikonenko, Alexander; Mendez, Pablo; Michurina, Tatyana V; Enikolopov, Grigori; Muller, Dominique

2013-10-29

Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.

Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling

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

Folkvord, Sigurd; Flatmark, Kjersti; Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital

2010-10-01

Purpose: Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). Methods and Materials: Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatmentmore » as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. Results: In the patient population, 73% and 15% were scored as good responders (TRG 1-2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4-5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%. Phosphosubstrate signatures generated by poor-responding tumors indicated high kinase activity, which was inhibited by the kinase inhibitor sunitinib, and several discriminating phosphosubstrates represented proteins derived from signaling pathways implicated in radioresistance. Conclusions: Multiplex kinase activity profiling may identify functional biomarkers predictive of tumor response to preoperative CRT in LARC.« less

Demand Creation for Polio Vaccine in Persistently Poor-Performing Communities of Northern Nigeria: 2013-2014.

PubMed

Warigon, Charity; Mkanda, Pascal; Muhammed, Ado; Etsano, Andrew; Korir, Charles; Bawa, Samuel; Gali, Emmanuel; Nsubuga, Peter; Erbeto, Tesfaya B; Gerlong, George; Banda, Richard; Yehualashet, Yared G; Vaz, Rui G

2016-05-01

Poliomyelitis remains a global threat despite availability of oral polio vaccine (OPV), proven to reduce the burden of the paralyzing disease. In Nigeria, children continue to miss the opportunity to be fully vaccinated, owing to factors such as unmet health needs and low uptake in security-compromised and underserved communities. We describe the implementation and evaluation of several activities to create demand for polio vaccination in persistently poor-performing local government areas (LGAs). We assessed the impact of various polio-related interventions, to measure the contribution of demand creation activities in 77 LGAs at very high risk for polio, located across 10 states in northern Nigeria. Interventions included provision of commodities along with the polio vaccine. There was an increasing trend in the number of children reached by different demand creation interventions. A total of 4 819 847 children were vaccinated at health camps alone. There was a reduction in the number of wards in which >10% of children were missed by supplementary immunization activities due to noncompliance with vaccination recommendations, a rise in the proportion of children who received ≥4 OPV doses, and a decrease in the proportion of children who were underimmunized or unimmunized. Demand creation interventions increased the uptake of polio vaccines in persistently poor-performing high-risk communities in northern Nigeria during September 2013-November 2014. © 2016 World Health Organization; licensee Oxford Journals.

Tracking Vaccination Teams During Polio Campaigns in Northern Nigeria by Use of Geographic Information System Technology: 2013–2015

PubMed Central

Touray, Kebba; Mkanda, Pascal; Tegegn, Sisay G.; Nsubuga, Peter; Erbeto, Tesfaye B.; Banda, Richard; Etsano, Andrew; Shuaib, Faisal; Vaz, Rui G.

2016-01-01

Introduction. Nigeria is among the 3 countries in which polio remains endemic. The country made significant efforts to reduce polio transmission but remains challenged by poor-quality campaigns and poor team performance in some areas. This article demonstrates the application of geographic information system technology to track vaccination teams to monitor settlement coverage, reduce the number of missed settlements, and improve team performance. Methods. In each local government area where tracking was conducted, global positioning system–enabled Android phones were given to each team on a daily basis and were used to record team tracks. These tracks were uploaded to a dashboard to show the level of coverage and identify areas missed by the teams. Results. From 2012 to June 2015, tracking covered 119 immunization days. A total of 1149 tracking activities were conducted. Of these, 681 (59%) were implemented in Kano state. There was an improvement in the geographic coverage of settlements and an overall reduction in the number of missed settlements. Conclusions. The tracking of vaccination teams provided significant feedback during polio campaigns and enabled supervisors to evaluate performance of vaccination teams. The reports supported other polio program activities, such as review of microplans and the deployment of other interventions, for increasing population immunity in northern Nigeria. PMID:26609004

Dose-response relation between physical activity and cognitive function: guangzhou biobank cohort study.

PubMed

Xu, Lin; Jiang, Chao Qiang; Lam, Tai Hing; Zhang, Wei Sen; Thomas, G Neil; Cheng, Kar Keung

2011-11-01

To examine, via cross-sectional analysis, the dose-response association between physical activity and cognitive function in Chinese subjects. A total of 27,651 participants aged 50 to 85 years were recruited from 2003 to 2008. Information on potential confounders, including demographic and anthropometric characteristics, socioeconomic position, lifestyle, and disease history, was collected by standardized interview and procedures. Cognitive function was assessed by the delayed 10-word recall test (DWRT). When the International Physical Activity Questionnaire was used, we found that most of the participants were classified as physically active (53.1%), with 42.4% moderately active and 4.5% physically inactive. Significant dose-response relations across quintiles of metabolic equivalent value (METs) with DWRT score in participants with or without good self-rated health were found (all p for trend <.001). In participants with poor self-rated heath, compared with the first quintile of METs, those in the fifth quintile (highest METs) had a significantly reduced risk for mild cognitive impairment by 28% (adjusted odds ratio, 0.72; 95% confidence interval, 0.58-0.89, p < .01; p for trend = .006). After additional adjustment for depression, we found that the association between physical activity and DWRT score remained significant. A significant dose-response relationship between physical activity and cognitive function was found, and the association was more pronounced in participants with poor self-rated health. Copyright © 2011 Elsevier Inc. All rights reserved.

The role of neighborhood economic context on physical activity among children: Evidence from the Geographic Research on Wellbeing (GROW) study.

PubMed

Kim, Yeonwoo; Cubbin, Catherine

2017-08-01

Less than half of young children in the U.S. meet physical activity recommendations. While neighborhood economic context has been shown to be associated with physical activity, it is unknown whether this association varies according to family economic context. This study thus investigates whether neighborhood economic context, measured by poverty concentration and income inequality, are associated with physical activity among poor and non-poor children using data from the Geographic Research on Wellbeing study, California, 2012-2013 (N=2670). Poor children who resided in (a) poor and equal neighborhoods or (b) non-poor and equal neighborhoods were more likely to engage in sufficient physical activity than were children residing in non-poor and unequal neighborhoods. Poor children in (a) non-poor and equal neighborhoods, (b) poor and equal neighborhoods, or (c) poor and unequal neighborhoods were less likely to report insufficient physical activity than those in non-poor and unequal neighborhoods. Neighborhood economic context was not associated with physical activity among non-poor children. Findings suggest that neighborhood economic context presents a social barrier to physical activity among poor children. Increasing physical activity among poor children in non-poor and unequal neighborhoods should be a high policy priority. Perceived social cohesion, perceived neighborhood safety, and park and walkability indicators did not mediate the associations between neighborhood economic context and physical activity. Further research needs to explore the mechanisms by which neighborhood economic context affects physical activity among children. Copyright © 2017 Elsevier Inc. All rights reserved.

Patient-Related Determinants of Glycaemic Control in People with Type 2 Diabetes in the Gulf Cooperation Council Countries: A Systematic Review.

PubMed

Alramadan, Mohammed J; Afroz, Afsana; Hussain, Sultana Monira; Batais, Mohammed Ali; Almigbal, Turky H; Al-Humrani, Hassan Ahmad; Albaloshi, Ahmed; Romero, Lorena; Magliano, Dianna J; Billah, Baki

2018-01-01

The aim of this systematic review is to assess patient-related factors affecting glycaemic control among people with type 2 diabetes in the Arabian Gulf Council countries. MEDLINE, Embase, PsycINFO, CINAHL, and Cochrane CENTRAL databases were searched from their date of inception to May 2016. Two researchers independently identified eligible studies and assessed the risk of bias. A total of 13 studies met the inclusion criteria. One study was population based, six recruited participants from multiple centres, and the remaining were single centred. The majority of the studies were of low to moderate quality. Factors associated with poor glycaemic control include longer duration of diabetes, low level of education, poor compliance to diet and medication, poor attitude towards the disease, poor self-management behaviour, anxiety, depression, renal impairment, hypertension, and dyslipidaemia. Healthcare providers should be aware of these factors and provide appropriate education and care especially for those who have poor glycaemic control. Innovative educational programs should be implemented in the healthcare systems to improve patient compliance and practices. A variation in the results of the included studies was observed, and some potentially important risk factors such as dietary habits, physical activity, family support, and cognitive function were not adequately addressed. Further research is needed in this area.

Reasons for Schizophrenia Patients Remaining out of Treatment: Results from a Prospective Study in a Rural South Indian Community.

PubMed

Kumar, Channaveerachari Naveen; Thirthalli, Jagadisha; Suresha, Kudumallige Krishnappa; Venkatesh, Basappa K; Kishorekumar, Kengeri V; Arunachala, Udupi; Gangadhar, Bangalore N

2016-01-01

A few studies have examined the factors associated with schizophrenia patients remaining untreated in India. We identified 184 schizophrenia patients in a rural community, offered the treatment with antipsychotics and followed them up in their Primary Health Centers for 1-year. Twenty-nine (15.8%) patients remained untreated at both the baseline and 1-year follow-up despite our best attempts to keep them under the treatment umbrella. They were interviewed in detail regarding the reasons for remaining untreated. This group was compared with another group of patients (n = 69) who had stopped the treatment at baseline but were successfully brought under the treatment umbrella throughout the 1-year follow-up period. The reasons for remaining untreated were (n; %): (a) Unsatisfactory improvement with previous treatment attempts (19; 65.5%), (b) poor bond between the patients and the families (6; 20.7%), (c) active symptoms not allowing any treatment efforts from the family members (6; 20.7%), (d) magico-religious beliefs about the illness and its treatment (4; 13.8%), (e) poor social support (3; 10.3%), (f) adverse effects of the medications (2; 6.9%), and (g) perception of recovery and cure (1; 3.4%). For many patients, a constellation of these reasons was responsible for them remaining untreated. In contrast, the common reasons for those who restarted medications to have stopped the treatment at some time were the lack of awareness, the need to continue medications (47; 68.1%), and the financial constraints (28; 40.6%). The predominant reason for schizophrenia patients not remaining on the treatment in this rural community was the families' lack of faith in antipsychotic treatment. Provision of comprehensive treatment package including medical, psychosocial and rehabilitative services, and sensitizing the community about benefits of the treatment may help in ensuring that all patients with psychosis receive the best care.

Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy

PubMed Central

Wu, Zhi-Qiang; Shi, Yang-Yang; Zaorsky, Nicholas G.; Deng, Lei; Yuan, Zhi-Yong; Lu, You; Wang, Ping

2016-01-01

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer. PMID:27429198

[Bioavailability of antiglaucoma drugs].

PubMed

Demailly, P

2000-05-01

The biodisponibility of antiglaucoma drugs, generally delivered in an aqueous eye-drop solution depends on their capacity to cross the cornea. The structure of the cornea forms a barrier to strongly lipophilic substances and the continuous renewal of the lacrimal film creates a major obstacle, preventing active substances from penetrating the eye. Active substances must thus be delivered in highly concentrated solutions. The systemic bioavailability of antiglaucoma drugs taken orally, for example beta-blockers, is well known, their behavior after eye-drop administration remains poorly elucidated and highly dependent on individual susceptibility. We reviewed the literature on pilocarpine, beta-blockers, adrenergic drugs (dipivalyl-epinephrine, apraclonidine, brimonidine), carbon anhydrase inhibitors (acetazolamide, dorzolamide).

Restoration of outer segments of foveal photoreceptors after resolution of central serous chorioretinopathy.

PubMed

Ojima, Yumiko; Tsujikawa, Akitaka; Yamashiro, Kenji; Ooto, Sotaro; Tamura, Hiroshi; Yoshimura, Nagahisa

2010-01-01

To study morphologically and functionally the prognosis of damaged outer segments of the foveal photoreceptor layer in eyes with resolved central serous chorioretinopathy (CSC). We studied retrospectively the medical records of 70 patients (74 eyes) with resolved CSC. Optical coherence tomography was used to detect the junctions between inner and outer segments of the photoreceptors (IS/OS) as a hallmark of the integrity of the outer photoreceptor layer. In 53 eyes (71.6%), the IS/OS line was clearly detected beneath the fovea immediately after resolution of the retinal detachment, with good visual acuity (VA). In the remaining 21 eyes (28.4%), however, the foveal IS/OS line could not be detected shortly after resolution of CSC, and VA was variable, ranging from 0.1 to 1.5 (median, 0.9). Of these 21 eyes, 15 had a follow-up examination with OCT, and in four the foveal IS/OS line was not detected at the follow-up and vision in these eyes remained poor. However, nine eyes showed recovery of the foveal IS/OS line during follow-up, and these eyes had substantial visual recovery. Immediately after resolution of active CSC, although the IS/OS line cannot be detected beneath the fovea, it often shows restoration over time, with visual recovery, though in some eyes no restoration takes place and the prognosis remains poor.

Modeling and Deorphanization of Orphan GPCRs.

PubMed

Diaz, Constantino; Angelloz-Nicoud, Patricia; Pihan, Emilie

2018-01-01

Despite tremendous efforts, approximately 120 GPCRs remain orphan. Their physiological functions and their potential roles in diseases are poorly understood. Orphan GPCRs are extremely important because they may provide novel therapeutic targets for unmet medical needs. As a complement to experimental approaches, molecular modeling and virtual screening are efficient techniques to discover synthetic surrogate ligands which can help to elucidate the role of oGPCRs. Constitutively activated mutants and recently published active structures of GPCRs provide stimulating opportunities for building active molecular models for oGPCRs and identifying activators using virtual screening of compound libraries. We describe the molecular modeling and virtual screening process we have applied in the discovery of surrogate ligands, and provide examples for CCKA, a simulated oGPCR, and for two oGPCRs, GPR52 and GPR34.

Associations between physical activity and sedentary behavior with sleep quality and quantity in young adults.

PubMed

Kakinami, Lisa; O'Loughlin, Erin K; Brunet, Jennifer; Dugas, Erika N; Constantin, Evelyn; Sabiston, Catherine M; O'Loughlin, Jennifer

2017-02-01

Intensity and duration of physical activity (PA) and sedentary behavior are individually associated with sleep, but their independent associations are poorly characterized. The objectives of this study were to determine if PA and/or sedentary behavior are/is associated with sleep quality and/or quantity in a young adult sample. Cross-sectional. Montreal, Canada. Participants (n=658) from the Nicotine Dependence in Teens Study. PA measures included total minutes of light, moderate, and vigorous PA in the past week; sedentary measures included number of hours per day watching television (TV) and using the computer for leisure activities in the past week. Sleep measures included (1) the Pittsburgh Sleep Quality Index, which assesses sleep quality in the past month, and (2) number of hours of sleep per night in the past month. Data were analyzed using multiple logistic regression adjusting for age, sex, and mother's education. In multivariable analyses, each additional hour of TV and computer use per day was associated with a 17% and 13% increase, respectively, in the odds of reporting poor sleep quality. After additionally adjusting for PA, the association between TV use and poor sleep quality remained significant (odds ratio: 1.15, 95% confidence interval: 1.01-1.28). Sedentary behavior was not associated with sleep quantity. PA intensity and duration were not associated with sleep quality or quantity. More time spent doing sedentary activities was associated with poorer sleep quality, but PA was not associated. Clinicians treating young adults with sleep problems should inquire about sedentary behavior. Copyright © 2016 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.

Poor Response to Periodontal Treatment May Predict Future Cardiovascular Disease.

PubMed

Holmlund, A; Lampa, E; Lind, L

2017-07-01

Periodontal disease has been associated with cardiovascular disease (CVD), but whether the response to the treatment of periodontal disease affects this association has not been investigated in any large prospective study. Periodontal data obtained at baseline and 1 y after treatment were available in 5,297 individuals with remaining teeth who were treated at a specialized clinic for periodontal disease. Poor response to treatment was defined as having >10% sites with probing pocket depth >4 mm deep and bleeding on probing at ≥20% of the sites 1 y after active treatment. Fatal/nonfatal incidence rate of CVD (composite end point of myocardial infarction, stroke, and heart failure) was obtained from the Swedish cause-of-death and hospital discharge registers. Poisson regression analysis was performed to analyze future risk of CVD. During a median follow-up of 16.8 y (89,719 person-years at risk), those individuals who did not respond well to treatment (13.8% of the sample) had an increased incidence of CVD ( n = 870) when compared with responders (23.6 vs. 15.3%, P < 0.001). When adjusting for calendar time, age, sex, educational level, smoking, and baseline values for bleeding on probing, probing pocket depth >4 mm, and number of teeth, the incidence rate ratio for CVD among poor responders was 1.28 (95% CI, 1.07 to 1.53; P = 0.007) as opposed to good responders. The incidence rate ratio among poor responders increased to 1.39 (95% CI, 1.13 to 1.73; P = 0.002) for those with the most remaining teeth. Individuals who did not respond well to periodontal treatment had an increased risk for future CVD, indicating that successful periodontal treatment might influence progression of subclinical CVD.

Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly controlled asthmatics.

PubMed

Kasaian, M T; Lee, J; Brennan, A; Danto, S I; Black, K E; Fitz, L; Dixon, A E

2018-04-17

A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control. To identify signatures as determinants of asthma disease control, we performed proteomics using Olink proximity extension analysis. Up to 3 longitudinal serum samples were collected from 23 controlled and 25 poorly controlled asthmatics. Nine of the controlled and 8 of the poorly controlled subjects also provided 2 longitudinal sputum samples. The study included an additional cohort of 9 subjects whose serum was collected within 48 hours of asthma exacerbation. Two separate pre-defined Proseek Multiplex panels (INF and CVDIII) were run to quantify 181 separate protein analytes in serum and sputum. Panels consisting of 9 markers in serum (CCL19, CCL25, CDCP1, CCL11, FGF21, FGF23, Flt3L, IL-10Rβ, IL-6) and 16 markers in sputum (tPA, KLK6, RETN, ADA, MMP9, Chit1, GRN, PGLYRP1, MPO, HGF, PRTN3, DNER, PI3, Chi3L1, AZU1, and OPG) distinguished controlled and poorly controlled asthmatics. The sputum analytes were consistent with a pattern of neutrophil activation associated with poor asthma control. The serum analyte profile of the exacerbation cohort resembled that of the controlled group rather than that of the poorly controlled asthmatics, possibly reflecting a therapeutic response to systemic corticosteroids. Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control. © 2018 John Wiley & Sons Ltd.

Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease.

PubMed

Ng, Chee-Hoe; Basil, Adeline H; Hang, Liting; Tan, Royston; Goh, Kian-Leong; O'Neill, Sharon; Zhang, Xiaodong; Yu, Fengwei; Lim, Kah-Leong

2017-07-01

Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, that is, AMPK-mediated neuroprotection appears to require PGC-1α. Importantly, we further showed that genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1α-related strategies for neuroprotection in PD. Copyright © 2017 National Neuroscience Institute. Published by Elsevier Inc. All rights reserved.

Residents' diverse perspectives of the impact of neighbourhood renewal on quality of life and physical activity engagement: Improvements but unresolved issues

PubMed Central

Coulson, J.C.; Fox, K.R.; Lawlor, D.A.; Trayers, T.

2011-01-01

Few studies have been published on the reactions of residents to modifications of their residential landscape. We explored residents' experiences of home zone remodelling and construction of a new cycle-walkway in a deprived neighbourhood with a particular focus on aspects of quality of life and physical activity participation. Focus groups (n=5 groups, 21 individuals) were used to investigate residents' perceptions of the effects of neighbourhood change on their lives. Consultation by planners was received positively. Several aspects of the neighbourhood were perceived to have improved, including spatial aesthetics, lighting and streetscape planting. However, influence on physical activity was minimal. Car-focused behaviour and ownership remained dominant, and safety related concerns limited behavioural choices. Residents highlighted many socio-environmental challenges that remained such as sense of neighbourhood safety, poor public transport provision, people's parking behaviour locally, and problem neighbours, and these tended to dominate conversations. Infrastructural intervention may be one important part of multi-layered solutions to improved neighbourhood life. PMID:21145277

Demand Creation for Polio Vaccine in Persistently Poor-Performing Communities of Northern Nigeria: 2013–2014

PubMed Central

Warigon, Charity; Mkanda, Pascal; Muhammed, Ado; Etsano, Andrew; Korir, Charles; Bawa, Samuel; Gali, Emmanuel; Nsubuga, Peter; Erbeto, Tesfaya B.; Gerlong, George; Banda, Richard; Yehualashet, Yared G.; Vaz, Rui G.

2016-01-01

Introduction. Poliomyelitis remains a global threat despite availability of oral polio vaccine (OPV), proven to reduce the burden of the paralyzing disease. In Nigeria, children continue to miss the opportunity to be fully vaccinated, owing to factors such as unmet health needs and low uptake in security-compromised and underserved communities. We describe the implementation and evaluation of several activities to create demand for polio vaccination in persistently poor-performing local government areas (LGAs). Methods. We assessed the impact of various polio-related interventions, to measure the contribution of demand creation activities in 77 LGAs at very high risk for polio, located across 10 states in northern Nigeria. Interventions included provision of commodities along with the polio vaccine. Results. There was an increasing trend in the number of children reached by different demand creation interventions. A total of 4 819 847 children were vaccinated at health camps alone. There was a reduction in the number of wards in which >10% of children were missed by supplementary immunization activities due to noncompliance with vaccination recommendations, a rise in the proportion of children who received ≥4 OPV doses, and a decrease in the proportion of children who were underimmunized or unimmunized. Conclusions. Demand creation interventions increased the uptake of polio vaccines in persistently poor-performing high-risk communities in northern Nigeria during September 2013–November 2014. PMID:26908717

Fitness and exercise as correlates of sleep complaints: is it all in our minds?

PubMed

Gerber, Markus; Brand, Serge; Holsboer-Trachsler, Edith; Pühse, Uwe

2010-05-01

Restoring sleep is associated with psychological well-being. In contrast, poor sleep leads to impaired daily cognitive, emotional, and social functioning. Both commonplace and expert opinion hold that exercise has a favorable impact on preventing poor sleep and improving its quality. However, the scientific basis for this opinion remains limited, and results are mixed. The aim of the present study, therefore, was to explore the impact of perceived physical fitness, exercise, and a perceived lack of activity on sleep in early adulthood. Gender-related patterns were also examined. A total of 862 participants (639 females and 223 males; mean +/- SD = 24.67 +/- 5.91 yr) took part in the study. Respondents completed a series of self-report questionnaires assessing perceived physical fitness, exercise, perceived lack of physical activity, insomnia (Insomnia Severity Index), dysfunctional sleep-related thoughts (Fragebogen zur Erfassung allgemeiner Persönlichkeitsmerkmale Schlafgestörter), and quality of sleep (Pittsburgh Sleep Quality Index). High perceived physical fitness, but not exercise, was associated with favorable scores for various sleep indicators. A perceived lack of physical activity was associated with poor sleep. Perceived physical fitness and exercise were moderately correlated. Compared with males, females reported more sleep difficulties and also more dysfunctional sleep-related thoughts. For early adulthood, findings did not support commonplace or expert opinion that exercise behavior has a favorable influence on sleep. Rather, the findings lend support to the importance of cognitive processes in the onset and maintenance of sleep complaints.

IQ-domain GTPase-activating protein 1 promotes the malignant phenotype of invasive ductal breast carcinoma via canonical Wnt pathway.

PubMed

Zhao, Huan-Yu; Han, Yang; Wang, Jian; Yang, Lian-He; Zheng, Xiao-Ying; Du, Jiang; Wu, Guang-Ping; Wang, En-Hua

2017-06-01

IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ-domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ-domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase-activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients.

Effects of cadmium, naphthalene, and DDVP on gut carbohydrases activity in bream (Abramis brama L. ) and Mozambique tilapia (Oreochromis mossambicus Peters)

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

Golovanova, I.L.; Chuiko, G.M.; Pavlov, D.F.

1994-03-01

Previous research has shown that sublethal concentrations of cadmium, naphthalene and dichlorvos (DDVP) decreased growth rates in bream and Mozambique tilapia. One of the factors known to affect fish growth is the activity of gut digestive enzymes such as of lipases, proteases, carbohydrases. We assumed that toxicant-induced inhibition of the digestive enzyme activity and, consequently, the impaired digestion of food may contribute to the reduction of growth in fish exposed to toxicants. However, the influence of toxicants on digestive enzyme activities is poorly studied. The contribution of toxicant-induced changes of digestive enzymes activity to growth rate retardation in exposed fishmore » remains unknown. The goal of this study was to examine the influence of an organophosphorus insecticide DDVP, a polyaromatic hydrocarbon naphthalene, and a metal cadmium on fish gut carbohydrase (CH) activity. 14 refs., 2 tabs.« less

Assessment of activity in Sarcoidosis. Sensitivity and specificity of 67Gallium scintigraphy, serum ACE levels, chest roentgenography, and blood lymphocyte subpopulations

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

Klech, H.; Kohn, H.; Kummer, F.

1982-12-01

The value of different factors are examined to assess activity in 60 patients with biopsy-proven sarcoidosis. In patients with active sarcoidosis (n . 35), /sup 67/Ga scans proved to be the most sensitive method (94 percent sensitivity), followed by serum angiotensin I converting enzyme (S-ACE) levels, chest x-ray films, and lymphocyte assays. In patients with peripheral pulmonary lesions, chest x-ray films failed in 32 percent of cases to document activity (68 percent sensitivity) whereas /sup 67/Ga scans and S-ACE levels remained to give reliable results. Despite poor specificity, negative /sup 67/Ga scans together with normal ACE levels have a highmore » predictive value for exclusion of active sarcoidosis. In patients with peripheral pulmonary lesions, chest roentgenography is of doubtful value for staging lung involvement and assessment of activity including monitoring and control of therapy.« less

Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

PubMed Central

Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu; Snyder, Nathaniel W; Worth, Andrew J; Iyer, Shankar S; Wang, Jiawei; Ben-Sahra, Issam; Byles, Vanessa; Polynne-Stapornkul, Tiffany; Espinosa, Erika C; Lamming, Dudley; Manning, Brendan D; Zhang, Yijing; Blair, Ian A; Horng, Tiffany

2016-01-01

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation. DOI: http://dx.doi.org/10.7554/eLife.11612.001 PMID:26894960

Real-Time Observation of Human LINE-1 Retrotransposon Activity in Bacteria

NASA Astrophysics Data System (ADS)

Kaur, Davneet; Kuhlman, Thomas; Kuhlman Team; Nigel Goldenfeld Collaboration

Transposable elements (TEs) are fundamental building blocks of all genomes. Retrotransposable elements (RTEs) are one of the two primary classes of TEs that are ubiquitous in eukaryotes. They propagate through a copy-and-paste mechanism utilizing reverse-transcribed mRNA intermediates. This leads to disruption and dispersal of coding and control elements throughout the genome, and consequently TEs are thought to be a major driving force behind diversification. However, RTEs are absent in most prokaryotes including E. coli. and the reason for this remains an open question. Despite their prevalence, there still remain many unanswered questions about how `hot' or active L1 RTEs (L1Hs) function. In particular, their rates of activity and their effects upon their host are currently poorly understood and only roughly estimated within the limitations of available technology. To address these unanswered questions, we have constructed and released an L1H element in E. coli to quantify its rates of activity and physiological effects on its host. To overcome the technical limitations, we've designed fluorescent visualization and quantification techniques that make real time high resolution observations of retrotransposition events as they occur in living cells.

Child Poverty and Its Lasting Consequence. Low-Income Working Families. Paper 21

ERIC Educational Resources Information Center

Ratcliffe, Caroline; McKernan, Signe-Mary

2012-01-01

One in six newborns were born poor over the past 40 years, and nearly half remained poor half their childhoods. These persistently poor children are nearly 90 percent more likely than never-poor children to enter their 20s without completing high school and are four times more likely to give birth outside of marriage during their teenage years.…

Working Poor Families in the Chicago Metropolitan Area. Statistical Profile and Proceedings of the Working Poor Policy Forum (Chicago, Illinois, December 8, 1993).

ERIC Educational Resources Information Center

Latino Inst., Chicago, IL.

A statistical profile of the working poor in Chicago (Illinois) and the proceedings of the Working Poor Policy Forum held to discuss the findings of the profile are presented. In America it is supposed to be impossible to work and remain chronically poor, but in fact this is not the case. There are many ways to define the income working families…

Promoting Access to Education for Disabled Children in Low-Income Countries: Do We Need to Know How Many Disabled Children There Are?

ERIC Educational Resources Information Center

Croft, Alison

2013-01-01

Poor people are most likely to be disabled, and the exclusion of disabled people from education means that they are also more likely to remain poor. Despite calls for better data to inform the extension of education for disabled children, data in this field remain weak. This paper asks whether a national survey of disability prevalence is the best…

[Grave's ophthalmopathy: therapeutic strategy. Review of 30 patients].

PubMed

Boulétreau, P; Ordonnez, I; Orgiazzi, J; Breton, P; Freidel, M

2005-04-01

Graves' ophthalmopathy is the primary etiology for exophthalmos in adults. It is a complex orbital disease whose pathophysiology remains controversial. Since its initial description more than 150 years ago, its heterogeneous clinical manifestations and poorly understood links with thyroid pathology remain unresolved issues. Disease activity is the main determinant for the management of Graves' ophthalmopathy, but treatments are often symptomatic, aiming at decreasing orbital inflammation. We report a retrospective analysis of 30 patients diagnosed with Graves' ophthalmopathy followed in our department between 1991 and 2002. Following a phase of medical management of their disease, all patients underwent surgical orbital decompression. Medical and surgical care provided as well as results are presented with a mean follow-up of 23 months. Based on our clinical experience, new concepts in the field of Graves' ophthalmopathy are discussed. Disease activity, evaluated through various means, appears to be the primary guide for therapeutic management. Moreover, the importance of a multidisciplinary approach is highlighted, in order to improve the management of this difficult disorder.

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

PubMed

Sindreu, Carlos; Palmiter, Richard D; Storm, Daniel R

2011-02-22

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory.

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory

PubMed Central

Sindreu, Carlos; Palmiter, Richard D.; Storm, Daniel R.

2011-01-01

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory. PMID:21245308

Amino Acid Sensing in Skeletal Muscle

PubMed Central

Moro, Tatiana; Ebert, Scott M.; Adams, Christopher M.; Rasmussen, Blake B.

2016-01-01

Aging impairs skeletal muscle protein synthesis, leading to muscle weakness and atrophy. However, the underlying molecular mechanisms remain poorly understood. Here, we review evidence that mTORC1- and ATF4-mediated amino acid sensing pathways, triggered by impaired amino acid delivery to aged skeletal muscle, may play important roles in skeletal muscle aging. Interventions that alleviate age-related impairments in muscle protein synthesis, strength and/or muscle mass appear to do so by reversing age-related changes in skeletal muscle amino acid delivery, mTORC1 activity and/or ATF4 activity. An improved understanding of the mechanisms and roles of amino acid sensing pathways in skeletal muscle may lead to evidence-based strategies to attenuate sarcopenia. PMID:27444066

Early-life exposure to caffeine affects the construction and activity of cortical networks in mice.

PubMed

Fazeli, Walid; Zappettini, Stefania; Marguet, Stephan Lawrence; Grendel, Jasper; Esclapez, Monique; Bernard, Christophe; Isbrandt, Dirk

2017-09-01

The consumption of psychoactive drugs during pregnancy can have deleterious effects on newborns. It remains unclear whether early-life exposure to caffeine, the most widely consumed psychoactive substance, alters brain development. We hypothesized that maternal caffeine ingestion during pregnancy and the early postnatal period in mice affects the construction and activity of cortical networks in offspring. To test this hypothesis, we focused on primary visual cortex (V1) as a model neocortical region. In a study design mimicking the daily consumption of approximately three cups of coffee during pregnancy in humans, caffeine was added to the drinking water of female mice and their offspring were compared to control offspring. Caffeine altered the construction of GABAergic neuronal networks in V1, as reflected by a reduced number of somatostatin-containing GABA neurons at postnatal days 6-7, with the remaining ones showing poorly developed dendritic arbors. These findings were accompanied by increased synaptic activity in vitro and elevated network activity in vivo in V1. Similarly, in vivo hippocampal network activity was altered from the neonatal period until adulthood. Finally, caffeine-exposed offspring showed increased seizure susceptibility in a hyperthermia-induced seizure model. In summary, our results indicate detrimental effects of developmental caffeine exposure on mouse brain development. Copyright © 2017 Elsevier Inc. All rights reserved.

Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict.

PubMed

Zavala, Baltazar; Damera, Srikanth; Dong, Jian Wilson; Lungu, Codrin; Brown, Peter; Zaghloul, Kareem A

2017-01-01

Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing

PubMed Central

Das, Subhamoy; Baker, Aaron B.

2016-01-01

Wound healing is an intricate process that requires complex coordination between many cell types and an appropriate extracellular microenvironment. Chronic wounds often suffer from high protease activity, persistent infection, excess inflammation, and hypoxia. While there has been intense investigation to find new methods to improve cutaneous wound care, the management of chronic wounds, burns, and skin wound infection remain challenging clinical problems. Ideally, advanced wound dressings can provide enhanced healing and bridge the gaps in the healing processes that prevent chronic wounds from healing. These technologies have great potential for improving outcomes in patients with poorly healing wounds but face significant barriers in addressing the heterogeneity and clinical complexity of chronic or severe wounds. Active wound dressings aim to enhance the natural healing process and work to counter many aspects that plague poorly healing wounds, including excessive inflammation, ischemia, scarring, and wound infection. This review paper discusses recent advances in the development of biomaterials and nanoparticle therapeutics to enhance wound healing. In particular, this review focuses on the novel cutaneous wound treatments that have undergone significant preclinical development or are currently used in clinical practice. PMID:27843895

Nurse managers' experiences in continuous quality improvement in resource-poor healthcare settings.

PubMed

Kakyo, Tracy Alexis; Xiao, Lily Dongxia

2017-06-01

Ensuring safe and quality care for patients in hospitals is an important part of a nurse manager's role. Continuous quality improvement has been identified as one approach that leads to the delivery of quality care services to patients and is widely used by nurse managers to improve patient care. Nurse managers' experiences in initiating continuous quality improvement activities in resource-poor healthcare settings remain largely unknown. Research evidence is highly demanded in these settings to address disease burden and evidence-based practice. This interpretive qualitative study was conducted to gain an understanding of nurse managers' Continuous Quality Improvement experiences in rural hospitals in Uganda. Nurse managers in rural healthcare settings used their role to prioritize quality improvement activities, monitor the Continuous Quality Improvement process, and utilize in-service education to support continuous quality improvement. The nurse managers in our sample encountered a number of barriers during the implementation of Continuous Quality Improvement, including: limited patient participation, lack of materials, and limited human resources. Efforts to address the challenges faced through good governance and leadership development require more attention. © 2017 John Wiley & Sons Australia, Ltd.

“Tell Juliana”: Acceptability of the Candidate Microbicide VivaGel® and Two Placebo Gels Among Ethnically Diverse, Sexually Active Young Women Participating in a Phase 1 Microbicide Study

PubMed Central

Giguere, Rebecca; Dolezal, Curtis; Chen, Beatrice A.; Kahn, Jessica; Zimet, Greg; Mabragaña, Marina; Leu, Cheng-Shiun; McGowan, Ian

2011-01-01

This study assessed acceptability of the candidate microbicide VivaGel® and two placebo gels among 61 sexually active young US and Puerto Rican women at three sites. Participants were randomly assigned to use one of the gels twice per day for 14 days. At trial completion, 59% of the women in the VivaGel® group reported being likely to use the gel in the future, whereas 23% were unlikely to use it and 18% were undecided. Participants reported problems with all three gels, including the “universal” placebo containing hydroxyethyl cellulose (HEC). The most frequent complaints were leakage, interference with sexual behavior, and decreased sexual satisfaction. Some of the complaints are not new but remain unresolved. Women’s perceived risk of HIV infection may determine whether the gels are used. Users also may want a choice of viscosity. Poor acceptability of vaginal microbicide formulations may result in poor adherence to gel use during efficacy trials and compromise validity of results. PMID:21863338

Disordered Actomyosin Is Sufficient to Promote Cooperative and Telescopic Contractility

NASA Astrophysics Data System (ADS)

Murrell, Michael; Linsmeier, Ian; Banerjee, Shiladitya; Kim, Tae Yoon; Jung, Wonyeong; Oakes, Patrick

While the molecular interactions between myosin motors and F-actin are well known, the relationship between F-actin organization and myosin-mediated force generation remains poorly understood. Here, we explore the accumulation of myosin-induced stresses within a 2D biomimetic model of the actomyosin cortex, where myosin activity is controlled spatially and temporally using light. By controlling the geometry and the duration of myosin activation, we show that contraction of disordered actomyosin is highly cooperative, telescopic with the activation area and generates a pattern of mechanical stresses consistent with those observed in contractile cells. We quantitatively reproduce these properties using an in vitro isotropic model of the actomyosin cytoskeleton, and explore the physical origins of telescopic contractility in disordered networks using agent-based simulations. NSF CMMI-1525316.

2'-Deoxyribosyltransferase from Leishmania mexicana, an efficient biocatalyst for one-pot, one-step synthesis of nucleosides from poorly soluble purine bases.

PubMed

Crespo, N; Sánchez-Murcia, P A; Gago, F; Cejudo-Sanches, J; Galmes, M A; Fernández-Lucas, Jesús; Mancheño, José Miguel

2017-10-01

Processes catalyzed by enzymes offer numerous advantages over chemical methods although in many occasions the stability of the biocatalysts becomes a serious concern. Traditionally, synthesis of nucleosides using poorly water-soluble purine bases, such as guanine, xanthine, or hypoxanthine, requires alkaline pH and/or high temperatures in order to solubilize the substrate. In this work, we demonstrate that the 2'-deoxyribosyltransferase from Leishmania mexicana (LmPDT) exhibits an unusually high activity and stability under alkaline conditions (pH 8-10) across a broad range of temperatures (30-70 °C) and ionic strengths (0-500 mM NaCl). Conversely, analysis of the crystal structure of LmPDT together with comparisons with hexameric, bacterial homologues revealed the importance of the relationships between the oligomeric state and the active site architecture within this family of enzymes. Moreover, molecular dynamics and docking approaches provided structural insights into the substrate-binding mode. Biochemical characterization of LmPDT identifies the enzyme as a type I NDT (PDT), exhibiting excellent activity, with specific activity values 100- and 4000-fold higher than the ones reported for other PDTs. Interestingly, LmPDT remained stable during 36 h at different pH values at 40 °C. In order to explore the potential of LmPDT as an industrial biocatalyst, enzymatic production of several natural and non-natural therapeutic nucleosides, such as vidarabine (ara A), didanosine (ddI), ddG, or 2'-fluoro-2'-deoxyguanosine, was carried out using poorly water-soluble purines. Noteworthy, this is the first time that the enzymatic synthesis of 2'-fluoro-2'-deoxyguanosine, ara G, and ara H by a 2'-deoxyribosyltransferase is reported.

Tuberculosis in the tropics.

PubMed

Krause, V L; Britton, W J

1993-09-20

Until recently tuberculosis was considered a well controlled disease, at least in developed countries. In developing countries, more than seven million people are affected by active tuberculosis. This situation is exacerbated by poor infrastructure to support tuberculosis control measures and the interaction between tuberculosis and infection with the human immunodeficiency virus. The three major strategies for controlling tuberculosis remain BCG vaccination in children, appropriate preventive therapy and, most importantly, reducing the sources of infection through case finding and curative treatment. Research and resources to improve on these strategies should be given high priority by the international health community.

Hurricane and Monsoon Tracking with Driftsondes

NASA Astrophysics Data System (ADS)

Drobinski, Philippe; Cocquerez, Philippe; Doerenbecher, A.; Hock, Terrence; Lavaysse, C.; Parsons, D.; Redelsperger, J. L.

Tropical cyclones (TCs) are a typical weather threat. The threat can apply to humans, their properties, and activities. Their prediction, particularly their trajectory and intensity, remains difficult. In addition, TCs develop above the tropical oceans where the coverage by in situ observations is poor and within cloud clusters (mesoscale convective systems MCS) that limit the ability of numerical weather prediction (NWP) models to assimilate satellite data [18]. Improved forecast of TCs trajectories is a huge benefit in terms of material costs of evacuations and damage, not being able to quantify saved life.

The President's Veto of the Minimum Wage Bill: Impact on Poor and Minority Workers.

ERIC Educational Resources Information Center

Shapiro, Isaac

Restoration of an adequate minimum wage remains a critical ingredient in efforts to provide income security for poor and minority workers. The experience of recent years indicates that work does not provide economic security for many poor, Black, and Hispanic workers. National and minority unemployment rates have dropped during the economic…

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Age-related associations between work over-commitment and zest for work among Swedish employees from a cross-sectional and longitudinal perspective.

PubMed

Runeson-Broberg, Roma; du Prel, Jean-Baptist; Westerholm, Peter; Nordin, Maria; Knutsson, Anders; Alfredsson, Lars; Fahlén, Göran; Peter, Richard

2017-01-01

In aging societies, zest for work may be pivotal when deciding to stay occupationally active longer. Psychosocial work stress is a prevalent public health problem and may have an impact on zest for work. Work over-commitment (WOC) is a personal coping strategy for work stress with excessive striving and a health risk. However, the long-term effect of WOC on zest for work is poorly understood. To investigate the age-related associations of work over-commitment with zest for work. During 1996-1998 and 2000-2003, predominantly industrial workers (n = 2940) participated in the WOLF-Norrland study and responded to a questionnaire referring to socio-demographics, WOC, zest for work, effort-reward imbalance proxies, and mental health. Age-adjusted multiple logistic regressions were performed with original and imputed datasets. Cross-sectionally, work overcommitted middle-aged employees had an increased prevalence of poor zest for work compared to their contemporaries without WOC (OR: 3.74 [95%-CI 2.19; 6.40]). However, in a longitudinal analysis associations between onset of 'poor zest for work' and the WOC subscales 'need for approval' (OR: 3.29 [95%-CI 1.04; 10.37]) and 'inability to withdraw from work' (OR: 5.14 [95%-CI 1.32; 20.03]) were observed. The longitudinal findings among older employees could be relevant regarding the expected need to remain occupationally active longer.

Mapping cortical haemodynamics during neonatal seizures using diffuse optical tomography: A case study

PubMed Central

Singh, Harsimrat; Cooper, Robert J.; Wai Lee, Chuen; Dempsey, Laura; Edwards, Andrea; Brigadoi, Sabrina; Airantzis, Dimitrios; Everdell, Nick; Michell, Andrew; Holder, David; Hebden, Jeremy C.; Austin, Topun

2014-01-01

Seizures in the newborn brain represent a major challenge to neonatal medicine. Neonatal seizures are poorly classified, under-diagnosed, difficult to treat and are associated with poor neurodevelopmental outcome. Video-EEG is the current gold-standard approach for seizure detection and monitoring. Interpreting neonatal EEG requires expertise and the impact of seizures on the developing brain remains poorly understood. In this case study we present the first ever images of the haemodynamic impact of seizures on the human infant brain, obtained using simultaneous diffuse optical tomography (DOT) and video-EEG with whole-scalp coverage. Seven discrete periods of ictal electrographic activity were observed during a 60 minute recording of an infant with hypoxic–ischaemic encephalopathy. The resulting DOT images show a remarkably consistent, high-amplitude, biphasic pattern of changes in cortical blood volume and oxygenation in response to each electrographic event. While there is spatial variation across the cortex, the dominant haemodynamic response to seizure activity consists of an initial increase in cortical blood volume prior to a large and extended decrease typically lasting several minutes. This case study demonstrates the wealth of physiologically and clinically relevant information that DOT–EEG techniques can yield. The consistency and scale of the haemodynamic responses observed here also suggest that DOT–EEG has the potential to provide improved detection of neonatal seizures. PMID:25161892

Changes in the activity of a CpG neuron after the reinforcement of an operantly conditioned behavior in Lymnaea.

PubMed

Spencer, Gaynor E; Kazmi, Mustapha H; Syed, Naweed I; Lukowiak, Ken

2002-10-01

We have previously shown that the aerial respiratory behavior of the mollusk Lymnaea stagnalis can be operantly conditioned, and the central pattern generating (CPG) neurons underlying this behavior have been identified. As neural correlates of operant conditioning remain poorly defined in both vertebrates and invertebrates, we have used the Lymnaea respiratory CPG to investigate neuronal changes associated with the change in behavior after conditioning. After operant conditioning of the intact animals, semi-intact preparations were dissected, so that changes in the respiratory behavior (pneumostome openings) and underlying activity of the identified CPG neuron, right pedal dorsal 1 (RPeD1), could be monitored simultaneously. RPeD1 was studied because it initiates the rhythmic activity of the CPG and receives chemo-sensory input from the pneumostome area. Pneumostome openings and RPeD1 activity were monitored both before and after a reinforcing training stimulus applied to the open pneumostome of operantly conditioned and yoked control preparations. After presentation of the reinforcing stimulus, there was a significant reduction in both breathing behavior and RPeD1 activity in operant preparations but not in yoked and naïve controls. Furthermore these changes were only significant in the subgroup of operantly conditioned animals described as good learners and not in poor learners. These data strongly suggest that changes in RPeD1 activity may underlie the behavioral changes associated with the reinforcement of operant conditioning of the respiratory behavior.

The pathways from perceived discrimination to self-rated health: An investigation of the roles of distrust, social capital, and health behaviors

PubMed Central

Chen, Danhong; Yang, Tse-Chuan

2014-01-01

Although there has been extensive research on the adverse impacts of perceived discrimination on health, it remains unclear how perceived discrimination gets under the skin. This paper develops a comprehensive structural equation model (SEM) by incorporating both the direct effects of perceived discrimination on self-rated health (SRH), a powerful predictor for many health outcomes, and the indirect effects of perceived discrimination on SRH through health care system distrust, neighborhood social capital, and health behaviors and health conditions. Applying SEM to 9,880 adults (aged between 18 and 100) in the 2008 Southeastern Pennsylvania Household Health Survey, we not only confirmed the positive and direct association between discrimination and poor or fair SRH, but also verified two underlying mechanisms: 1) perceived discrimination is associated with lower neighborhood social capital, which further contributes to poor or fair SRH; and 2) perceived discrimination is related to risky behaviors (e.g., reduced physical activity and sleep quality, and intensified smoking) that lead to worse health conditions, and then result in poor or fair SRH. Moreover, we found that perceived discrimination is negatively associated with health care system distrust, but did not find a significant relationship between distrust and poor or fair SRH. PMID:24581063

Breast Tumors with Elevated Expression of 1q Candidate Genes Confer Poor Clinical Outcome and Sensitivity to Ras/PI3K Inhibition

PubMed Central

Viveka Thangaraj, Soundara; Periasamy, Jayaprakash; Bhaskar Rao, Divya; Barnabas, Georgina D.; Raghavan, Swetha; Ganesan, Kumaresan

2013-01-01

Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA–drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors. PMID:24147022

Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals.

PubMed

Toneto, Aline Tatiane; Ferreira Ramos, Luiz Alberto; Salomão, Emilianne Miguel; Tomasin, Rebeka; Aereas, Miguel Arcanjo; Gomes-Marcondes, Maria Cristina Cintra

2016-12-01

The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart. Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity. Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity. Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

Desmopressin therapy to assist the functional identification and characterisation of von Willebrand disease: differential utility from combining two (VWF:CB and VWF:RCo) von Willebrand factor activity assays?

PubMed

Favaloro, Emmanuel J; Thom, Jim; Patterson, David; Just, Sarah; Dixon, Tracy; Koutts, Jerry; Baccala, Maria; Rowell, John; Baker, Ross

2009-04-01

We performed a retrospective audit of desmopressin (DDAVP) usage to assist in the functional characterisation of von Willebrand disease (VWD). Data was evaluated for 208 patients, comprising those with VWD (Type 1 [n=160], Type 2A [n=19], Type 2M [n=10]), plus 19 individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre- and post-DDAVP evaluation of factor VIII (FVIII:C), von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo) activity, VWF collagen binding (VWF:CB) activity, and in one laboratory an alternate VWF activity assay. In brief, combined usage of VWF:RCo and VWF:CB appears to provide improved functional characterisation and/or 'classification' of VWD types, in particular better differentiation of Type 2A and 2M VWD, and clearer validation of a Type 1 VWD diagnosis. Thus, (i) Type 1 VWD displayed generally good absolute and relative rises in all test parameters, although relative rises were greatest for FVIII:C and VWF:CB, and CB/Ag ratio increases overshadowed those for RCo/Ag; (ii) Type 2A VWD patients showed good absolute and relative rises in both FVIII:C and VWF:Ag, but poor absolute rises in both VWF:CB and VWF:RCo; although small rises in both CB/Ag and RCo/Ag were also observed, both ratios tended to remain below 0.7; (iii) finally, Type 2 M VWD patients generally showed good absolute and relative rises in FVIII:C, VWF:Ag and VWF:CB, but a poor absolute and relative rise in VWF:RCo; thus, there were good rises in CB/Ag ratios but little change in RCo/Ag, which tended to remain below 0.7. Future multi-centre prospective investigations are warranted to validate these findings and to investigate their therapeutic implications.

Role of Obesity in Asthma: Mechanisms and Management Strategies.

PubMed

Scott, Hayley A; Wood, Lisa G; Gibson, Peter G

2017-08-01

Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear. Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences. In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population.

Exploring the relationship between boredom and sustained attention.

PubMed

Malkovsky, Ela; Merrifield, Colleen; Goldberg, Yael; Danckert, James

2012-08-01

Boredom is a common experience, prevalent in neurological and psychiatric populations, yet its cognitive characteristics remain poorly understood. We explored the relationship between boredom proneness, sustained attention and adult symptoms of attention deficit hyperactivity disorder (ADHD). The results showed that high boredom-prone individuals (HBP) performed poorly on measures of sustained attention and showed increased symptoms of ADHD and depression. The results also showed that HBP individuals can be characterised as either apathetic-in which the individual is unconcerned with his/her environment, or as agitated-in which the individual is motivated to engage in meaningful activities, although attempts to do so fail to satisfy. Apathetic boredom proneness was associated with attention lapses, whereas agitated boredom proneness was associated with decreased sensitivity to errors of sustained attention, and increased symptoms of adult ADHD. Our results suggest there is a complex relationship between attention and boredom proneness.

Activity-Induced Remodeling of Olfactory Bulb Microcircuits Revealed by Monosynaptic Tracing

PubMed Central

Arenkiel, Benjamin R.; Hasegawa, Hiroshi; Yi, Jason J.; Larsen, Rylan S.; Wallace, Michael L.; Philpot, Benjamin D.; Wang, Fan; Ehlers, Michael D.

2011-01-01

The continued addition of new neurons to mature olfactory circuits represents a remarkable mode of cellular and structural brain plasticity. However, the anatomical configuration of newly established circuits, the types and numbers of neurons that form new synaptic connections, and the effect of sensory experience on synaptic connectivity in the olfactory bulb remain poorly understood. Using in vivo electroporation and monosynaptic tracing, we show that postnatal-born granule cells form synaptic connections with centrifugal inputs and mitral/tufted cells in the mouse olfactory bulb. In addition, newly born granule cells receive extensive input from local inhibitory short axon cells, a poorly understood cell population. The connectivity of short axon cells shows clustered organization, and their synaptic input onto newborn granule cells dramatically and selectively expands with odor stimulation. Our findings suggest that sensory experience promotes the synaptic integration of new neurons into cell type-specific olfactory circuits. PMID:22216277

Evidence that displacement activities facilitate behavioural transitions in ring-tailed lemurs.

PubMed

Buckley, Victoria; Semple, Stuart

2012-07-01

Displacement activities are behavioural patterns defined by their apparent irrelevance to an animal's ongoing actions. Despite being identified in diverse taxa, their function remains poorly understood. One hypothesis posits that displacement activities facilitate transitions between different behaviours by mediating changes in animals' motivational state. Under this hypothesis, it is predicted that displacement activities will occur more frequently around changes in behaviour than at other times, and also that rates of displacement activities will be higher before than after such behavioural transitions. We tested these two predictions in wild ring-tailed lemurs (Lemur catta). During focal observations, animals' behavioural state was continuously recorded, as were all occurrences of self-scratching, a common displacement activity in this species. Self-scratching rates were found to be significantly elevated both before and after behavioural transitions. Furthermore, self-scratching rates were significantly higher before behavioural transitions occurred than after. These results, therefore, provide support for the hypothesis that displacement activities facilitate behavioural transitions in L. catta. Copyright © 2012 Elsevier B.V. All rights reserved.

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.

PubMed

Nora, Elphège P; Goloborodko, Anton; Valton, Anne-Laure; Gibcus, Johan H; Uebersohn, Alec; Abdennur, Nezar; Dekker, Job; Mirny, Leonid A; Bruneau, Benoit G

2017-05-18

The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization

PubMed Central

Nora, Elphège P.; Goloborodko, Anton; Valton, Anne-Laure; Gibcus, Johan H.; Uebersohn, Alec; Abdennur, Nezar; Dekker, Job; Mirny, Leonid A.; Bruneau, Benoit G.

2017-01-01

Summary The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Further, our data support that CTCF mediates transcriptional insulator function through enhancer-blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding these results provide new fundamental insights into the rules governing mammalian genome organization. PMID:28525758

Earliest Archaeological Evidence of Persistent Hominin Carnivory

PubMed Central

Ferraro, Joseph V.; Plummer, Thomas W.; Pobiner, Briana L.; Oliver, James S.; Bishop, Laura C.; Braun, David R.; Ditchfield, Peter W.; Seaman, John W.; Binetti, Katie M.; Seaman, John W.; Hertel, Fritz; Potts, Richard

2013-01-01

The emergence of lithic technology by ∼2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated faunal evidence, however, is poorly preserved prior to ∼1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to ∼2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence – spanning hundreds to thousands of years – and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution. PMID:23637995

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

NASA Astrophysics Data System (ADS)

House, Carrie D.; Wang, Bi-Dar; Ceniccola, Kristin; Williams, Russell; Simaan, May; Olender, Jacqueline; Patel, Vyomesh; Baptista-Hon, Daniel T.; Annunziata, Christina M.; Silvio Gutkind, J.; Hales, Tim G.; Lee, Norman H.

2015-06-01

Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.

Active Brownian rods

NASA Astrophysics Data System (ADS)

Peruani, Fernando

2016-11-01

Bacteria, chemically-driven rods, and motility assays are examples of active (i.e. self-propelled) Brownian rods (ABR). The physics of ABR, despite their ubiquity in experimental systems, remains still poorly understood. Here, we review the large-scale properties of collections of ABR moving in a dissipative medium. We address the problem by presenting three different models, of decreasing complexity, which we refer to as model I, II, and III, respectively. Comparing model I, II, and III, we disentangle the role of activity and interactions. In particular, we learn that in two dimensions by ignoring steric or volume exclusion effects, large-scale nematic order seems to be possible, while steric interactions prevent the formation of orientational order at large scales. The macroscopic behavior of ABR results from the interplay between active stresses and local alignment. ABR exhibit, depending on where we locate ourselves in parameter space, a zoology of macroscopic patterns that ranges from polar and nematic bands to dynamic aggregates.

Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy.

PubMed

Kawamura, Kiyoko; Wada, Akihiko; Wang, Ji-Yang; Li, Quanhai; Ishii, Akihiro; Tsujimura, Hideki; Takagi, Toshiyuki; Itami, Makiko; Tada, Yuji; Tatsumi, Koichiro; Shimada, Hideaki; Hiroshima, Kenzo; Tagawa, Masatoshi

2016-01-01

Activation-induced cytidine deaminase (AID) is involved in somatic hypermutation and class switch recombination processes in the antibody formation. The AID activity induces gene mutations and could be associated with transformation processes of B cells. Nevertheless, the relation between AID expression and the prognosis of B cell lymphoma patients remains uncharacterized. We examined expression levels of the AID gene in 89 lymph node specimens from lymphoma and non-lymphoma patients with Northern blot analysis and investigated an association with their survival. The AID gene was preferentially expressed in B cell lymphoma in particular in diffuse large B cell lymphoma and follicular lymphoma. We confirmed AID protein expression in the mRNA-positive but not in the negative specimens with Western blot analysis and immunohistochemical staining. Survival of the patients treated with cyclophosphamide-/doxorubicin-/vincristine-/prednisone-based chemotherapy demonstrated that the prognosis of diffuse large B cell patients was unfavorable in the mRNA-positive group compared with the negative group, and that AID expression levels were correlated with the poor prognosis. In contrast, AID expression was not linked with the prognosis of follicular lymphoma patients. AID expression is a predictive marker for an unfavorable outcome in DLBCL patients treated with the chemotherapy.

Relationship between functional vision and balance and mobility performance in community-dwelling older adults.

PubMed

Aartolahti, Eeva; Häkkinen, Arja; Lönnroos, Eija; Kautiainen, Hannu; Sulkava, Raimo; Hartikainen, Sirpa

2013-10-01

Vision is an important prerequisite for balance control and mobility. The role of objectively measured visual functions has been previously studied but less is known about associations of functional vision, that refers to self-perceived vision-based ability to perform daily activities. The aim of the study was to investigate the relationship between functional vision and balance and mobility performance in a community-based sample of older adults. This study is part of a Geriatric Multidisciplinary Strategy for the Good Care of the Elderly project (GeMS). Participants (576) aged 76-100 years (mean age 81 years, 70 % women) were interviewed using a seven-item functional vision questionnaire (VF-7). Balance and mobility were measured by the Berg balance scale (BBS), timed up and go (TUG), chair stand test, and maximal walking speed. In addition, self-reported fear of falling, depressive symptoms (15-item Geriatric Depression Scale), cognition (Mini-Mental State Examination) and physical activity (Grimby) were assessed. In the analysis, participants were classified into poor, moderate, or good functional vision groups. The poor functional vision group (n = 95) had more comorbidities, depressed mood, cognition decline, fear of falling, and reduced physical activity compared to participants with moderate (n = 222) or good functional vision (n = 259). Participants with poor functional vision performed worse on all balance and mobility tests. After adjusting for gender, age, chronic conditions, and cognition, the linearity remained statistically significant between functional vision and BBS (p = 0.013), TUG (p = 0.010), and maximal walking speed (p = 0.008), but not between functional vision and chair stand (p = 0.069). Poor functional vision is related to weaker balance and mobility performance in community-dwelling older adults. This highlights the importance of widespread assessment of health, including functional vision, to prevent balance impairment and maintain independent mobility among older population.

New insights into environmental enteric dysfunction

USDA-ARS?s Scientific Manuscript database

Environmental enteric dysfunction (EED) has been recognised as an important contributing factor to physical and cognitive stunting, poor response to oral vaccines, limited resilience to acute infections and ultimately global childhood mortality. The aetiology of EED remains poorly defined but the ep...

Bergmann glia modulate cerebellar Purkinje cell bistability via Ca2+-dependent K+ uptake

PubMed Central

Wang, Fushun; Xu, Qiwu; Wang, Weishan; Takano, Takahiro; Nedergaard, Maiken

2012-01-01

Recent studies have shown that cerebellar Bergmann glia display coordinated Ca2+ transients in live mice. However, the functional significance of Bergmann glial Ca2+ signaling remains poorly understood. Using transgenic mice that allow selective stimulation of glial cells, we report here that cytosolic Ca2+ regulates uptake of K+ by Bergmann glia, thus providing a powerful mechanism for control of Purkinje cell-membrane potential. The decline in extracellular K+ evoked by agonist-induced Ca2+ in Bergmann glia transiently increased spike activity of Purkinje cells in cerebellar slices as well as in live anesthetized mice. Thus, Bergmann glia play a previously unappreciated role in controlling the membrane potential and thereby the activity of adjacent Purkinje cells. PMID:22547829

Mechanism of action of rapalogues: the antiangiogenic hypothesis.

PubMed

Faivre, Sandrine; Raymond, Eric

2008-11-01

mTOR interacts with multiple proteins involved in major signal transduction pathways controlling cell growth, proliferation, and apoptosis. mTOR is acknowledged to play major roles in cellular interplays between cancer and stroma cells, including endothelial cells. Rapalogues demonstrated antitumour activity in several hypervascularized tumours in clinical trials. Whether rapalogues directly affect cancer cells or other stroma cells in tumours remains poorly understood. Knowing whether rapalogues act directly against cancer cells and/or could be considered as antiangiogenic agents has major implications in terms of medical indications and may help to further improve their drug development. Herein, we hypothesize that current rapalogues demonstrating activity in hypervascularized tumours may primarily act through antiangiogenic effects in patients, a hypothesis that certainly requires further translational investigations.

Visualizing the chain-flipping mechanism in fatty-acid biosynthesis

DOE PAGES

Beld, Joris; Cang, Hu; Burkart, Michael D.

2014-10-29

The acyl carrier protein (ACP) from fatty acid synthases sequesters elongating products within its hydrophobic core, but this dynamic mechanism remains poorly understood. In this paper, we exploited solvatochromic pantetheine probes attached to ACP that fluoresce when sequestered. The addition of a catalytic partner lures the cargo out of the ACP and into the active site of the enzyme, thus enhancing fluorescence to reveal the elusive chain-flipping mechanism. This activity was confirmed by the use of a dual solvatochromic cross-linking probe and solution-phase NMR spectroscopy. Finally, the chain-flipping mechanism was visualized by single-molecule fluorescence techniques, thus demonstrating specificity between themore » Escherichia coli ACP and its ketoacyl synthase catalytic partner KASII.« less

A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development

PubMed Central

Ciarlo, Christie; Kaufman, Charles K; Kinikoglu, Beste; Michael, Jonathan; Yang, Song; D′Amato, Christopher; Blokzijl-Franke, Sasja; den Hertog, Jeroen; Schlaeger, Thorsten M; Zhou, Yi; Liao, Eric

2017-01-01

The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that disrupt neural crest development, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits FGF-stimulated PI3K/Akt signaling, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest differentiation. PMID:28832322

Fluorescent sensors reporting the activity of ammonium transceptors in live cells

DOE PAGES

De Michele, Roberto; Ast, Cindy; Loqué, Dominique; ...

2013-07-02

Ammonium serves as key nitrogen source and metabolic intermediate, yet excess causes toxicity. Ammonium uptake is mediated by ammonium transporters, whose regulation is poorly understood. While transport can easily be characterized in heterologous systems, measuring transporter activity in vivo remains challenging. Here we developed a simple assay for monitoring activity in vivo by inserting circularly-permutated GFP into conformation-sensitive positions of two plant and one yeast ammonium transceptors (‘AmTrac’ and ‘MepTrac’). Addition of ammonium to yeast cells expressing the sensors triggered concentration-dependent fluorescence intensity (FI) changes that strictly correlated with the activity of the transporter. Fluorescence-based activity sensors present a novelmore » technology for monitoring the interaction of the transporters with their substrates, the activity of transporters and their regulation in vivo, which is particularly valuable in the context of analytes for which no radiotracers exist, as well as for cell-specific and subcellular transport processes that are otherwise difficult to track.« less

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.

PubMed

Courtney, Adam H; Amacher, Jeanine F; Kadlecek, Theresa A; Mollenauer, Marianne N; Au-Yeung, Byron B; Kuriyan, John; Weiss, Arthur

2017-08-03

The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck, which prevents its adoption of an active open conformation. These results suggest a negative feedback loop that responds to signaling events that tune active Lck amounts and TCR sensitivity. Copyright © 2017 Elsevier Inc. All rights reserved.

Marital quality and diabetes: results from the Health and Retirement Study.

PubMed

Whisman, Mark A; Li, Angela; Sbarra, David A; Raison, Charles L

2014-08-01

Poor marital quality is associated with many different indicators of poor health, including immunologic and metabolic responses that have relevance for distal disease outcomes such as diabetes. We conducted this study to evaluate whether poor marital quality was associated with the prevalence of diabetes in a population-based sample of Americans over the age of 50. Participants were married adults from the 2006 (N = 3,898) and 2008 (N = 3,452) waves of the Health and Retirement Study. Participants completed an interview and a self-report questionnaire, and current use of diabetes medication and glycosylated hemoglobin obtained from blood spot samples were used to index diabetes status. Marital quality was assessed with items regarding perceived frequency of positive and negative exchanges with partner. Decreasing frequency of positive exchanges and increasing frequency of negative exchanges with one's spouse were associated with higher prevalence of diabetes among men, but not women at both waves; gender significantly moderated the associations between partner exchanges and diabetes status for the 2006 data. The association between frequency of partner exchanges and diabetes status generally remained significant in men after accounting for demographic characteristics and other risk factors (obesity, hypertension, low physical activity). Poor marital quality as operationalized by rates of positive and negative partner exchanges was associated with increased prevalence of diabetes in men. These results are consistent with prior work on marriage and health, and suggest that poor marital quality may be a unique risk factor for diabetes.

Efficacy of navigation may be influenced by retrosplenial cortex-mediated learning of landmark stability.

PubMed

Auger, Stephen D; Zeidman, Peter; Maguire, Eleanor A

2017-09-01

Human beings differ considerably in their ability to orient and navigate within the environment, but it has been difficult to determine specific causes of these individual differences. Permanent, stable landmarks are thought to be crucial for building a mental representation of an environment. Poor, compared to good, navigators have been shown to have difficulty identifying permanent landmarks, with a concomitant reduction in functional MRI (fMRI) activity in the retrosplenial cortex. However, a clear association between navigation ability and the learning of permanent landmarks has not been established. Here we tested for such a link. We had participants learn a virtual reality environment by repeatedly moving through it during fMRI scanning. The environment contained landmarks of which participants had no prior experience, some of which remained fixed in their locations while others changed position each time they were seen. After the fMRI learning phase, we divided participants into good and poor navigators based on their ability to find their way in the environment. The groups were closely matched on a range of cognitive and structural brain measures. Examination of the learning phase during scanning revealed that, while good and poor navigators learned to recognise the environment's landmarks at a similar rate, poor navigators were impaired at registering whether landmarks were stable or transient, and this was associated with reduced engagement of the retrosplenial cortex. Moreover, a mediation analysis showed that there was a significant effect of landmark permanence learning on navigation performance mediated through retrosplenial cortex activity. We conclude that a diminished ability to process landmark permanence may be a contributory factor to sub-optimal navigation, and could be related to the level of retrosplenial cortex engagement. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

How do older employees with health problems remain productive at work?: a qualitative study.

PubMed

Leijten, Fenna; van den Heuvel, Swenneke; Geuskens, Goedele; Ybema, Jan Fekke; de Wind, Astrid; Burdorf, Alex; Robroek, Suzan

2013-03-01

The goal of this qualitative study was to gain insight into how older employees remain productive at work in spite of health problems. Twenty-six semi-structured telephone interviews were conducted with older employees, 46-63 years of age, who reported a poor health in the Study on Transitions in Employment, Ability, and Motivation. Demographic, health, and work information was gathered, followed by information on adjustments made in response to health problems. Inductive and deductive analyses were done independently by two researchers. Four pathways through which poor health could influence productivity were identified: (1) poor health did not influence productivity; (2) poor health created a temporary imbalance in demands and external and internal resources after which adjustments were made and productivity was maintained; (3) adjustments were made in response to an imbalance, but productivity remained reduced; and (4) no adjustments were made and productivity was reduced. Whether and which adjustments occurred was influenced by factors in various domains, such as: visibility of the problem (health), autonomy (work-related), support (relational), and the ability to ask for help (personal). Sustainable productivity was influenced by internal factors that enhanced or hindered the creation of a balance, and by whether appropriate adjustments were made. The influence that health can have on productivity depends on the individuals' unique imbalance and personal disposition. Helpful a priori work place characteristics and personal well-being should be promoted so that a balance between demands and resources can be found in times of poor health.

Aerosol-delivered programmed cell death 4 enhanced apoptosis, controlled cell cycle and suppressed AP-1 activity in the lungs of AP-1 luciferase reporter mice.

PubMed

Hwang, S-K; Jin, H; Kwon, J T; Chang, S-H; Kim, T H; Cho, C-S; Lee, K H; Young, M R; Colburn, N H; Beck, G R; Yang, H-S; Cho, M-H

2007-09-01

The long-term survival of lung cancer patients treated with conventional therapies remains poor and therefore the need for novel approaches remains high. This has led to the re-emergence of aerosol delivery as a therapeutic intervention. In this study, glucosylated polyethylenimine (GPEI) was used as carrier to investigate programmed cell death 4 (PDCD4) and PDCD4 mutant (D418A), an eIF4A-binding mutant, on PDCD4-related signaling and activator protein-1 (AP-1) activity in the lungs of AP-1 luciferase reporter mice. After confirming the efficiency of GPEI as a carrier in lungs, the effects of aerosol-delivered PDCD4 were investigated in AP-1 luciferase reporter mice. Aerosol delivery of GPEI/PDCD4 through a nose-only inhalation facilitated the apoptosis of lungs whereas aerosol PDCD4 mutant did not. Also, such aerosol delivery regulated proteins relevant to cell-cycle control and suppressed AP-1 activity. Results obtained by western blot analysis, immunohistochemistry, luciferase assay and deoxynucleotidyl-transferase-mediated nick end labeling study suggest that combined actions such as facilitating apoptosis, controlling cell cycle and suppression of AP-1 activity by PDCD4 may provide useful tool for designing lung tumor prevention and treatment by which PDCD4 functions as a transformation suppressor in the future.

5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells

PubMed Central

Malashchuk, Igor; Lajoie, Brian R.; Mardaryev, Andrei N.; Gdula, Michal R.; Sharov, Andrey A.; Kohwi-Shigematsu, Terumi; Fessing, Michael Y.

2017-01-01

Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription. PMID:28863138

An ultra-relativistic outflow from a neutron star accreting gas from a companion.

PubMed

Fender, Rob; Wu, Kinwah; Johnston, Helen; Tzioumis, Tasso; Jonker, Peter; Spencer, Ralph; Van Der Klis, Michiel

2004-01-15

Collimated relativistic outflows-also known as jets-are amongst the most energetic phenomena in the Universe. They are associated with supermassive black holes in distant active galactic nuclei, accreting stellar-mass black holes and neutron stars in binary systems and are believed to be responsible for gamma-ray bursts. The physics of these jets, however, remains something of a mystery in that their bulk velocities, compositions and energetics remain poorly determined. Here we report the discovery of an ultra-relativistic outflow from a neutron star accreting gas within a binary stellar system. The velocity of the outflow is comparable to the fastest-moving flows observed from active galactic nuclei, and its strength is modulated by the rate of accretion of material onto the neutron star. Shocks are energized further downstream in the flow, which are themselves moving at mildly relativistic bulk velocities and are the sites of the observed synchrotron emission from the jet. We conclude that the generation of highly relativistic outflows does not require properties that are unique to black holes, such as an event horizon.

Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance.

PubMed

Mercer, Susan L; Coop, Andrew

2011-01-01

Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

Soil mineral assemblage influences on microbial communities and carbon cycling under fresh organic matter input

NASA Astrophysics Data System (ADS)

Finley, B. K.; Schwartz, E.; Koch, B.; Dijkstra, P.; Hungate, B. A.

2017-12-01

The interactions between soil mineral assemblages and microbial communities are important drivers of soil organic carbon (SOC) cycling and storage, although the mechanisms driving these interactions remain unclear. There is increasing evidence supporting the importance of associations with poorly crystalline, short-range order (SRO) minerals in protection of SOC from microbial utilization. However, how the microbial processing of SRO-associated SOC may be influenced by fresh organic matter inputs (priming) remains poorly understood. The influence on SRO minerals on soil microbial community dynamics is uncertain as well. Therefore, we conducted a priming incubation by adding either a simulated root exudate mixture or conifer needle litter to three soils from a mixed-conifer ecosystem. The parent material of the soils were andesite, basalt, and granite and decreased in SRO mineral content, respectively. We also conducted a parallel quantitative stable isotope probing incubation by adding 18O-labelled water to the soils to isotopically label microbial DNA in situ. This allowed us to characterize and identify the active bacterial and archaeal community and taxon-specific growth under fresh organic matter input. While the granite soil (lowest SRO content), had the largest total mineralization, the least priming occurred. The andesite and basalt soils (greater SRO content) had lower total respiration, but greater priming. Across all treatments, the granite soil, while having the lowest species richness of the entire community (249 taxa, both active and inactive), had a larger active community (90%) in response to new SOC input. The andesite and basalt soils, while having greater total species richness of the entire community at 333 and 325 taxa, respectively, had fewer active taxa in response to new C compared to the granite soil (30% and 49% taxa, respectively). These findings suggest that the soil mineral assemblage is an important driver on SOC cycling under fresh organic matter inputs, as well as on the activity and diversity of the microbial community. Often, microbial diversity is associated with function. Our results suggest that the soil environment, in this case SRO mineral content, may be more important on SOC cycling and storage than microbial diversity alone.

Applications of alignment-free methods in epigenomics.

PubMed

Pinello, Luca; Lo Bosco, Giosuè; Yuan, Guo-Cheng

2014-05-01

Epigenetic mechanisms play an important role in the regulation of cell type-specific gene activities, yet how epigenetic patterns are established and maintained remains poorly understood. Recent studies have supported a role of DNA sequences in recruitment of epigenetic regulators. Alignment-free methods have been applied to identify distinct sequence features that are associated with epigenetic patterns and to predict epigenomic profiles. Here, we review recent advances in such applications, including the methods to map DNA sequence to feature space, sequence comparison and prediction models. Computational studies using these methods have provided important insights into the epigenetic regulatory mechanisms.

STUDIES ON RARE AND POORLY KNOWN LEECHES (ANNELIDA: HIRUDINEA: GLOSSIPHONIIDAE) IN EASTERN NORTH AMERICA

EPA Science Inventory

Three taxa within the leech family Glossiphoniidae, Actinobdella inequiannulata, Placobdella hollensis, and Theromyzon spp., though widespread in eastern North America, remain poorly known with respect to their biology and systematics. All three taxa have been collected in New E...

Research Review: The Neurobiology and Genetics of Maltreatment and Adversity

ERIC Educational Resources Information Center

McCrory, Eamon; De Brito, Stephane A.; Viding, Essi

2010-01-01

The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individual's genetic make-up influence neurobiological development across infancy and childhood, which in…

Plexin-B2 promotes invasive growth of malignant glioma

PubMed Central

Pingle, Sandeep C.; Kesari, Santosh; Wang, Huaien; Yong, Raymund L.; Zou, Hongyan; Friedel, Roland H.

2015-01-01

Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma. PMID:25762646

Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer.

PubMed

Narayanan, Sathiya Pandi; Singh, Smriti; Gupta, Amit; Yadav, Sandhya; Singh, Shree Ram; Shukla, Sanjeev

2015-10-28

The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silico pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Disability transitions and health expectancies among adults 45 years and older in Malawi: a cohort-based model.

PubMed

Payne, Collin F; Mkandawire, James; Kohler, Hans-Peter

2013-01-01

Falling fertility and increasing life expectancy contribute to a growing elderly population in sub-Saharan Africa (SSA); by 2060, persons aged 45 y and older are projected to be 25% of SSA's population, up from 10% in 2010. Aging in SSA is associated with unique challenges because of poverty and inadequate social supports. However, despite its importance for understanding the consequences of population aging, the evidence about the prevalence of disabilities and functional limitations due to poor physical health among older adults in SSA continues to be very limited. Participants came from 2006, 2008, and 2010 waves of the Malawi Longitudinal Survey of Families and Health, a study of the rural population in Malawi. We investigate how poor physical health results in functional limitations that limit the day-to-day activities of individuals in domains relevant to this subsistence-agriculture context. These disabilities were parameterized based on questions from the SF-12 questionnaire about limitations in daily living activities. We estimated age-specific patterns of functional limitations and the transitions over time between different disability states using a discrete-time hazard model. The estimated transition rates were then used to calculate the first (to our knowledge) microdata-based health expectancies calculated for SSA. The risks of experiencing functional limitations due to poor physical health are high in this population, and the onset of disabilities happens early in life. Our analyses show that 45-y-old women can expect to spend 58% (95% CI, 55%-64%) of their remaining 28 y of life (95% CI, 25.7-33.5) with functional limitations; 45-y-old men can expect to live 41% (95% CI, 35%-46%) of their remaining 25.4 y (95% CI, 23.3-28.8) with such limitations. Disabilities related to functional limitations are shown to have a substantial negative effect on individuals' labor activities, and are negatively related to subjective well-being. Individuals in this population experience a lengthy struggle with disabling conditions in adulthood, with high probabilities of remitting and relapsing between states of functional limitation. Given the strong association of disabilities with work efforts and subjective well-being, this research suggests that current national health policies and international donor-funded health programs in SSA inadequately target the physical health of mature and older adults.

From Nose to Brain: Un-Sensed Electrical Currents Applied in the Nose Alter Activity in Deep Brain Structures

PubMed Central

Weiss, Tali; Shushan, Sagit; Ravia, Aharon; Hahamy, Avital; Secundo, Lavi; Weissbrod, Aharon; Ben-Yakov, Aya; Holtzman, Yael; Cohen-Atsmoni, Smadar; Roth, Yehudah; Sobel, Noam

2016-01-01

Rules linking patterns of olfactory receptor neuron activation in the nose to activity patterns in the brain and ensuing odor perception remain poorly understood. Artificially stimulating olfactory neurons with electrical currents and measuring ensuing perception may uncover these rules. We therefore inserted an electrode into the nose of 50 human volunteers and applied various currents for about an hour in each case. This induced assorted non-olfactory sensations but never once the perception of odor. To validate contact with the olfactory path, we used functional magnetic resonance imaging to measure resting-state brain activity in 18 subjects before and after un-sensed stimulation. We observed stimulation-induced neural decorrelation specifically in primary olfactory cortex, implying contact with the olfactory path. These results suggest that indiscriminate olfactory activation does not equate with odor perception. Moreover, this effort serendipitously uncovered a novel path for minimally invasive brain stimulation through the nose. PMID:27591145

PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling

PubMed Central

Kang, Seok-Gu; Kim, Rae-Kwon; Cui, Yan-Hong; Lee, Hae-June; Kim, Min-Jung; Lee, Jae-Seong; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

2016-01-01

Poor prognosis of glioblastoma (GBM) is attributable to the propensity of tumor cells to infiltrate into the brain parenchyma. Protein kinase C (PKC) isozymes are highly expressed or aberrantly activated in GBM. However, how this signaling node translates to GBM cell invasiveness remains unknown. Here, we report that among PKC isoforms, PKCδ is strongly associated with infiltration of GBM cells. Notably, PKCδ enhanced Tyr418 phosphorylation of the non-receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness. Furthermore, we showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM. In agreement, inhibition either component in the c-MET/PKCδ/SRC/STAT3 signaling axis effectively blocked the NOTCH2 signaling and invasiveness of GBM cells. Taken together, our findings shed a light on the signaling mechanisms behind the constitutive activation of PKCδ signaling in GBM. PMID:26700818

Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation.

PubMed

Oh, Jung Hwa; Lee, Tae-Jin; Kim, Sang Hyun; Choi, Yung Hyun; Lee, Sang Han; Lee, Jin Man; Kim, Young-Ho; Park, Jong-Wook; Kwon, Taeg Kyu

2008-12-01

Withaferin A, a major chemical constituent of Withania somnifera, has been reported for its tumor cell growth inhibitory activity, antitumor effects, and impairing metastasis and angiogenesis. The mechanism by which withaferin A initiates apoptosis remains poorly understood. In the present report, we investigated the effect of withaferin A on the apoptotic pathway in U937 human promonocytic cells. We show that withaferin A induces apoptosis in association with the activation of caspase-3. JNK and Akt signal pathways play crucial roles in withaferin A-induced apoptosis in U937 cells. Furthermore, we have shown that overexpression of Bcl-2 and active Akt (myr-Akt) in U937 cells inhibited the induction of apoptosis, activation of caspase-3, and PLC-gamma1 cleavage by withaferin A. Taken together, our results indicated that the JNK and Akt pathways and inhibition of NF-kappaB activity were key regulators of apoptosis in response to withaferin A in human leukemia U937 cells.

AKT Kinase Activity Is Required for Lithium to Modulate Mood-Related Behaviors in Mice

PubMed Central

Pan, Jen Q; Lewis, Michael C; Ketterman, Josh K; Clore, Elizabeth L; Riley, Misha; Richards, Keenan R; Berry-Scott, Erin; Liu, Xiulin; Wagner, Florence F; Holson, Edward B; Neve, Rachael L; Biechele, Travis L; Moon, Randall T; Scolnick, Edward M; Petryshen, Tracey L; Haggarty, Stephen J

2011-01-01

Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response—activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice—and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment. PMID:21389981

Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence

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

Ortega, Corrie; Anderson, Lindsey N.; Frando, Andrew

The transition between replication and non-replication underlies much of Mycobacterium tuberculosis (Mtb) pathogenicity, as non- or slowly replicating Mtb are responsible for persistence and poor treatment outcomes. Therapeutic targeting of non-replicating, persistent populations is a priority for tuberculosis treatment, but only few drug targets in non-replicating Mtb are currently known. Here, we directly measure the activity of the highly diverse and druggable serine hydrolases (SHs) during active replication and non-replication by activity-based proteomics. We predict serine hydrolase activity for 78 proteins, including 27 proteins with previously unknown function, and identify 37 SHs that remain active even in the absence ofmore » replication, providing a set of candidate persistence targets. Non-replication was associated with large shifts in the activity of the majority of SHs. These activity changes were largely independent of SH abundance, indicating extensive post-translational regulation. By probing a large cross-section of druggable Mtb enzyme space during replication and non-replication, we identify new SHs and suggest new persistence targets.« less

Psychosocial mechanisms linking the social environment to mental health in African Americans

USDA-ARS?s Scientific Manuscript database

Resource-poor social environments predict poor health, but the mechanisms and processes linking the social environment to psychological health and well-being remain unclear. This study explored psychosocial mediators of the association between the social environment and mental health in African Amer...

Re-employment, job quality, health and allostatic load biomarkers: prospective evidence from the UK Household Longitudinal Study

PubMed Central

Chandola, Tarani; Zhang, Nan

2018-01-01

Abstract Background There is little evidence on whether becoming re-employed in poor quality work is better for health and well-being than remaining unemployed. We examined associations of job transition with health and chronic stress-related biomarkers among a population-representative cohort of unemployed British adults. Methods A prospective cohort of 1116 eligible participants aged 35 to 75 years, who were unemployed at wave 1 (2009/10) of the UK Household Longitudinal Study, were followed up at waves 2 (2010/11) and 3 (2011/12) for allostatic load biomarkers and self-reported health. Negative binomial and multiple regression models estimated the association between job adversity and these outcomes. Results Compared with adults who remained unemployed, formerly unemployed adults who transitioned into poor quality jobs had higher levels of overall allostatic load (0.51, 0.32–0.71), log HbA1c (0.06, <0.001–0.12), log triglycerides (0.39, 0.22–0.56), log C-reactive protein (0.45, 0.16–0.75), log fibrinogen (0.09, 0.01–0.17) and total cholesterol to high-density lipoprotein (HDL) ratio (1.38, 0.88–1.88). Moreover, physically healthier respondents at wave 1 were more likely to transition into good quality and poor quality jobs after 1 year than those who remained unemployed. Conclusions Formerly unemployed adults who transitioned into poor quality work had greater adverse levels of biomarkers compared with their peers who remained unemployed. The selection of healthier unemployed adults into these poor quality or stressful jobs was unlikely to explain their elevated levels of chronic stress-related biomarkers. Job quality cannot be disregarded from the employment success of the unemployed, and may have important implications for their health and well-being. PMID:29024973

[The maturation steps of human immunodeficiency virus and the role of proteolysis].

PubMed

Bukrinskaia, A G; Grigor'ev, V B; Korablina, E V; Gur'ev, E L; Vorkunova, G K

2010-01-01

HIV-1 virions are as immature noninfectious particles lacking a central core. Shortly after budding, virions temporally mature and acquire cores and infectious activity. The cause of maturation remains poorly studied. We have revealed that the virions produced early after infection following 24-36 hours, never mature and remain noninfectious, and only virions produced 48-72 hours after infection mature. The mature virions contain 3 times more genomic viral RNA than "early" virus. The "early" virions contain the same proteolytically cleaved Gag proteins as mature virions in contrast to the accepted version. The virus protease inhibitor Indinavir sulfate (IS) fully blocks infectivity when added early after infection. The early proteolysis of Gag precursor in the infected cells and inclusion into the virions of cellularly cleaved matrix protein (cMA) are shown in the IS-treated cells. cMA is associated with genomic viral RNA.

Alternative splicing in plant immunity.

PubMed

Yang, Shengming; Tang, Fang; Zhu, Hongyan

2014-06-10

Alternative splicing (AS) occurs widely in plants and can provide the main source of transcriptome and proteome diversity in an organism. AS functions in a range of physiological processes, including plant disease resistance, but its biological roles and functional mechanisms remain poorly understood. Many plant disease resistance (R) genes undergo AS, and several R genes require alternatively spliced transcripts to produce R proteins that can specifically recognize pathogen invasion. In the finely-tuned process of R protein activation, the truncated isoforms generated by AS may participate in plant disease resistance either by suppressing the negative regulation of initiation of immunity, or by directly engaging in effector-triggered signaling. Although emerging research has shown the functional significance of AS in plant biotic stress responses, many aspects of this topic remain to be understood. Several interesting issues surrounding the AS of R genes, especially regarding its functional roles and regulation, will require innovative techniques and additional research to unravel.

Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

PubMed Central

Annambhotla, Suman; Bourgeois, Sebastian; Wang, Xinwen; Lin, Peter H.; Yao, Qizhi; Chen, Changyi

2010-01-01

Abdominal Aortic Aneurysm (AAA) is an increasingly common clinical condition with fatal implications. It is associated with advanced age, male gender, cigarette smoking, atherosclerosis, hypertension, and genetic predisposition. Although significant evidence has emerged in the last decade, the molecular mechanisms of AAA formation remains poorly understood. Currently, the treatment for AAA remains primarily surgical with the lone innovation of endovascular therapy. With advance in the human genome, understanding precisely which molecules and genes mediate AAA development and blocking their activity at the molecular level could lead to important new discoveries and therapies. This review summarizes recent updates in molecular mechanisms of AAA formation including animal models, autoimmune components, infection, key molecules and cytokines, mechanical forces, genetics and pharmacotherapy. This review will be helpful to those who want to recognize the newest endeavors within the field and identify possible lines of investigation in AAA. PMID:18259804

Activity-Dependence of Synaptic Vesicle Dynamics

PubMed Central

Forte, Luca A.

2017-01-01

The proper function of synapses relies on efficient recycling of synaptic vesicles. The small size of synaptic boutons has hampered efforts to define the dynamical states of vesicles during recycling. Moreover, whether vesicle motion during recycling is regulated by neural activity remains largely unknown. We combined nanoscale-resolution tracking of individual synaptic vesicles in cultured hippocampal neurons from rats of both sexes with advanced motion analyses to demonstrate that the majority of recently endocytosed vesicles undergo sequences of transient dynamical states including epochs of directed, diffusional, and stalled motion. We observed that vesicle motion is modulated in an activity-dependent manner, with dynamical changes apparent in ∼20% of observed boutons. Within this subpopulation of boutons, 35% of observed vesicles exhibited acceleration and 65% exhibited deceleration, accompanied by corresponding changes in directed motion. Individual vesicles observed in the remaining ∼80% of boutons did not exhibit apparent dynamical changes in response to stimulation. More quantitative transient motion analyses revealed that the overall reduction of vesicle mobility, and specifically of the directed motion component, is the predominant activity-evoked change across the entire bouton population. Activity-dependent modulation of vesicle mobility may represent an important mechanism controlling vesicle availability and neurotransmitter release. SIGNIFICANCE STATEMENT Mechanisms governing synaptic vesicle dynamics during recycling remain poorly understood. Using nanoscale resolution tracking of individual synaptic vesicles in hippocampal synapses and advanced motion analysis tools we demonstrate that synaptic vesicles undergo complex sets of dynamical states that include epochs of directed, diffusive, and stalled motion. Most importantly, our analyses revealed that vesicle motion is modulated in an activity-dependent manner apparent as the reduction in overall vesicle mobility in response to stimulation. These results define the vesicle dynamical states during recycling and reveal their activity-dependent modulation. Our study thus provides fundamental new insights into the principles governing synaptic function. PMID:28954868

A GABAergic nigrotectal pathway for coordination of drinking behavior

PubMed Central

Rossi, Mark A.; Li, Haofang E.; Lu, Dongye; Kim, Il Hwan; Bartholomew, Ryan A.; Gaidis, Erin; Barter, Joseph W.; Kim, Namsoo; Cai, Min Tong; Soderling, Scott H.; Yin, Henry H.

2016-01-01

The contribution of basal ganglia outputs to consummatory behavior remains poorly understood. We recorded from the substantia nigra pars reticulata (SNR), the major basal ganglia output nucleus, during self-initiated drinking. The firing rates of many lateral SNR neurons were time-locked to individual licks. These neurons send GABAergic projections to the deep layers of the orofacial region of the lateral tectum (superior colliculus, SC). Many tectal neurons are also time-locked to licking, but their activity is usually antiphase to that of SNR neurons, suggesting inhibitory nigrotectal projections. We used optogenetics to selectively activate the GABAergic nigrotectal afferents in the deep layers of the SC. Photo-stimulation of the nigrotectal projections transiently inhibited the activity of the lick-related tectal neurons, disrupted their licking-related oscillatory pattern, and suppressed self-initiated drinking. These results demonstrate that GABAergic nigrotectal projections play a crucial role in coordinating drinking behavior. PMID:27043290

Cis-regulatory RNA elements that regulate specialized ribosome activity.

PubMed

Xue, Shifeng; Barna, Maria

2015-01-01

Recent evidence has shown that the ribosome itself can play a highly regulatory role in the specialized translation of specific subpools of mRNAs, in particular at the level of ribosomal proteins (RP). However, the mechanism(s) by which this selection takes place has remained poorly understood. In our recent study, we discovered a combination of unique RNA elements in the 5'UTRs of mRNAs that allows for such control by the ribosome. These mRNAs contain a Translation Inhibitory Element (TIE) that inhibits general cap-dependent translation, and an Internal Ribosome Entry Site (IRES) that relies on a specific RP for activation. The unique combination of an inhibitor of general translation and an activator of specialized translation is key to ribosome-mediated control of gene expression. Here we discuss how these RNA regulatory elements provide a new level of control to protein expression and their implications for gene expression, organismal development and evolution.

Memory retrieval and the parietal cortex: a review of evidence from a dual-process perspective.

PubMed

Vilberg, Kaia L; Rugg, Michael D

2008-01-01

Although regions of the parietal cortex have been consistently implicated in episodic memory retrieval, the functional roles of these regions remain poorly understood. The present review presents a meta-analysis of findings from event-related fMRI studies reporting the loci of retrieval effects associated with familiarity- and recollection-related recognition judgments. The results of this analysis support previous suggestions that retrieval-related activity in lateral parietal cortex dissociates between superior regions, where activity likely reflects the task relevance of different classes of recognition test items, and more inferior regions where retrieval-related activity appears closely linked to successful recollection. It is proposed that inferior lateral parietal cortex forms part of a neural network supporting the 'episodic buffer' [Baddeley, A. D. (2000). The episodic buffer: A new component of working memory? Trends in Cognitive Sciences, 4, 417-423].

Time-specific ecological niche modeling predicts spatial dynamics of vector insects and human dengue cases.

PubMed

Peterson, A Townsend; Martínez-Campos, Carmen; Nakazawa, Yoshinori; Martínez-Meyer, Enrique

2005-09-01

Numerous human diseases-malaria, dengue, yellow fever and leishmaniasis, to name a few-are transmitted by insect vectors with brief life cycles and biting activity that varies in both space and time. Although the general geographic distributions of these epidemiologically important species are known, the spatiotemporal variation in their emergence and activity remains poorly understood. We used ecological niche modeling via a genetic algorithm to produce time-specific predictive models of monthly distributions of Aedes aegypti in Mexico in 1995. Significant predictions of monthly mosquito activity and distributions indicate that predicting spatiotemporal dynamics of disease vector species is feasible; significant coincidence with human cases of dengue indicate that these dynamics probably translate directly into transmission of dengue virus to humans. This approach provides new potential for optimizing use of resources for disease prevention and remediation via automated forecasting of disease transmission risk.

Peptidomic analysis reveals proteolytic activity of kefir microorganisms on bovine milk proteins

PubMed Central

Dallas, David C.; Citerne, Florine; Tian, Tian; Silva, Vitor L. M.; Kalanetra, Karen M.; Frese, Steven A.; Robinson, Randall C.; Mills, David A.; Barile, Daniela

2015-01-01

Scope The microorganisms that make up kefir grains are well known for lactose fermentation, but the extent to which they hydrolyze and consume milk proteins remains poorly understood. Peptidomics technologies were used to examine the proteolytic activity of kefir grains on bovine milk proteins. Methods and results Gel electrophoresis revealed substantial digestion of milk proteins by kefir grains, with mass spectrometric analysis showing the release of 609 protein fragments and alteration of the abundance of >1,500 peptides that derived from 27 milk proteins. Kefir contained 25 peptides identified from the literature as having biological activity, including those with antihypertensive, antimicrobial, immunomodulatory, opioid and anti-oxidative functions. 16S rRNA and shotgun metagenomic sequencing identified the principle taxa in the culture as Lactobacillus species. Conclusion The model kefir sample contained thousands of protein fragments released in part by kefir microorganisms and in part by native milk proteases. PMID:26616950

Resonant activation of population extinctions

NASA Astrophysics Data System (ADS)

Spalding, Christopher; Doering, Charles R.; Flierl, Glenn R.

2017-10-01

Understanding the mechanisms governing population extinctions is of key importance to many problems in ecology and evolution. Stochastic factors are known to play a central role in extinction, but the interactions between a population's demographic stochasticity and environmental noise remain poorly understood. Here we model environmental forcing as a stochastic fluctuation between two states, one with a higher death rate than the other. We find that, in general, there exists a rate of fluctuations that minimizes the mean time to extinction, a phenomenon previously dubbed "resonant activation." We develop a heuristic description of the phenomenon, together with a criterion for the existence of resonant activation. Specifically, the minimum extinction time arises as a result of the system approaching a scenario wherein the severity of rare events is balanced by the time interval between them. We discuss our findings within the context of more general forms of environmental noise and suggest potential applications to evolutionary models.

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape

PubMed Central

Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter

2018-01-01

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. PMID:29553368

FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment

PubMed Central

Dimitrova, Emilia; Nakayama, Manabu; Koseki, Yoko; Konietzny, Rebecca; Kessler, Benedikt M; Koseki, Haruhiko

2018-01-01

CpG islands are gene regulatory elements associated with the majority of mammalian promoters, yet how they regulate gene expression remains poorly understood. Here, we identify FBXL19 as a CpG island-binding protein in mouse embryonic stem (ES) cells and show that it associates with the CDK-Mediator complex. We discover that FBXL19 recruits CDK-Mediator to CpG island-associated promoters of non-transcribed developmental genes to prime these genes for activation during cell lineage commitment. We further show that recognition of CpG islands by FBXL19 is essential for mouse development. Together this reveals a new CpG island-centric mechanism for CDK-Mediator recruitment to developmental gene promoters in ES cells and a requirement for CDK-Mediator in priming these developmental genes for activation during cell lineage commitment. PMID:29809150

Rectified directional sensing in long-range cell migration

PubMed Central

Nakajima, Akihiko; Ishihara, Shuji; Imoto, Daisuke; Sawai, Satoshi

2014-01-01

How spatial and temporal information are integrated to determine the direction of cell migration remains poorly understood. Here, by precise microfluidics emulation of dynamic chemoattractant waves, we demonstrate that, in Dictyostelium, directional movement as well as activation of small guanosine triphosphatase Ras at the leading edge is suppressed when the chemoattractant concentration is decreasing over time. This ‘rectification’ of directional sensing occurs only at an intermediate range of wave speed and does not require phosphoinositide-3-kinase or F-actin. From modelling analysis, we show that rectification arises naturally in a single-layered incoherent feedforward circuit with zero-order ultrasensitivity. The required stimulus time-window predicts ~5 s transient for directional sensing response close to Ras activation and inhibitor diffusion typical for protein in the cytosol. We suggest that the ability of Dictyostelium cells to move only in the wavefront is closely associated with rectification of adaptive response combined with local activation and global inhibition. PMID:25373620

Peptidomic analysis reveals proteolytic activity of kefir microorganisms on bovine milk proteins.

PubMed

Dallas, David C; Citerne, Florine; Tian, Tian; Silva, Vitor L M; Kalanetra, Karen M; Frese, Steven A; Robinson, Randall C; Mills, David A; Barile, Daniela

2016-04-15

The microorganisms that make up kefir grains are well known for lactose fermentation, but the extent to which they hydrolyze and consume milk proteins remains poorly understood. Peptidomics technologies were used to examine the proteolytic activity of kefir grains on bovine milk proteins. Gel electrophoresis revealed substantial digestion of milk proteins by kefir grains, with mass spectrometric analysis showing the release of 609 protein fragments and alteration of the abundance of >1500 peptides that derived from 27 milk proteins. Kefir contained 25 peptides identified from the literature as having biological activity, including those with antihypertensive, antimicrobial, immunomodulatory, opioid and anti-oxidative functions. 16S rRNA and shotgun metagenomic sequencing identified the principle taxa in the culture as Lactobacillus species. The model kefir sample contained thousands of protein fragments released in part by kefir microorganisms and in part by native milk proteases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Twin Screw Extruder Production of MTTP Decoy Flares SERDP WP-1240

DTIC Science & Technology

2005-12-01

5 3. Carnauba Wax ( wax from palm tree exudate, a common ingredient in high quality car polish) Hazards of the remaining formulations were...1. Microsere 5866, a microcrystalline wax derived from refining petroleum 2. Elvax 250, poly(ethylene-co-vinyl acetate) (hot glue ingredient...5866 Poor performance when 1-gm sample ignited Elvax 250 Poor performance when 1-gm sample ignited Carnuba Wax Poor performance when 1-gm sample

Effect of retinal impulse blockage on cytochrome oxidase-poor interpuffs in the macaque striate cortex: quantitative EM analysis of neurons.

PubMed

Wong-Riley, M T; Trusk, T C; Kaboord, W; Huang, Z

1994-09-01

One of the hallmarks of the primate striate cortex is the presence of cytochrome oxidase-rich puffs in its supragranular layers. Neurons in puffs have been classified as type A, B, and C in ascending order of cytochrome oxidase content, with type C cells being the most vulnerable to retinal impulse blockade. The present study aimed at analysing cytochrome oxidase-poor interpuffs with reference to their metabolic cell types and the effect of intraretinal tetrodotoxin treatment. The same three metabolic types were found in interpuffs, except that type B and C neurons were smaller and less cytochrome oxidase-reactive in interpuffs than in puffs. Type A neurons had small perikarya, low levels of cytochrome oxidase, and received exclusively symmetric axosomatic synapses. The largest neurons were pyramidal, type B cells with moderate cytochrome oxidase activity and were also contacted exclusively by symmetric axosomatic synapses. Type C cells medium-sized with a rich supply of large, darkly reactive mitochondria and possessed all the characteristics of GABAergic neurons. They were the only cell type that received both symmetric and asymmetric axosomatic synapses. Two weeks of monocular tetrodotoxin blockade in adult monkeys caused all three major cell types in deprived interpuffs to suffer a significant downward shift in the size and cytochrome oxidase reactivity of their mitochondria, but the effects were more severe in type B and C neurons. In nondeprived interpuffs, all three cell types gained both in size and absolute number of mitochondria, and type A cells also had an elevated level of cytochrome oxidase, indicating that they might be functioning at a competitive advantage over cells in deprived columns. However, type B and C neurons showed a net loss of darkly reactive mitochondria, indicating that these cells became less active. Thus, mature interpuff neurons remained vulnerable to retinal impulse blockade and the metabolic capacity of these cells remains tightly regulated by neuronal activity.

Evidence for a palaeo-subglacial lake on the Antarctic continental shelf

PubMed Central

Kuhn, Gerhard; Hillenbrand, Claus-Dieter; Kasten, Sabine; Smith, James A.; Nitsche, Frank O.; Frederichs, Thomas; Wiers, Steffen; Ehrmann, Werner; Klages, Johann P.; Mogollón, José M.

2017-01-01

Subglacial lakes are widespread beneath the Antarctic Ice Sheet but their control on ice-sheet dynamics and their ability to harbour life remain poorly characterized. Here we present evidence for a palaeo-subglacial lake on the Antarctic continental shelf. A distinct sediment facies recovered from a bedrock basin in Pine Island Bay indicates deposition within a low-energy lake environment. Diffusive-advection modelling demonstrates that low chloride concentrations in the pore water of the corresponding sediments can only be explained by initial deposition of this facies in a freshwater setting. These observations indicate that an active subglacial meltwater network, similar to that observed beneath the extant ice sheet, was also active during the last glacial period. It also provides a new framework for refining the exploration of these unique environments. PMID:28569750

Loss of l(3)mbt leads to acquisition of the ping-pong cycle in Drosophila ovarian somatic cells

PubMed Central

Sumiyoshi, Tetsutaro; Sato, Kaoru; Yamamoto, Hitomi; Iwasaki, Yuka W.; Siomi, Haruhiko; Siomi, Mikiko C.

2016-01-01

In Drosophila germ cells, PIWI-interacting RNAs (piRNAs) are amplified through a PIWI slicer-dependent feed-forward loop termed the ping-pong cycle, yielding secondary piRNAs. However, the detailed mechanism remains poorly understood, largely because an ex vivo model system amenable to biochemical analyses has not been available. Here, we show that CRISPR-mediated loss of function of lethal (3) malignant brain tumor [l(3)mbt] leads to ectopic activation of the germ-specific ping-pong cycle in ovarian somatic cells. Perinuclear foci resembling nuage, the ping-pong center, appeared following l(3)mbt mutation. This activation of the ping-pong machinery in cultured cells will greatly facilitate elucidation of the mechanism underlying secondary piRNA biogenesis in Drosophila. PMID:27474440

Healthcare Access and Health Beliefs of the Indigenous Peoples in Remote Amazonian Peru

PubMed Central

Brierley, Charlotte K.; Suarez, Nicolas; Arora, Gitanjli; Graham, Devon

2014-01-01

Little is published about the health issues of traditional communities in the remote Peruvian Amazon. This study assessed healthcare access, health perceptions, and beliefs of the indigenous population along the Ampiyacu and Yaguasyacu rivers in north-eastern Peru. One hundred and seventy-nine adult inhabitants of 10 remote settlements attending health clinics were interviewed during a medical services trip in April 2012. Demographics, health status, access to healthcare, health education, sanitation, alcohol use, and smoke exposure were recorded. Our findings indicate that poverty, household overcrowding, and poor sanitation remain commonplace in this group. Furthermore, there are poor levels of health education and on-going barriers to accessing healthcare. Healthcare access and health education remain poor in the remote Peruvian Amazon. This combined with poverty and its sequelae render this population vulnerable to disease. PMID:24277789

The Other Poor: Rural Poverty and Education.

ERIC Educational Resources Information Center

Books, Sue

1997-01-01

This paper argues that rural poverty remains relatively invisible because, although shameful, it is profitable, and the rural poor pose little threat to their suburban neighbors. This is illustrated via interrogation concerning a rural poultry plant fire. The paper examines implications of this case for foundations scholars and educational…

Mathematics Anxiety in the Navajo Reservation School.

ERIC Educational Resources Information Center

Hadfield, Oakley D.; And Others

Of the many factors that have been proposed as a rationale for poor mathematics conceptualization by American Indians, cultural factors remain the most popular when explanations are submitted. Additionally, the accepted fault for poor achievement is focused upon mathematics anxiety. A study of American Indian school mathematics achievement and…

Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study.

PubMed

Jansen, Diahann T S L; Emery, Paul; Smolen, Josef S; Westhovens, Rene; Le Bars, Manuela; Connolly, Sean E; Ye, June; Toes, René E M; Huizinga, Tom W J

2018-01-01

To evaluate the effects of the T-cell costimulation blocker abatacept on anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) in early rheumatoid arthritis (RA), and associations between changes in serological status and clinical response. Post hoc analysis of the phase III AGREE study in methotrexate (MTX)-naïve patients with early RA and poor prognostic factors. Patients were randomised to abatacept (~10 mg/kg intravenously according to weight range) or placebo, plus MTX over 12 months followed by open-label abatacept plus MTX for 12 months. Autoantibody titres were determined by ELISA at baseline and months 6 and 12 (double-blind phase). Conversion to seronegative status and its association with clinical response were assessed at months 6 and 12. Abatacept plus MTX was associated with a greater decrease in ACPA (but not RF) titres and higher rates of both ACPA and RF conversion to seronegative status versus MTX alone. More patients converting to ACPA seronegative status receiving abatacept plus MTX achieved remission according to Disease Activity Score in 28 joints (C-reactive protein) or Clinical Disease Activity Index than patients who remained ACPA seropositive. Patients who converted to ACPA seronegative status treated with abatacept plus MTX had a greater probability of achieving sustained remission and less radiographic progression than MTX alone or patients who remained ACPA seropositive (either treatment). Treatment with abatacept plus MTX was more likely to induce conversion to ACPA/RF seronegative status in patients with early, erosive RA. Conversion to ACPA seronegative status was associated with better clinical and radiographic outcomes. NCT00122382.

Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study

PubMed Central

Emery, Paul; Smolen, Josef S; Westhovens, Rene; Le Bars, Manuela; Connolly, Sean E; Ye, June; Toes, René E M; Huizinga, Tom W J

2018-01-01

Objective To evaluate the effects of the T-cell costimulation blocker abatacept on anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) in early rheumatoid arthritis (RA), and associations between changes in serological status and clinical response. Methods Post hoc analysis of the phase III AGREE study in methotrexate (MTX)-naïve patients with early RA and poor prognostic factors. Patients were randomised to abatacept (~10 mg/kg intravenously according to weight range) or placebo, plus MTX over 12 months followed by open-label abatacept plus MTX for 12 months. Autoantibody titres were determined by ELISA at baseline and months 6 and 12 (double-blind phase). Conversion to seronegative status and its association with clinical response were assessed at months 6 and 12. Results Abatacept plus MTX was associated with a greater decrease in ACPA (but not RF) titres and higher rates of both ACPA and RF conversion to seronegative status versus MTX alone. More patients converting to ACPA seronegative status receiving abatacept plus MTX achieved remission according to Disease Activity Score in 28 joints (C-reactive protein) or Clinical Disease Activity Index than patients who remained ACPA seropositive. Patients who converted to ACPA seronegative status treated with abatacept plus MTX had a greater probability of achieving sustained remission and less radiographic progression than MTX alone or patients who remained ACPA seropositive (either treatment). Conclusions Treatment with abatacept plus MTX was more likely to induce conversion to ACPA/RF seronegative status in patients with early, erosive RA. Conversion to ACPA seronegative status was associated with better clinical and radiographic outcomes. Trial registration number NCT00122382 PMID:29657830

Association Between Spousal Caregiver Well-Being and Care Recipient Healthcare Expenditures.

PubMed

Ankuda, Claire K; Maust, Donovan T; Kabeto, Mohammed U; McCammon, Ryan J; Langa, Kenneth M; Levine, Deborah A

2017-10-01

To measure the association between spousal depression, general health, fatigue and sleep, and future care recipient healthcare expenditures and emergency department (ED) use. Prospective cohort study. Health and Retirement Study. Home-dwelling spousal dyads in which one individual (care recipient) was aged 65 and older and had one or more activity of daily living or instrumental activity of daily living disabilities and was enrolled in Medicare Part B (N = 3,101). Caregiver sleep (Jenkins Sleep Scale), depressive symptoms (Center for Epidemiologic Studies Depression-8 Scale), and self-reported general health measures. Primary outcome was care recipient Medicare expenditures. Secondary outcome was care recipient ED use. Follow-up was 6 months. Caregiver depressive symptoms score and six of 17 caregiver well-being measures were prospectively associated with higher care recipient expenditures after minimal adjustment (P < .05). Higher care recipient expenditures remained significantly associated with caregiver fatigue (cost increase, $1,937, 95% confidence interval (CI) = $770-3,105) and caregiver sadness (cost increase, $1,323, 95% CI = $228-2,419) after full adjustment. Four of 17 caregiver well-being measures, including severe fatigue, were significantly associated with care recipient ED use after minimal adjustment (P < .05). Greater odds of care recipient ED use remained significantly associated with caregiver fatigue (odds ratio (OR) = 1.24, 95% CI = 1.01-1.52) and caregiver fair to poor health (OR = 1.23, 95% CI = 1.04-1.45) after full adjustment. Caregiver total sleep score was not associated with care recipient outcomes. Poor caregiver well-being, particularly severe fatigue, is independently and prospectively associated with higher care recipient Medicare expenditures and ED use. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Mechanisms of Soil Aggregation: a biophysical modeling framework

NASA Astrophysics Data System (ADS)

Ghezzehei, T. A.; Or, D.

2016-12-01

Soil aggregation is one of the main crosscutting concepts in all sub-disciplines and applications of soil science from agriculture to climate regulation. The concept generally refers to adhesion of primary soil particles into distinct units that remain stable when subjected to disruptive forces. It is one of the most sensitive soil qualities that readily respond to disturbances such as cultivation, fire, drought, flooding, and changes in vegetation. These changes are commonly quantified and incorporated in soil models indirectly as alterations in carbon content and type, bulk density, aeration, permeability, as well as water retention characteristics. Soil aggregation that is primarily controlled by organic matter generally exhibits hierarchical organization of soil constituents into stable units that range in size from a few microns to centimeters. However, this conceptual model of soil aggregation as the key unifying mechanism remains poorly quantified and is rarely included in predictive soil models. Here we provide a biophysical framework for quantitative and predictive modeling of soil aggregation and its attendant soil characteristics. The framework treats aggregates as hotspots of biological, chemical and physical processes centered around roots and root residue. We keep track of the life cycle of an individual aggregate from it genesis in the rhizosphere, fueled by rhizodeposition and mediated by vigorous microbial activity, until its disappearance when the root-derived resources are depleted. The framework synthesizes current understanding of microbial life in porous media; water holding and soil binding capacity of biopolymers; and environmental controls on soil organic matter dynamics. The framework paves a way for integration of processes that are presently modeled as disparate or poorly coupled processes, including storage and protection of carbon, microbial activity, greenhouse gas fluxes, movement and storage of water, resistance of soils against erosion.

Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity.

PubMed

Hatfield, Steven D; Daniels, Keith A; O'Donnell, Carey L; Waggoner, Stephen N; Welsh, Raymond M

2018-06-01

Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NK LCMV ) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NK VACV ) exhibited weaker cytolytic activity against each of these target cells. Relative to NK LCMV cells, NK VACV cells exhibited a more immature (CD11b - CD27 + ) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4. NK VACV cells expressed higher levels of the inhibitory molecule NKG2A than NK LCMV cells. Consistent with this apparent lethargy, NK VACV cells only weakly constrained VACV-specific CD4 T-cell responses. This suggests that NK cell regulation of adaptive immunity, while universal, may be limited with viruses that poorly activate NK cells. Published by Elsevier Inc.

The yeast H+-ATPase Pma1 promotes Rag/Gtr-dependent TORC1 activation in response to H+-coupled nutrient uptake.

PubMed

Saliba, Elie; Evangelinos, Minoas; Gournas, Christos; Corrillon, Florent; Georis, Isabelle; André, Bruno

2018-03-23

The yeast Target of Rapamycin Complex 1 (TORC1) plays a central role in controlling growth. How amino acids and other nutrients stimulate its activity via the Rag/Gtr GTPases remains poorly understood. We here report that the signal triggering Rag/Gtr-dependent TORC1 activation upon amino-acid uptake is the coupled H + influx catalyzed by amino-acid/H + symporters. H + -dependent uptake of other nutrients, ionophore-mediated H + diffusion, and inhibition of the vacuolar V-ATPase also activate TORC1. As the increase in cytosolic H + elicited by these processes stimulates the compensating H + -export activity of the plasma membrane H + -ATPase (Pma1), we have examined whether this major ATP-consuming enzyme might be involved in TORC1 control. We find that when the endogenous Pma1 is replaced with a plant H + -ATPase, H + influx or increase fails to activate TORC1. Our results show that H + influx coupled to nutrient uptake stimulates TORC1 activity and that Pma1 is a key actor in this mechanism. © 2018, Saliba et al.

Partitioning-defective Protein 6 (Par-6) Activates Atypical Protein Kinase C (aPKC) by Pseudosubstrate Displacement*

PubMed Central

Graybill, Chiharu; Wee, Brett; Atwood, Scott X.; Prehoda, Kenneth E.

2012-01-01

Atypical protein kinase C (aPKC) controls cell polarity by modulating substrate cortical localization. Aberrant aPKC activity disrupts polarity, yet the mechanisms that control aPKC remain poorly understood. We used a reconstituted system with purified components and a cultured cell cortical displacement assay to investigate aPKC regulation. We find that aPKC is autoinhibited by two domains within its NH2-terminal regulatory half, a pseudosubstrate motif that occupies the kinase active site, and a C1 domain that assists in this process. The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. We propose that, along with its previously described roles in controlling aPKC localization, Par-6 allosterically activates aPKC to allow for high spatial and temporal control of substrate phosphorylation and polarization. PMID:22544755

The association between dental health and nutritional status in chronic obstructive pulmonary disease.

PubMed

Terashima, Takeshi; Chubachi, Shotaro; Matsuzaki, Tatsu; Nakajima, Takahiro; Satoh, Minako; Iwami, Eri; Yoshida, Kyouko; Katakura, Akira; Betsuyaku, Tomoko

2017-11-01

Chronic obstructive pulmonary disease (COPD) and periodontitis are chronic inflammatory systemic diseases with common risk factors (smoking and aging). In COPD, poor periodontal health could result in inadequate nutrition, potentially causing loss of muscle volume. The purpose of this case-control study was to examine our hypothesis that COPD patients have poorer periodontal health and poorer nutritional status than non-COPD patients. Periodontal status was assessed using bleeding on probing (BOP), pocket depth (PD), and plaque-control ratio (PCR). Nutritional status was assessed using body mass index, lean body mass, and serum albumin levels. The COPD group ( n = 60) had fewer remaining teeth, greater BOP, greater PD, and lower serum albumin levels compared with smokers without COPD ( n = 41) and nonsmokers ( n = 35; p < 0.001). COPD was an independent risk factor for poor periodontal health, demonstrated by fewer remaining teeth (relative risk (RR), 5.48; p = 0.0024), BOP (RR, 12.8; p = 0.0009), and having >30% of remaining teeth with a PD ≥ 4 mm (RR, 4.82; p = 0.011). A significant negative correlation existed between the number of teeth with a PD ≥ 4 mm and serum albumin level ( r 2 = 0.127; p = 0.013). We demonstrated that poor periodontal health was associated with hypoalbuminemia, suggesting poor nutritional status and inflammation in COPD.

New-onset refractory status epilepticus

PubMed Central

Foreman, Brandon P.; Alvarez, Vincent; Cabrera Kang, Christian; Probasco, John C.; Jongeling, Amy C.; Meyers, Emma; Espinera, Alyssa; Haas, Kevin F.; Schmitt, Sarah E.; Gerard, Elizabeth E.; Gofton, Teneille; Kaplan, Peter W.; Lee, Jong W.; Legros, Benjamin; Szaflarski, Jerzy P.; Westover, Brandon M.; LaRoche, Suzette M.; Hirsch, Lawrence J.

2015-01-01

Objectives: The aims of this study were to determine the etiology, clinical features, and predictors of outcome of new-onset refractory status epilepticus. Methods: Retrospective review of patients with refractory status epilepticus without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, in 13 academic medical centers. The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale). Results: Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis. Full data were available in 125 cases (62 cryptogenic). Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%) died. Predictors of poor outcome included duration of status epilepticus, use of anesthetics, and medical complications. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last follow-up, but epilepsy developed in 37% with most survivors (92%) remaining on antiseizure medications. Immune therapies were used less frequently in cryptogenic cases, despite a comparable prevalence of inflammatory CSF changes. Conclusions: Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation. PMID:26296517

The cytostatic effect of 9-cis-retinoic acid, tretinoin, and isotretinoin on three different human bladder cancer cell lines in vitro.

PubMed

Laaksovirta, S; Rajala, P; Nurmi, M; Tammela, T L; Laato, M

1999-01-01

Retinoids have been shown to have activity in both preclinical and clinical bladder cancer studies but their exact role in its treatment and prevention remains obscure. In this study cytostatic activity of a novel 9-cis-retinoic acid (9-cis-RA) was compared with two other retinoids: tretinoin and isotretinoin, in three different bladder cancer cell lines: RT4 (well differentiated), 5637 (moderately differentiated) and T24 (poorly differentiated). The three retinoids were incubated at concentrations of 0.3, 3 and 30 microg/ml with bladder cancer cells in microtitre plates for 3 and 6 days. The cytostatic effect was estimated by using luminometric measuring of ATP activity of viable cells in suspension. Compared with the older retinoids, tretinoin and isotretinoin, the highest concentration of 9-cis-RA had a cytostatic efficacy in all three bladder cancer cell lines tested. A clear dose response relationship was observed in isotretinoin-treated cultures after 6 days and in all 9-cis-RA-treated cultures. Tretinoin was either ineffective or had a stimulating effect on poorly differentiated tumour cells. To conclude, isotretinoin and 9-cis-RA had a cytostatic effect on human bladder cancer cells in vitro. However, the possibility of stimulating cancer growth at small doses, at least with tretinoin, and toxicity at high doses must be considered when planning clinical trials.

Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells

PubMed Central

Zeppa, Joseph J.; Kasper, Katherine J.; Mohorovic, Ivor; Mazzuca, Delfina M.

2017-01-01

The globally prominent pathogen Streptococcus pyogenes secretes potent immunomodulatory proteins known as superantigens (SAgs), which engage lateral surfaces of major histocompatibility class II molecules and T-cell receptor (TCR) β-chain variable domains (Vβs). These interactions result in the activation of numerous Vβ-specific T cells, which is the defining activity of a SAg. Although streptococcal SAgs are known virulence factors in scarlet fever and toxic shock syndrome, mechanisms by how SAgs contribute to the life cycle of S. pyogenes remain poorly understood. Herein, we demonstrate that passive immunization against the Vβ8-targeting SAg streptococcal pyrogenic exotoxin A (SpeA), or active immunization with either wild-type or a nonfunctional SpeA mutant, protects mice from nasopharyngeal infection; however, only passive immunization, or vaccination with inactive SpeA, resulted in high-titer SpeA-specific antibodies in vivo. Mice vaccinated with wild-type SpeA rendered Vβ8+ T cells poorly responsive, which prevented infection. This phenotype was reproduced with staphylococcal enterotoxin B, a heterologous SAg that also targets Vβ8+ T cells, and rendered mice resistant to infection. Furthermore, antibody-mediated depletion of T cells prevented nasopharyngeal infection by S. pyogenes, but not by Streptococcus pneumoniae, a bacterium that does not produce SAgs. Remarkably, these observations suggest that S. pyogenes uses SAgs to manipulate Vβ-specific T cells to establish nasopharyngeal infection. PMID:28794279

Overexpression of nucleostemin contributes to an advanced malignant phenotype and a poor prognosis in oral squamous cell carcinoma

PubMed Central

Yoshida, R; Nakayama, H; Nagata, M; Hirosue, A; Tanaka, T; Kawahara, K; Nakagawa, Y; Matsuoka, Y; Sakata, J; Arita, H; Hiraki, A; Shinohara, M; Ito, T

2014-01-01

Background: Nucleostemin (NS) is essential for the maintenance of stem cell properties, the functions of which remain poorly understood in cancer cells. The purpose of this study was to explore the impact of NS on malignancy and its clinical significance in oral squamous cell carcinoma (OSCC) patients. Methods: We investigated the effects of NS on the proliferation and invasion of OSCC using NS-overexpressing or -knockdown OSCC cells. We assessed the activation of the STAT3 (signal transducer and activator of transcription 3) signalling pathway and the downstream targets in the cells with different expression levels of NS. An immunohistochemical analysis of NS was also performed in 54 OSCC patients who were treated with preoperative chemoradiotherapy and surgery. Results: The overexpression of NS significantly enhanced the proliferation and invasive potential of OSCC cells. On the other hand, downregulation of NS suppressed the invasiveness of the cells. The alterations of these malignant phenotypes were associated with the activation of STAT3 signalling and its downstream targets. An immunohistochemical analysis demonstrated that a high NS tumour expression level significantly correlated with an advanced T-stage and N-stage. Furthermore, a Cox regression analysis revealed that the NS status (hazard ratio, 9.09; P=0.002) was a significant progression factor for OSCC patients. Conclusions: Our results suggest that targeting NS may provide a promising treatment for highly malignant OSCC. PMID:25314067

Association between erythrocyte Na+K+-ATPase activity and some blood lipids in type 1 diabetic patients from Lagos, Nigeria

PubMed Central

Iwalokun, Bamidele A; Iwalokun, Senapon O

2007-01-01

Background Altered levels of erythrocyte Na+K+-ATPase, atherogenic and anti-atherogenic lipid metabolites have been implicated in diabetic complications but their pattern of interactions remains poorly understood. This study evaluated this relationship in Nigerian patients with Type 1 diabetes mellitus. Methods A total of 34 consented Type 1 diabetic patients and age -matched 27 non-diabetic controls were enrolled. Fasting plasma levels of total cholesterol, triglycerides and HDL-cholesterol were determined spectrophotometrically and LDL-cholesterol estimated using Friedewald formula. Total protein content and Na+K+-ATPase activity were also determined spectrophotometrically from ghost erythrocyte membrane prepared by osmotic lysis. Results Results indicate significant (P < 0.05) reduction in Na+K+-ATPase activity in the Type 1 diabetic patients (0.38 ± 0.08 vs. 0.59 ± 0.07 uM Pi/mgprotein/h) compared to the control but with greater reduction in the diabetic subgroup with poor glycemic control (n = 20) and in whom cases of hypercholesterolemia (8.8%), hypertriglyceridemia (2.9%) and elevated LDL-cholesterol (5.9% each) were found. Correlation analyses further revealed significant (P < 0.05) inverse correlations [r = -(0.708-0.797] between all the atherogenic lipid metabolites measured and Na+K+-ATPase in this subgroup contrary to group with good glycemic control or non-diabetic subjects in which significant (P < 0.05) Na+K+-ATPase and HDL-C association were found (r = 0.427 - 0.489). The Na+K+-ATPase from the diabetic patients also exhibited increased sensitivity to digoxin and alterations in kinetic constants Vmax and Km determined by glycemic status of the patients. Conclusion It can be concluded that poor glycemic control evokes greater reduction in erythrocyte Na+K+-ATPase activity and promote enzyme-blood atherogenic lipid relationships in Type 1 diabetic Nigerian patients. PMID:17908327

Neighborhood poverty and suicidal thoughts and attempts in late adolescence.

PubMed

Dupéré, V; Leventhal, T; Lacourse, E

2009-08-01

Suicide tends to concentrate in disadvantaged neighborhoods, and neighborhood disadvantage is associated with many important risk factors for youth suicide. However, no study has directly investigated the link between neighborhood poverty and youth suicidal behaviors, while controlling for pre-existing vulnerabilities. The objective of this study was to determine whether living in a poor neighborhood is associated with suicidal thoughts and attempts in late adolescence over and above background vulnerabilities, and whether this association can be explained by late-adolescence psychosocial risks: depression, social support, negative life events (NLEs), delinquent activities, substance abuse and exposure to suicide. The potential moderating role of neighborhood poverty was also examined. A subset of 2776 participants was selected from the Canadian National Longitudinal Survey of Children and Youth (NLSCY). Late-adolescence suicidal behaviors and risk factors were self-reported. The 2001 Canadian Census was used to characterize neighborhoods during early and middle adolescence. Late-childhood family and individual controls were assessed through parent-report. At the bivariate level, the odds of reporting suicidal thoughts were about twice as high in poor than non-poor neighborhoods, and the odds of attempting suicide were about four times higher. After controlling for background vulnerabilities, neighborhood poverty remained significantly associated with both suicidal thoughts and attempts. However, these associations were not explained by late-adolescence psychosocial risks. Rather, youth living in poor neighborhoods may be at greater risk through the amplification of other risk factors in disadvantaged neighborhoods. Potential explanations for the increased vulnerability of youth living in poor neighborhoods are discussed.

Frontal Brain Activity and Behavioral Indicators of Affective States are Weakly Affected by Thermal Stimuli in Sheep Living in Different Housing Conditions

PubMed Central

Vögeli, Sabine; Wolf, Martin; Wechsler, Beat; Gygax, Lorenz

2015-01-01

Many stimuli evoke short-term emotional reactions. These reactions may play an important role in assessing how a subject perceives a stimulus. Additionally, long-term mood may modulate the emotional reactions but it is still unclear in what way. The question seems to be important in terms of animal welfare, as a negative mood may taint emotional reactions. In the present study with sheep, we investigated the effects of thermal stimuli on emotional reactions and the potential modulating effect of mood induced by manipulations of the housing conditions. We assume that unpredictable, stimulus-poor conditions lead to a negative and predictable, stimulus-rich conditions to a positive mood state. The thermal stimuli were applied to the upper breast during warm ambient temperatures: hot (as presumably negative), intermediate, and cold (as presumably positive). We recorded cortical activity by functional near-infrared spectroscopy, restlessness behavior (e.g., locomotor activity, aversive behaviors), and ear postures as indicators of emotional reactions. The strongest hemodynamic reaction was found during a stimulus of intermediate valence independent of the animal’s housing conditions, whereas locomotor activity, ear movements, and aversive behaviors were seen most in sheep from the unpredictable, stimulus-poor housing conditions, independent of stimulus valence. We conclude that, sheep perceived the thermal stimuli and differentiated between some of them. An adequate interpretation of the neuronal activity pattern remains difficult, though. The effects of housing conditions were small indicating that the induction of mood was only modestly efficacious. Therefore, a modulating effect of mood on the emotional reaction was not found. PMID:26664938

Brain Activation during Sentence Comprehension among Good and Poor Readers

PubMed Central

Keller, Timothy A.; Cherkassky, Vladimir L.; Lee, Donghoon; Hoeft, Fumiko; Whitfield-Gabrieli, Susan; Gabrieli, John D. E.; Just, Marcel Adam

2008-01-01

This study sought to increase current understanding of the neuro-psychological basis of poor reading ability by using fMRI to examine brain activation during a visual sentence comprehension task among good and poor readers in the third (n = 32) and fifth (n = 35) grades. Reading ability, age, and the combination of both factors made unique contributions to cortical activation. The main finding was of parietotemporal underactivation (less activation than controls) among poor readers at the 2 grade levels. A positive linear relationship (spanning both the poor and good readers) was found between reading ability and activation in the left posterior middle temporal and postcentral gyri and in the right inferior parietal lobule such that activation increased with reading ability. Different developmental trajectories characterized good and poor readers in the left angular gyrus: activation increased with age among good readers, a change that failed to occur among poor readers. The parietotemporal cortex is discussed in terms of its role in reading acquisition, with the left angular gyrus playing a key role. It is proposed that the functioning of the cortical network underlying reading is dependent on a combination of interacting factors, including physiological maturation, neural integrity, skill level, and the nature of the task. PMID:17317678

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

PubMed

Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

2016-02-25

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Toward a Mechanistic Understanding of Environmentally Forced Zoonotic Disease Emergence: Sin Nombre Hantavirus

PubMed Central

Carver, Scott; Mills, James N.; Parmenter, Cheryl A.; Parmenter, Robert R.; Richardson, Kyle S.; Harris, Rachel L.; Douglass, Richard J.; Kuenzi, Amy J.; Luis, Angela D.

2015-01-01

Understanding the environmental drivers of zoonotic reservoir and human interactions is crucial to understanding disease risk, but these drivers are poorly predicted. We propose a mechanistic understanding of human–reservoir interactions, using hantavirus pulmonary syndrome as a case study. Crucial processes underpinning the disease's incidence remain poorly studied, including the connectivity among natural and peridomestic deer mouse host activity, virus transmission, and human exposure. We found that disease cases were greatest in arid states and declined exponentially with increasing precipitation. Within arid environments, relatively rare climatic conditions (e.g., El Niño) are associated with increased rainfall and reservoir abundance, producing more frequent virus transmission and host dispersal. We suggest that deer mice increase their occupancy of peridomestic structures during spring–summer, amplifying intraspecific transmission and human infection risk. Disease incidence in arid states may increase with predicted climatic changes. Mechanistic approaches incorporating reservoir behavior, reservoir–human interactions, and pathogen spillover could enhance our understanding of global hantavirus ecology, with applications to other directly transmitted zoonoses. PMID:26955081

Interleukin 10 (IL-10)-mediated Immunosuppression

PubMed Central

Mittal, Sharad K.; Cho, Kyung-Jin; Ishido, Satoshi; Roche, Paul A.

2015-01-01

Efficient immune responses require regulated antigen presentation to CD4 T cells. IL-10 inhibits the ability of dendritic cells (DCs) and macrophages to stimulate antigen-specific CD4 T cells; however, the mechanisms by which IL-10 suppresses antigen presentation remain poorly understood. We now report that IL-10 stimulates expression of the E3 ubiquitin ligase March-I in activated macrophages, thereby down-regulating MHC-II, CD86, and antigen presentation to CD4 T cells. By contrast, IL-10 does not stimulate March-I expression in DCs, does not suppress MHC-II or CD86 expression on either resting or activated DCs, and does not affect antigen presentation by activated DCs. IL-10 does, however, inhibit the process of DC activation itself, thereby reducing the efficiency of antigen presentation in a March-I-independent manner. Thus, IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is March- I-independent. PMID:26408197

Evidence from molecular dynamics simulations of conformational preorganization in the ribonuclease H active site

PubMed Central

Stafford, Kate A.; Palmer III, Arthur G.

2014-01-01

Ribonuclease H1 (RNase H) enzymes are well-conserved endonucleases that are present in all domains of life and are particularly important in the life cycle of retroviruses as domains within reverse transcriptase. Despite extensive study, especially of the E. coli homolog, the interaction of the highly negatively charged active site with catalytically required magnesium ions remains poorly understood. In this work, we describe molecular dynamics simulations of the E. coli homolog in complex with magnesium ions, as well as simulations of other homologs in their apo states. Collectively, these results suggest that the active site is highly rigid in the apo state of all homologs studied and is conformationally preorganized to favor the binding of a magnesium ion. Notably, representatives of bacterial, eukaryotic, and retroviral RNases H all exhibit similar active-site rigidity, suggesting that this dynamic feature is only subtly modulated by amino acid sequence and is primarily imposed by the distinctive RNase H protein fold. PMID:25075292

Skilled movements require non-apoptotic Bax/Bak pathway-mediated corticospinal circuit reorganization

PubMed Central

Gu, Zirong; Serradj, Najet; Ueno, Masaki; Liang, Mishi; Li, Jie; Baccei, Mark L.; Martin, John H.; Yoshida, Yutaka

2017-01-01

Early postnatal mammals, including human babies, can perform only basic motor tasks. The acquisition of skilled behaviors occurs later, requiring anatomical changes in neural circuitry to support the development of coordinated activation or suppression of functionally related muscle groups. How this circuit reorganization occurs during postnatal development remains poorly understood. Here we explore the connectivity between corticospinal (CS) neurons in the motor cortex and muscles in mice. Using trans-synaptic viral and electrophysiological assays, we identify the early postnatal reorganization of CS circuitry for antagonistic muscle pairs. We further show that this synaptic rearrangement requires the activity-dependent, non-apoptotic Bax/Bak-caspase signaling cascade. Adult Bax/Bak mutant mice exhibit aberrant co-activation of antagonistic muscle pairs and skilled grasping deficits but normal reaching and retrieval behaviors. Our findings reveal key cellular and molecular mechanisms driving postnatal motor circuit reorganization and the resulting impacts on muscle activation patterns and the execution of skilled movements. PMID:28472660

A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity

PubMed Central

Fagnocchi, Luca; Cherubini, Alessandro; Hatsuda, Hiroshi; Fasciani, Alessandra; Mazzoleni, Stefania; Poli, Vittoria; Berno, Valeria; Rossi, Riccardo L.; Reinbold, Rolland; Endele, Max; Schroeder, Timm; Rocchigiani, Marina; Szkarłat, Żaneta; Oliviero, Salvatore; Dalton, Stephen; Zippo, Alessio

2016-01-01

Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity. PMID:27301576

Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells

PubMed Central

Temprana, Silvio G.; Mongiat, Lucas A.; Yang, Sung M.; Trinchero, Mariela F.; Alvarez, Diego D.; Kropff, Emilio; Giacomini, Damiana; Beltramone, Natalia; Lanuza, Guillermo M.; Schinder, Alejandro F.

2014-01-01

SUMMARY Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (four-week-old) GCs can efficiently drive distal CA3 targets, but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition towards maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus. PMID:25533485

A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity.

PubMed

Fagnocchi, Luca; Cherubini, Alessandro; Hatsuda, Hiroshi; Fasciani, Alessandra; Mazzoleni, Stefania; Poli, Vittoria; Berno, Valeria; Rossi, Riccardo L; Reinbold, Rolland; Endele, Max; Schroeder, Timm; Rocchigiani, Marina; Szkarłat, Żaneta; Oliviero, Salvatore; Dalton, Stephen; Zippo, Alessio

2016-06-15

Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity.

Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences.

PubMed

Martinez, Fernando O; Helming, Laura; Milde, Ronny; Varin, Audrey; Melgert, Barbro N; Draijer, Christina; Thomas, Benjamin; Fabbri, Marco; Crawshaw, Anjali; Ho, Ling Pei; Ten Hacken, Nick H; Cobos Jiménez, Viviana; Kootstra, Neeltje A; Hamann, Jörg; Greaves, David R; Locati, Massimo; Mantovani, Alberto; Gordon, Siamon

2013-02-28

The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4–activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma.

Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.

PubMed

Temprana, Silvio G; Mongiat, Lucas A; Yang, Sung M; Trinchero, Mariela F; Alvarez, Diego D; Kropff, Emilio; Giacomini, Damiana; Beltramone, Natalia; Lanuza, Guillermo M; Schinder, Alejandro F

2015-01-07

Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus. Copyright © 2015 Elsevier Inc. All rights reserved.

Fast and slow transitions in frontal ensemble activity during flexible sensorimotor behavior.

PubMed

Siniscalchi, Michael J; Phoumthipphavong, Victoria; Ali, Farhan; Lozano, Marc; Kwan, Alex C

2016-09-01

The ability to shift between repetitive and goal-directed actions is a hallmark of cognitive control. Previous studies have reported that adaptive shifts in behavior are accompanied by changes of neural activity in frontal cortex. However, neural and behavioral adaptations can occur at multiple time scales, and their relationship remains poorly defined. Here we developed an adaptive sensorimotor decision-making task for head-fixed mice, requiring them to shift flexibly between multiple auditory-motor mappings. Two-photon calcium imaging of secondary motor cortex (M2) revealed different ensemble activity states for each mapping. When adapting to a conditional mapping, transitions in ensemble activity were abrupt and occurred before the recovery of behavioral performance. By contrast, gradual and delayed transitions accompanied shifts toward repetitive responding. These results demonstrate distinct ensemble signatures associated with the start versus end of sensory-guided behavior and suggest that M2 leads in engaging goal-directed response strategies that require sensorimotor associations.

Spread of epileptic activity in human brain

NASA Astrophysics Data System (ADS)

Milton, John

1997-03-01

For many patients with medically refractory epilepsy surgical resection of the site of seizure onset (epileptic focus) offers the best hope for cure. Determination of the nature of seizure propagation should lead to improved methods for locating the epileptic focus (and hence reduce patient morbidity) and possibly to new treatment modalities directed at blocking seizure spread. Theoretical studies of neural networks emphasize the role of traveling waves for the propagation of activity. However, the nature of seizure propagation in human brain remains poorly characterized. The spread of epileptic activity in patients undergoing presurgical evaluation for epilepsy surgery was measured by placing subdural grids of electrodes (interelectrode spacings of 3-10 mm) over the frontal and temporal lobes. The exact location of each electrode relative to the surface of the brain was determined using 3--D MRI imaging techniques. Thus it is possible to monitor the spread of epileptic activity in both space and time. The observations are discussed in light of models for seizure propagation.

Punishment and Welfare: Paternal Incarceration and Families' Receipt of Public Assistance

ERIC Educational Resources Information Center

Sugie, Naomi F.

2012-01-01

The United States criminal justice and welfare systems are two important government institutions in the lives of the poor. Despite many theoretical discussions about their relationship, their operation at the level of offenders and families remains poorly understood. This paper utilizes Fragile Families and Child Wellbeing data to examine how…

NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice.

PubMed

Wree, Alexander; Eguchi, Akiko; McGeough, Matthew D; Pena, Carla A; Johnson, Casey D; Canbay, Ali; Hoffman, Hal M; Feldstein, Ariel E

2014-03-01

Inflammasome activation plays a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome-mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell-specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3-initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow-cytometry-based (fluorescence-activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)- and propidium iodide (PI)-positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3-mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5-fold increase in active Casp1/PI double-positive cells. Myeloid cell-restricted mutant NLRP3 activation resulted in a less-severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. Our data demonstrate that global and, to a lesser extent, myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3-mediated liver damage. © 2014 by the American Association for the Study of Liver Diseases.

In vitro Reactivity to Implant Metals Demonstrates a Person Dependent Association with both T-Cell and B-Cell Activation

PubMed Central

Hallab, Nadim James; Caicedo, Marco; Epstein, Rachael; McAllister, Kyron; Jacobs, Joshua J

2009-01-01

Hypersensitivity to metallic implants remains relatively unpredictable and poorly understood. We initially hypothesized that metal-induced lymphocyte proliferation responses to soluble metal challenge (ions) are mediated exclusively by early T-cell activation (not B-cells), typical of a Delayed-Type-Hypersensitivity response. We tested this by comparing proliferation (6-days) of primary lymphocytes with early T-cell and B-cell activation (48-hours) in three groups of subjects likely to demonstrate elevated metal-reactivity: Group 1(n=12) history of metal-sensitivity with no implant; Group 2a(n=6) well performing metal-on-metal THRs, and Group 2b(n=20) subjects with poorly performing metal-on-polymer total joint arthroplasties (TJA). Group 1 showed 100%(12/12) metal reactivity (Stimulation Index>2) to Ni. Group 2a&2b were 83%(5/6) and 75%(15/22) metal reactive (to Co, Cr or Ni) respectively. Of the n=32 metal reactive subjects to Co, Cr or Ni (SI>2), n=22/32 demonstrated >2-fold elevations in % of T-cell or B-cell activation (CD25+,CD69+) to metal challenge compared to untreated control. 18/22 metal-activated subjects demonstrated an exclusively T-cell or B-cell activation response to metal challenge, where 6/18 demonstrated exclusively B-cell activation and 12/18 demonstrated a T-cell only response, as measured by surface activation markers CD25+ and CD69+. However, there was no direct correlation (R2<0.1) between lymphocyte proliferation and % T-cell or B-cell activation (CD25+:CD69+). Proliferation assays (LTT) showed greater ability to detect metal reactivity than did subject-dependent results of flow-cytometry analysis of T-cell or B-cell activation. The high incidence of lymphocyte reactivity and activation, indicate that more complex than initially hypothesized immune responses may contribute to the etiology of debris induced osteolysis in metal-sensitive individuals. PMID:19235773

Cognitive Control Signals in Posterior Cingulate Cortex

PubMed Central

Hayden, Benjamin Y.; Smith, David V.; Platt, Michael L.

2010-01-01

Efficiently shifting between tasks is a central function of cognitive control. The role of the default network – a constellation of areas with high baseline activity that declines during task performance – in cognitive control remains poorly understood. We hypothesized that task switching demands cognitive control to shift the balance of processing toward the external world, and therefore predicted that switching between the two tasks would require suppression of activity of neurons within the posterior cingulate cortex (CGp). To test this idea, we recorded the activity of single neurons in CGp, a central node in the default network, in monkeys performing two interleaved tasks. As predicted, we found that basal levels of neuronal activity were reduced following a switch from one task to another and gradually returned to pre-switch baseline on subsequent trials. We failed to observe these effects in lateral intraparietal cortex, part of the dorsal fronto-parietal cortical attention network directly connected to CGp. These findings indicate that suppression of neuronal activity in CGp facilitates cognitive control, and suggest that activity in the default network reflects processes that directly compete with control processes elsewhere in the brain. PMID:21160560

β-arrestin drives MAP kinase signaling from clathrin-coated structures after GPCR dissociation

PubMed Central

Eichel, K.; Jullié, D.

2016-01-01

β-arrestins critically regulate G protein-coupled receptor (GPCR) signaling, not only 'arresting' the G protein signal but also modulating endocytosis and initiating a discrete G protein-independent signal via MAP kinase1–3. Despite enormous recent progress toward understanding biophysical aspects of arrestin function4,5, its cell biology remains relatively poorly understood. Two key tenets underlie the present dogma: (1) β-arrestin accumulates in clathrin-coated structures (CCSs) exclusively in physical complex with its activating GPCR, and (2) MAP kinase activation requires endocytosis of formed GPCR - β-arrestin complexes6–9. We show here, using β1-adrenergic receptors, that β-arrestin-2 (Arrestin 3) accumulates robustly in CCSs after dissociating from its activating GPCR and transduces the MAP kinase signal from CCSs. Moreover, inhibiting subsequent endocytosis of CCSs enhances the clathrin and β-arrestin -dependent MAP kinase signal. These results demonstrate β-arrestin 'activation at a distance', after dissociating from its activating GPCR, and signaling from CCSs. We propose a β-arrestin signaling cycle that is catalytically activated by the GPCR and energetically coupled to the endocytic machinery. PMID:26829388

Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors.

PubMed

Teissier, Anne; Chemiakine, Alexei; Inbar, Benjamin; Bagchi, Sneha; Ray, Russell S; Palmiter, Richard D; Dymecki, Susan M; Moore, Holly; Ansorge, Mark S

2015-12-01

Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation

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

Pai, Rama; Lin Cal; Tran, Teresa

2005-06-17

Although leptin is known to induce proliferative response in gastric cancer cells, the mechanism(s) underlying this action remains poorly understood. Here, we provide evidence that leptin-induced gastric cancer cell proliferation involves activation of STAT and ERK2 signaling pathways. Leptin-induced STAT3 phosphorylation is independent of ERK2 activation. Leptin increases SHP2 phosphorylation and enhances binding of Grb2 to SHP2. Inhibition of SHP2 expression with siRNA but not SHP2 phosphatase activity abolished leptin-induced ERK2 activation. While JAK inhibition with AG490 significantly reduced leptin-induced ERK2, STAT3 phosphorylation, and cell proliferation, SHP2 inhibition only partially reduced cancer cell proliferation. Immunostaining of gastric cancer tissues displayedmore » local overexpression of leptin and its receptor indicating that leptin might be produced and act locally in a paracrine or autocrine manner. These findings indicate that leptin promotes cancer growth by activating multiple signaling pathways and therefore blocking its action at the receptor level could be a rational therapeutic strategy.« less

Platelet–neutrophil interactions under thromboinflammatory conditions

PubMed Central

Li, Jing; Kim, Kyungho; Barazia, Andrew; Tseng, Alan

2015-01-01

Platelets primarily mediate hemostasis and thrombosis, whereas leukocytes are responsible for immune responses. Since platelets interact with leukocytes at the site of vascular injury, thrombosis and vascular inflammation are closely intertwined and occur consecutively. Recent studies using real-time imaging technology demonstrated that platelet–neutrophil interactions on the activated endothelium are an important determinant of microvascular occlusion during thromboinflammatory disease in which inflammation is coupled to thrombosis. Although the major receptors and counter receptors have been identified, it remains poorly understood how heterotypic platelet–neutrophil interactions are regulated under disease conditions. This review discusses our current understanding of the regulatory mechanisms of platelet– neutrophil interactions in thromboinflammatory disease. PMID:25650236

Activism needed for vaccines to reach South.

PubMed

1998-06-30

An AIDS vaccine remains the only feasible strategy for curbing the spread of HIV infection in resource-poor developing countries because of its low cost and logistic simplicity. However, the pace of vaccine development has been slowed by difficulties persuading pharmaceutical companies to invest time and money in such research. These companies do not perceive a financial advantage to vaccine development. The International AIDS Vaccine Initiative is attempting to create a market for an AIDS vaccine. It is also urging developing countries to develop their own vaccines so they have intellectual property rights. Any advances in this area will require political pressure from community activists.

New activators and inhibitors in the hair cycle clock: targeting stem cells’ state of competence

PubMed Central

Plikus, Maksim V.

2014-01-01

Summary The timing mechanism of the hair cycle remains poorly understood. However, it has become increasingly clear that the telogen-to-anagen transition is controlled jointly by at least the bone morphogenic protein (BMP), WNT, fibroblast growth factor (FGF), and transforming growth factor (TGF)-β signaling pathways. New research shows that Fgf18 signaling in hair follicle stem cells synergizes BMP-mediated refractivity, whereas Tgf-β2 signaling counterbalances it. Loss of Fgf18 signaling markedly accelerates anagen initiation, whereas loss of Tgf-β2 signaling significantly delays it, supporting key roles for these pathways in hair cycle timekeeping. PMID:22499035

Macrophage heterogeneity in tissues: phenotypic diversity and functions

PubMed Central

Gordon, Siamon; Plüddemann, Annette; Martinez Estrada, Fernando

2014-01-01

During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation. PMID:25319326

Community mobilisation in the 21st century: updating our theory of social change?

PubMed

Campbell, Catherine

2014-01-01

The article explores the Freirian theory of social change underpinning health-related community mobilisation in poor and marginalised communities. Highlighting potential shortcomings of its essentialist understandings of power and identity, and linear notions of change, it examines how lessons from the 'new left', and burgeoning global protest movements, can rejuvenate the field given the growing complexity of 21st-century social inequalities. It suggests the need for a pastiche of approaches to accommodate health struggles in different times and places. However, while needing some updating, Freire's profound and actionable understandings of the symbolic and material dimensions of social inequalities remain a powerful starting point for activism.

[Fanconi anemia: cellular and molecular features].

PubMed

Macé, G; Briot, D; Guervilly, J-H; Rosselli, F

2007-02-01

Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. 11 among 12 FA gene have been isolated. The biochemical functions of the FANC proteins remain poorly understood. Anyhow, to cope with DNA crosslinks a cell needs a functional FANC pathway. Moreover, the FANC proteins appear to be involved in cell protection against oxidative damage and in the control of TNF-alpha activity. In this review, we describe the current understanding of the FANC pathway and we present how it may be integrated in the complex networks of proteins involved in maintaining the cellular homeostasis.

The effects of caffeine on the cholinergic system.

PubMed

Pohanka, Miroslav

2014-01-01

Caffeine is a secondary metabolite of tea and coffee plants. It is the active psychostimulant ingredient of widely consumed beverages, chocolate and some drugs as well. The major pathways for caffeine including interaction with adenosine receptors have been identified but caffeine has several minor pathways as well that remain poorly understood including the cholinergic system. Given the role of caffeine in the cholinergic system, some molecular targets have been tracked and a mechanism of its action has been proposed in research studies. However, the biological effect of caffeine on the cholinergic system is not completely understood. The present review focuses on the role of caffeine in the cholinergic system.

Increased Rate of Poor Laryngoscopic Views in Patients Scheduled for Cardiac Surgery Versus Patients Scheduled for General Surgery: A Propensity Score-Based Analysis of 21,561 Cases.

PubMed

Heinrich, Sebastian; Ackermann, Andreas; Prottengeier, Johannes; Castellanos, Ixchel; Schmidt, Joachim; Schüttler, Jürgen

2015-12-01

Former analyses reported an increased rate of poor direct laryngoscopy view in cardiac surgery patients; however, these findings frequently could be attributed to confounding patient characteristics. In most of the reported cardiac surgery cohorts, the rate of well-known risk factors for poor direct laryngoscopy view such as male sex, obesity, or older age, were increased compared with the control groups. Especially in the ongoing debate on anesthesia staff qualification for cardiac interventions outside the operating room a detailed and stratified risk analysis seems necessary. Retrospective, anonymous, propensity score-based, matched-pair analysis. Single-center study in a university hospital. No active participants. Retrospective, anonymous chart analysis. The anesthesia records of patients undergoing cardiac surgery in a period of 6 consecutive years were analyzed retrospectively. The results were compared with those of a control group of patients who underwent general surgery. Poor laryngoscopic view was defined as Cormack and Lehane classification grade 3 or 4. The records of 21,561 general anesthesia procedures were reviewed for the study. The incidence of poor direct laryngoscopic views in patients scheduled for cardiac surgery was significantly increased compared with those of the general surgery cohort (7% v 4.2%). Using propensity score-based matched-pair analysis, equal subgroups were generated of each surgical department, with 2,946 patients showing identical demographic characteristics. After stratifying for demographic characteristics, the rate of poor direct laryngoscopy view remained statistically significantly higher in the cardiac surgery group (7.5% v 5.7%). Even with stratification for demographic risk factors, cardiac surgery patients showed a significantly higher rate of poor direct laryngoscopic view compared with general surgery patients. These results should be taken into account for human resource management and distribution of difficult airway equipment, especially when cardiac interventional programs are implemented in remote hospital locations. Copyright © 2015 Elsevier Inc. All rights reserved.

Isotopic signals of summer denitrification in a northern hardwood forested catchment.

PubMed

Wexler, Sarah K; Goodale, Christine L; McGuire, Kevin J; Bailey, Scott W; Groffman, Peter M

2014-11-18

Despite decades of measurements, the nitrogen balance of temperate forest catchments remains poorly understood. Atmospheric nitrogen deposition often greatly exceeds streamwater nitrogen losses; the fate of the remaining nitrogen is highly uncertain. Gaseous losses of nitrogen to denitrification are especially poorly documented and are often ignored. Here, we provide isotopic evidence (δ(15)NNO3 and δ(18)ONO3) from shallow groundwater at the Hubbard Brook Experimental Forest indicating extensive denitrification during midsummer, when transient, perched patches of saturation developed in hillslopes, with poor hydrological connectivity to the stream, while streamwater showed no isotopic evidence of denitrification. During small rain events, precipitation directly contributed up to 34% of streamwater nitrate, which was otherwise produced by nitrification. Together, these measurements reveal the importance of denitrification in hydrologically disconnected patches of shallow groundwater during midsummer as largely overlooked control points for nitrogen loss from temperate forest catchments.

Isotopic signals of summer denitrification in a northern hardwood forested catchment

PubMed Central

Wexler, Sarah K.; Goodale, Christine L.; Bailey, Scott W.; Groffman, Peter M.

2014-01-01

Despite decades of measurements, the nitrogen balance of temperate forest catchments remains poorly understood. Atmospheric nitrogen deposition often greatly exceeds streamwater nitrogen losses; the fate of the remaining nitrogen is highly uncertain. Gaseous losses of nitrogen to denitrification are especially poorly documented and are often ignored. Here, we provide isotopic evidence (δ15NNO3 and δ18ONO3) from shallow groundwater at the Hubbard Brook Experimental Forest indicating extensive denitrification during midsummer, when transient, perched patches of saturation developed in hillslopes, with poor hydrological connectivity to the stream, while streamwater showed no isotopic evidence of denitrification. During small rain events, precipitation directly contributed up to 34% of streamwater nitrate, which was otherwise produced by nitrification. Together, these measurements reveal the importance of denitrification in hydrologically disconnected patches of shallow groundwater during midsummer as largely overlooked control points for nitrogen loss from temperate forest catchments. PMID:25368188

Modifying the brain activation of poor readers during sentence comprehension with extended remedial instruction: a longitudinal study of neuroplasticity.

PubMed

Meyler, Ann; Keller, Timothy A; Cherkassky, Vladimir L; Gabrieli, John D E; Just, Marcel Adam

2008-08-01

This study used fMRI to longitudinally assess the impact of intensive remedial instruction on cortical activation among 5th grade poor readers during a sentence comprehension task. The children were tested at three time points: prior to remediation, after 100 h of intensive instruction, and 1 year after the instruction had ended. Changes in brain activation were also measured among 5th grade good readers at the same time points for comparison. The central finding was that prior to instruction, the poor readers had significantly less activation than good readers bilaterally in the parietal cortex. Immediately after instruction, poor readers made substantial gains in reading ability, and demonstrated significantly increased activation in the left angular gyrus and the left superior parietal lobule. Activation in these regions continued to increase among poor readers 1 year post-remediation, resulting in a normalization of the activation. These results are interpreted as reflecting changes in the processes involved in word-level and sentence-level assembly. Areas of overactivation were also found among poor readers in the medial frontal cortex, possibly indicating a more effortful and attentive guided reading strategy.

Modifying the Brain Activation of Poor Readers during Sentence Comprehension with Extended Remedial Instruction: A Longitudinal Study of Neuroplasticity

PubMed Central

Meyler, Ann; Keller, Timothy A.; Cherkassky, Vladimir L.; Gabrieli, John D. E.; Just, Marcel Adam

2008-01-01

This study used fMRI to longitudinally assess the impact of intensive remedial instruction on cortical activation among 5th grade poor readers during a sentence comprehension task. The children were tested at 3 time points: prior to remediation, after 100 hours of intensive instruction, and 1 year after the instruction had ended. Changes in brain activation were also measured among 5th grade good readers at the same time points for comparison. The central finding was that prior to instruction, the poor readers had significantly less activation than good readers bilaterally in the parietal cortex. Immediately after instruction, poor readers made substantial gains in reading ability, and demonstrated significantly increased activation in the left angular gyrus and the left superior parietal lobule. Activation in these regions continued to increase among poor readers 1 year post-remediation, resulting in a normalization of the activation. These results are interpreted as reflecting changes in the processes involved in word-level and sentence-level assembly. Areas of overactivation were also found among poor readers in the medial frontal cortex, possibly indicating a more effortful and attentionally-guided reading strategy. PMID:18495180

New tools for optimizing fluid resuscitation in acute pancreatitis

PubMed Central

Bortolotti, Perrine; Saulnier, Fabienne; Colling, Delphine; Redheuil, Alban; Preau, Sebastien

2014-01-01

Acute pancreatitis (AP) is a frequent disease with degrees of increasing severity responsible for high morbidity. Despite continuous improvement in care, mortality remains significant. Because hypovolemia, together with microcirculatory dysfunction lead to poor outcome, fluid therapy remains a cornerstone of the supportive treatment. However, poor clinical evidence actually support the aggressive fluid therapy recommended in recent guidelines since available data are controversial. Fluid management remains unclear and leads to current heterogeneous practice. Different strategies may help to improve fluid resuscitation in AP. On one hand, integration of fluid therapy in a global hemodynamic resuscitation has been demonstrated to improve outcome in surgical or septic patients. Tailored fluid administration after early identification of patients with high-risk of poor outcome presenting inadequate tissue oxygenation is a major part of this strategy. On the other hand, new decision parameters have been developed recently to improve safety and efficiency of fluid therapy in critically ill patients. In this review, we propose a personalized strategy integrating these new concepts in the early fluid management of AP. This new approach paves the way to a wide range of clinical studies in the field of AP. PMID:25473163

Nanonization strategies for poorly water-soluble drugs.

PubMed

Chen, Huabing; Khemtong, Chalermchai; Yang, Xiangliang; Chang, Xueling; Gao, Jinming

2011-04-01

Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. Published by Elsevier Ltd.

Bioassay of procoagulant albumin in human plasma.

PubMed

Grosset, A; Liu, L; Parker, C J; Rodgers, G M

1994-09-01

Procoagulant albumin (P-Al) is present in normal human plasma and increases monocyte and endothelial cell expression of tissue factor activity. To develop a bioassay for P-Al, we partially purified plasma from healthy volunteers and several patient groups using BaCl2 and (NH4)2SO4 precipitation. The samples were assayed for tissue factor (TF) inducing activity, expressed as a percentage increase compared to a serum-free media control. Over six months, the assay was reproducible in stored samples and in serial samples from normal volunteers. The plasma P-Al activities of 35 volunteers averaged 141 +/- 8.2% (SEM). There was no diurnal variation. There was no difference in the P-Al activity after a 12 hour fast and 2 hours after a large meal in 4 healthy volunteers. There was no increase in activity (r = 0.16) with the subject's age. The average activity from 16 poorly-controlled diabetics was 131 +/- 11% (SEM). No alteration in activity was seen with samples from patients with uremia, liver dysfunction, hemophilia, thrombotic events, or adenocarcinoma. These results indicate that P-Al activity can be bioassayed in individual patient samples; however, pathologic states associated with abnormal P-Al-induced tissue factor activity presently remain unidentified.

The chronology of Late Pleistocene thermal contraction cracking derived from sand wedge OSL dating in central and southern France

NASA Astrophysics Data System (ADS)

Andrieux, Eric; Bateman, Mark D.; Bertran, Pascal

2018-03-01

Much of France remained unglaciated during the Late Quaternary and was subjected to repeated phases of periglacial activity. Numerous periglacial features have been reported but disentangling the environmental and climatic conditions they formed under, the timing and extent of permafrost and the role of seasonal frost has remained elusive. The primary sandy infillings of relict sand-wedges and composite-wedge pseudomorphs record periglacial activity. As they contain well-bleached quartz-rich aeolian material they are suitable for optically stimulated luminescence dating (OSL). This study aims to reconstruct when wedge activity took place in two regions of France; Northern Aquitaine and in the Loire valley. Results from single-grain OSL measurements identify multiple phases of activity within sand wedges which suggest that wedge activity in France occurred at least 11 times over the last 100 ka. The most widespread events of thermal contraction cracking occurred between ca. 30 and 24 ka (Last Permafrost Maximum) which are concomitant with periods of high sand availability (MIS 2). Although most phases of sand-wedge growth correlate well with known Pleistocene cold periods, the identification of wedge activity during late MIS 5 and the Younger Dryas strongly suggests that these features do not only indicate permafrost but also deep seasonal ground freezing in the context of low winter insolation. These data also suggest that the overall young ages yielded by North-European sand-wedges likely result from poor record of periglacial periods concomitant with low sand availability and/or age averaging inherent with standard luminescence methods.

Structural Equations and Causal Explanations: Some Challenges for Causal SEM

ERIC Educational Resources Information Center

Markus, Keith A.

2010-01-01

One common application of structural equation modeling (SEM) involves expressing and empirically investigating causal explanations. Nonetheless, several aspects of causal explanation that have an impact on behavioral science methodology remain poorly understood. It remains unclear whether applications of SEM should attempt to provide complete…

Verbal Understanding and Pavlovian Processes

ERIC Educational Resources Information Center

Tonneau, François

2004-01-01

The behavioral processes through which people react appropriately to verbal descriptions remain poorly understood. I argue here that these processes are Pavlovian. Common objections to a Pavlovian account of symbolic behavior evidence a lack of familiarity with the relevant data or misunderstandings of operant theory. Although much remains to be…

Gastric Electrical Stimulation Decreases Gastric Distension-Induced Central Nociception Response through Direct Action on Primary Afferents

PubMed Central

Ouelaa, Wassila; Ghouzali, Ibtissem; Langlois, Ludovic; Fetissov, Serguei; Déchelotte, Pierre; Ducrotté, Philippe; Leroi, Anne Marie; Gourcerol, Guillaume

2012-01-01

Background & Aims Gastric electrical stimulation (GES) is an effective therapy to treat patients with chronic dyspepsia refractory to medical management. However, its mechanisms of action remain poorly understood. Methods Gastric pain was induced by performing gastric distension (GD) in anesthetized rats. Pain response was monitored by measuring the pseudo-affective reflex (e.g., blood pressure variation), while neuronal activation was determined using c-fos immunochemistry in the central nervous system. Involvement of primary afferents was assessed by measuring phosphorylation of ERK1/2 in dorsal root ganglia. Results GES decreased blood pressure variation induced by GD, and prevented GD-induced neuronal activation in the dorsal horn of the spinal cord (T9–T10), the nucleus of the solitary tract and in CRF neurons of the hypothalamic paraventricular nucleus. This effect remained unaltered within the spinal cord when sectioning the medulla at the T5 level. Furthermore, GES prevented GD-induced phosphorylation of ERK1/2 in dorsal root ganglia. Conclusions GES decreases GD-induced pain and/or discomfort likely through a direct modulation of gastric spinal afferents reducing central processing of visceral nociception. PMID:23284611

Opioid Analgesics and P-glycoprotein Efflux Transporters: A Potential Systems-Level Contribution to Analgesic Tolerance

PubMed Central

Mercer, Susan L.; Coop, Andrew

2012-01-01

Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationship development to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation. PMID:21050174

Bioactive Components in Fish Venoms

PubMed Central

Ziegman, Rebekah; Alewood, Paul

2015-01-01

Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite of there being over 2000 venomous fish species, piscine venoms have been relatively underrepresented in the literature thus far. Most studies have explored whole or partially fractioned venom, revealing broad pharmacology, which includes cardiovascular, neuromuscular, cytotoxic, inflammatory, and nociceptive activities. Several large proteinaceous toxins, such as stonustoxin, verrucotoxin, and Sp-CTx, have been isolated from scorpaenoid fish. These form pores in cell membranes, resulting in cell death and creating a cascade of reactions that result in many, but not all, of the physiological symptoms observed from envenomation. Additionally, Natterins, a novel family of toxins possessing kininogenase activity have been found in toadfish venom. A variety of smaller protein toxins, as well as a small number of peptides, enzymes, and non-proteinaceous molecules have also been isolated from a range of fish venoms, but most remain poorly characterized. Many other bioactive fish venom components remain to be discovered and investigated. These represent an untapped treasure of potentially useful molecules. PMID:25941767

Poorly controlled postoperative pain: prevalence, consequences, and prevention

PubMed Central

Gan, Tong J

2017-01-01

This review provides an overview of the clinical issue of poorly controlled postoperative pain and therapeutic approaches that may help to address this common unresolved health-care challenge. Postoperative pain is not adequately managed in greater than 80% of patients in the US, although rates vary depending on such factors as type of surgery performed, analgesic/anesthetic intervention used, and time elapsed after surgery. Poorly controlled acute postoperative pain is associated with increased morbidity, functional and quality-of-life impairment, delayed recovery time, prolonged duration of opioid use, and higher health-care costs. In addition, the presence and intensity of acute pain during or after surgery is predictive of the development of chronic pain. More effective analgesic/anesthetic measures in the perioperative period are needed to prevent the progression to persistent pain. Although clinical findings are inconsistent, some studies of local anesthetics and nonopioid analgesics have suggested potential benefits as preventive interventions. Conventional opioids remain the standard of care for the management of acute postoperative pain; however, the risk of opioid-related adverse events can limit optimal dosing for analgesia, leading to poorly controlled acute postoperative pain. Several new opioids have been developed that modulate μ-receptor activity by selectively engaging intracellular pathways associated with analgesia and not those associated with adverse events, creating a wider therapeutic window than unselective conventional opioids. In clinical studies, oliceridine (TRV130), a novel μ-receptor G-protein pathway-selective modulator, produced rapid postoperative analgesia with reduced prevalence of adverse events versus morphine. PMID:29026331

Poorly controlled postoperative pain: prevalence, consequences, and prevention.

PubMed

Gan, Tong J

2017-01-01

This review provides an overview of the clinical issue of poorly controlled postoperative pain and therapeutic approaches that may help to address this common unresolved health-care challenge. Postoperative pain is not adequately managed in greater than 80% of patients in the US, although rates vary depending on such factors as type of surgery performed, analgesic/anesthetic intervention used, and time elapsed after surgery. Poorly controlled acute postoperative pain is associated with increased morbidity, functional and quality-of-life impairment, delayed recovery time, prolonged duration of opioid use, and higher health-care costs. In addition, the presence and intensity of acute pain during or after surgery is predictive of the development of chronic pain. More effective analgesic/anesthetic measures in the perioperative period are needed to prevent the progression to persistent pain. Although clinical findings are inconsistent, some studies of local anesthetics and nonopioid analgesics have suggested potential benefits as preventive interventions. Conventional opioids remain the standard of care for the management of acute postoperative pain; however, the risk of opioid-related adverse events can limit optimal dosing for analgesia, leading to poorly controlled acute postoperative pain. Several new opioids have been developed that modulate μ-receptor activity by selectively engaging intracellular pathways associated with analgesia and not those associated with adverse events, creating a wider therapeutic window than unselective conventional opioids. In clinical studies, oliceridine (TRV130), a novel μ-receptor G-protein pathway-selective modulator, produced rapid postoperative analgesia with reduced prevalence of adverse events versus morphine.

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner.

PubMed

Zhao, Yahui; Luo, Aiping; Li, Sheng; Zhang, Wei; Chen, Hongyan; Li, Yi; Ding, Fang; Huang, Furong; Liu, Zhihua

2016-03-25

ID1 (inhibitor of differentiation/DNA binding 1) acts an important role in metastasis, tumorigenesis, and maintenance of cell viability. It has been shown that the up-regulation of ID1 is correlated with poor prognosis and the resistance to chemotherapy of human cancers. However, the underlying molecular mechanism remains elusive. Here, we determined for the first time that up-regulating ID1 upon etoposide activation was mediated through AP-1 binding sites within theID1promoter and confirmed that ID1 enhanced cell resistance to DNA damage-induced apoptosis in esophageal squamous cell carcinoma cells. Ablation of c-Jun/c-Fos or ID1 expression enhanced etoposide-mediated apoptosis through increasing activity of caspase 3 and PARP cleavage. Moreover, c-Jun/c-Fos and ID1 were positively correlated in human cancers. More importantly, simultaneous high expression of ID1 and c-Jun or c-Fos was correlated with poor survival in cancer patients. Collectively, we demonstrate the importance of c-Jun/c-Fos-ID1 signaling pathway in chemoresistance of esophageal cancer cells and provide considerable insight into understanding the underlying molecular mechanisms in esophageal squamous cell carcinoma cell biology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics.

PubMed

Sulzmaier, Florian J; Young-Robbins, Shirley; Jiang, Pengfei; Geerts, Dirk; Prechtl, Amanda M; Matter, Michelle L; Kesari, Santosh; Ramos, Joe W

2016-11-29

In glioblastoma (GBM), infiltration of primary tumor cells into the normal tissue and dispersal throughout the brain is a central challenge to successful treatment that remains unmet. Indeed, patients respond poorly to the current therapies of tumor resection followed by chemotherapy with radiotherapy and have only a 16-month median survival. It is therefore imperative to develop novel therapies. RSK2 is a kinase that regulates proliferation and adhesion and can promote metastasis. We demonstrate that active RSK2 regulates GBM cell adhesion and is essential for cell motility and invasion of patient-derived GBM neurospheres. RSK2 control of adhesion and migration is mediated in part by its effects on integrin-Filamin A complexes. Importantly, inhibition of RSK2 by either RSK inhibitors or shRNA silencing impairs invasion and combining RSK2 inhibitors with temozolomide improves efficacy in vitro. In agreement with the in vitro data, using public datasets, we find that RSK2 is significantly upregulated in vivo in human GBM patient tumors, and that high RSK2 expression significantly correlates with advanced tumor stage and poor patient survival. Together, our data provide strong evidence that RSK inhibitors could enhance the effectiveness of existing GBM treatment, and support RSK2 targeting as a promising approach for novel GBM therapy.

Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection.

PubMed

Inácio, Patricia; Zuzarte-Luís, Vanessa; Ruivo, Margarida T G; Falkard, Brie; Nagaraj, Nagarjuna; Rooijers, Koos; Mann, Matthias; Mair, Gunnar; Fidock, David A; Mota, Maria M

2015-08-01

Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s--the active form of the UPR mediator XBP1--and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection. © 2015 The Authors.

Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection

PubMed Central

Inácio, Patricia; Zuzarte-Luís, Vanessa; Ruivo, Margarida TG; Falkard, Brie; Nagaraj, Nagarjuna; Rooijers, Koos; Mann, Matthias; Mair, Gunnar; Fidock, David A; Mota, Maria M

2015-01-01

Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s—the active form of the UPR mediator XBP1—and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection. PMID:26113366

Suppressor of cytokine signalling (SOCS) 1 and 3 enhance cell adhesion and inhibit migration towards the chemokine eotaxin/CCL11.

PubMed

Stevenson, Nigel J; McFarlane, Cheryl; Ong, Seow Theng; Nahlik, Krystyna; Kelvin, Alyson; Addley, Mark R; Long, Aideen; Greaves, David R; O'Farrelly, Cliona; Johnston, James A

2010-11-05

Suppressors of cytokine signalling (SOCS) proteins regulate signal transduction, but their role in responses to chemokines remains poorly understood. We report that cells expressing SOCS1 and 3 exhibit enhanced adhesion and reduced migration towards the chemokine CCL11. Focal adhesion kinase (FAK) and the GTPase RhoA, control cell adhesion and migration and we show the presence of SOCS1 or 3 regulates expression and tyrosine phosphorylation of FAK, while also enhancing activation of RhoA. Our novel findings suggest that SOCS1 and 3 may control chemotaxis and adhesion by significantly enhancing both FAK and RhoA activity, thus localizing immune cells to the site of allergic inflammation. Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Association between levels of physical activity and poor self-rated health in Korean adults: The Third Korea National Health and Nutrition Examination Survey (KNHANES), 2005.

PubMed

Han, M A; Kim, K S; Park, J; Kang, M G; Ryu, S Y

2009-10-01

To investigate the association between level of physical activity and poor self-rated health in Korean adults. A cross-sectional study was conducted on 7,800 adults aged > or =19 years who completed the Health Interview and the Health Behavior Surveys, issued during the Third National Health and Nutrition Examination Survey (2005). The association between self-rated health and physical activity was tested using Chi-squared test. Multiple logistic regression analysis was used to calculate the odds ratios of poor self-rated health for different levels of physical activity after adjusting for physical and chronic medical conditions. The prevalence of poor self-rated health was significantly lower as the level of physical activity increased, and odds ratios for poor self-rated health were significantly lower for higher levels of physical activity after adjusting for age, marital status, educational status, smoking, alcohol consumption, and the number of physical impairments and chronic medical conditions. The association was similar in different age groups and among healthy respondents and respondents with physical impairments or chronic medical conditions. Physical activity was positively associated with self-rated health in Koreans. The independent association between a lower level of physical activity and poor self-rated health supports public health programmes that encourage regular physical activity.

Welfare, Work and Raising Children: Conversations with Twenty-One Maine Families.

ERIC Educational Resources Information Center

Hastedt, Christine B.; Smith, Rebekah J.

Five years after the massive overhaul of the nation's welfare system, 21 Maine families receiving public assistance spoke about their lives during welfare reform. The following were among the key themes that emerged throughout the conversations: (1) those leaving Temporary Assistance for Needy Families (TANF) often remain poor or very nearly poor;…

Parental "Choice": The Liberty Principle in Education Finance: New Scholar Section

ERIC Educational Resources Information Center

Ndimande, Bekisizwe

2006-01-01

Despite the promise of equal educational opportunities for all, most public schools in the townships of South Africa have remained poorly funded and thus have become dysfunctional. As a result most poor parents from townships have started to transfer their children to schools with better resources and education facilities in the suburban areas.…

Work ability in midlife as a predictor of mortality and disability in later life: a 28-year prospective follow-up study

PubMed Central

von Bonsdorff, Mikaela B.; Seitsamo, Jorma; Ilmarinen, Juhani; Nygård, Clas-Håkan; von Bonsdorff, Monika E.; Rantanen, Taina

2011-01-01

Background Poor work ability correlates with increased morbidity and early retirement from the workforce, but the association in old age is not known. We investigated work ability in midlife among white-collar and blue-collar employees as a predictor of mortality and disability 28 years later. Methods A total of 5971 occupationally active people aged 44–58 years participated in the Finnish Longitudinal Study of Municipal Employees (FLAME) in 1981. Perceived work ability relative to lifetime best was categorized as excellent, moderate or poor. In 2009, the ability to perform activities of daily living was assessed among 2879 respondents (71.0% of the survivors). Mortality data were available up to July 2009. Results At the 28-year follow-up, 1918 of the 5971 participants had died and 1403 had some form of disability. Rates of death per 1000 person-years among white-collar men were 7.7 for those with excellent work ability, 14.7 for those with moderate work ability and 23.5 for those with poor work ability. Among blue-collar men, the corresponding rates were 15.5, 20.2 and 25.3. In women, rates ranged between 6.3 and 10.6 per 1000 person-years. The age-adjusted hazard ratios (HRs) for mortality were two to three times higher among blue-collar male employees with lower work ability than among white-collar male employees with excellent work ability in midlife (i.e., the reference group). The odds of death or disability at follow-up compared with white-collar workers with excellent work ability were highest among blue-collar employees with poor work ability in midlife (odds ratio [OR] 4.56, 95% confidence interval [CI] 2.82–7.37 for men; OR 3.37, 95% CI 2.28–4.98 for women). Among the survivors, similar but slightly lower risks of disability 28 years later were found. Interpretation Perceived poor work ability in midlife was associated with accelerated deterioration in health and functioning and remains evident after 28 years of follow-up. PMID:21282315

Self-Reported Physical Activity is Not a Valid Method for Measuring Physical Activity in 15-Year-Old South African Boys and Girls.

PubMed

Monyeki, Makama Andries; Moss, Sarah J; Kemper, Han C G; Twisk, Jos W R

2018-06-06

Physical activity plays an important role in the prevention of chronic lifestyle-related diseases. The development of valid instruments for the assessment of physical activity remains a challenge in field studies. The purpose of the present study was therefore to determine the level of agreement between physical activity objectively measured by the ActiHeart ® (Cambridge Neurotechnology Ltd, Cambridge, UK) device and subjectively reported physical activity by means of the International Physical Activity Questionnaire Short Form (IPAQ-SF) among adolescents attending schools in the Tlokwe Local Municipality, South Africa. A cross-sectional study design was used with a total of 63 boys and 45 girls aged 15 years who took part in the Physical Activity and Health Longitudinal Study (PHALS). Stature and weight were measured according to standard International Society for the Advancement of Kinanthropometry (ISAK) protocols. Objective physical activity (PA) was measured by a combined heart rate and accelerometer device (ActiHeart ® ) for seven consecutive days. Time spent in moderate-to-vigorous intensity physical activity (MVPA) was assessed. Subjective physical activity was assessed with the self-reported IPAQ-SF. Objective PA indicated that 93% of the participants were inactive and only 6% were highly active. The IPAQ-SF showed that 24% were inactive, with 57% active. A non-significant correlation ( r = 0.11; p = 0.29) between the ActiHeart ® measure of activity energy expenditure (AEE) and total physical activity (IPAQ-SF) was observed. The Bland⁻Altman plot showed no agreement between the two measurement instruments and also a variation in the level of equivalence. When Cohen’s kappa ( κ ) was run to determine the agreement between the two measurement instruments for estimated physical activity, a poor agreement (κ = 0.011, p < 0.005) between the two was found. The poor level of agreement between the objective measure of physical activity (ActiHeart ® ) and the IPAQ-SF questionnaire should be interpreted cautiously. Future physical activity research using a combination of subjective and objective assessment methods in a large-scale cohort in adolescents is recommended.

Conformational changes accompany activation of reovirus RNA-dependent RNA transcription

PubMed Central

Mendez, Israel I.; Weiner, Scott G.; She, Yi-Min; Yeager, Mark; Coombs, Kevin M.

2009-01-01

Many critical biologic processes involve dynamic interactions between proteins and nucleic acids. Such dynamic processes are often difficult to delineate by conventional static methods. For example, while a variety of nucleic acid polymerase structures have been determined at atomic resolution, the details of how some multi-protein transcriptase complexes actively produce mRNA, as well as conformational changes associated with activation of such complexes, remain poorly understood. The mammalian reovirus innermost capsid (core) manifests all enzymatic activities necessary to produce mRNA from each of the 10 encased double-stranded RNA genes. We used rapid freezing and electron cryo-microscopy to trap and visualize transcriptionally active reovirus core particles and compared them to inactive core images. Rod-like density centered within actively transcribing core spike channels was attributed to exiting nascent mRNA. Comparative radial density plots of active and inactive core particles identified several structural changes in both internal and external regions of the icosahedral core capsid. Inactive and transcriptionally active cores were partially digested with trypsin and identities of initial tryptic peptides determined by mass spectrometry. Differentially-digested peptides, which also suggest transcription-associated conformational changes, were placed within the known 3-dimensional structures of major core proteins. PMID:18321727

Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades.

PubMed

Wang, Xun; Yu, Zhenlong; Wang, Chao; Cheng, Wei; Tian, Xiangge; Huo, Xiaokui; Wang, Yan; Sun, Chengpeng; Feng, Lei; Xing, Jinshan; Lan, Yulong; Sun, Dongdong; Hou, Qingjuan; Zhang, Baojing; Ma, Xiaochi; Zhang, Bo

2017-07-12

Glioblastoma multiforme (GBM) is one of the most refractory and palindromic central nervous system (CNS) neoplasms, and current treatments have poor effects in GBM patients. Hence, the identification of novel therapeutic targets and the development of effective treatment strategies are essential. Alantolactone (ATL) has a wide range of pharmacological activities, and its anti-tumor effect is receiving increasing attention. However, the molecular mechanism underlying the anti-GBM activity of ATL remains poorly understood. The biological functions of ATL in GBM cells were investigated using migration/invasion, colony formation and cell cycle/apoptosis assays. The localization of nuclear factor kappa B (NF-κB) p50/p65 and its binding to the cyclooxygenase 2 (COX-2) promoter were determined using confocal immunofluorescence, a streptavidin-agarose pulldown assay and a chromatin immunoprecipitation (ChIP) assay. IKKβ kinase activity was determined using a cell IKKβ kinase activity spectrophotometry quantitative detection kit and a molecular docking study. LC-MS/MS analysis was performed to determine the ability of ATL to traverse the blood-brain barrier (BBB). The in vivo anti-tumor efficacy of ATL was also analyzed in xenografted nude mice. Western blot analysis was performed to detect the protein expression levels. ATL significantly suppressed the growth of GBM in vivo and in vitro. ATL significantly reduced the expression of COX-2 by inhibiting the kinase activity of IKKβ by targeting the ATP-binding site and then attenuating the binding of NF-κB to the COX-2 promoter region. Furthermore, ATL induced apoptosis by activating the cytochrome c (cyt c)/caspase cascade signaling pathway. Moreover, ATL could penetrate the BBB. ATL exerts its anti-tumor effects in human GBM cells at least in part via NF-κB/COX-2-mediated signaling cascades by inhibiting IKKβ kinase activity. ATL, which is a natural small molecule inhibitor, is a promising candidate for clinical applications in the treatment of CNS tumors.

Out of School: A Phenomenological Exploration of Extended Non-Attendance

ERIC Educational Resources Information Center

Baker, Matt; Bishop, Felicity L.

2015-01-01

The concept of "extended non-attendance" ("school phobia" or "school refusal") was distinguished from truancy early in the twentieth century, and refers to children who fear school and avoid attending. Despite much subsequent research, outcomes for those affected remain poor, and their voices remain largely absent…

The Effect of Empowerment and Self-Determination on Health Outcomes

ERIC Educational Resources Information Center

Garces-Ozanne, Arlene; Kalu, Edna Ikechi; Audas, Richard

2016-01-01

There remains a persistent gap in health outcomes between wealthy and poor countries. Basic measures such as life expectancy and infant and under-five mortality remain divergent, with preventable deaths being unacceptably high, despite significant efforts to reduce these disparities. We examine the impact of empowerment, measured by Freedom…

A systems view of health care for the poor.

PubMed Central

Prasad, N.

1989-01-01

A systems view is a synthesis of health policy, medical sociology, public health, and common clinical problems to describe the current crisis in health care for the poor. Medical sociology and public health are particularly relevant to understand the complexity of clinical issues. Although preventive medicine is in desuetude, it is crucial if we are to reduce the future liability of postponed medical care among the poor. Medicaid metamorphosed to Medicare, as half of its outlays are spent on care of the elderly in nursing homes. Health care for the poor will remain a moral challenge to the architects of health policy and the medical profession. PMID:2659807

Lingual lipase activity in the orosensory detection of fat by humans

PubMed Central

Kulkarni, Bhushan V.

2014-01-01

Lingual lipase generates nonesterified fatty acids (NEFA) from dietary fats during oral processing by lipolysis. Lingual lipase in rodents has strong lipolytic activity and plays a critical role in oral detection of fats. The functional activity of lingual lipase during oral processing of high-fat foods in humans remains poorly characterized. Five commonly consumed high-fat foods varying in physical states and fatty acid composition (almond, almond butter, olive oil, walnut, and coconut) were masticated by 15 healthy human subjects at the rate of one chew per second with and without lipase inhibitor orlistat. Salivary NEFA concentrations were measured. To determine the role of lingual lipase in oral fat detection, sensory ratings were obtained from the same 15 human subjects for almond butter with and without orlistat. Lingual lipase was active during oral processing of almond and coconut. No activity of lingual lipase was detected during processing of almond butter. There was only weak evidence lingual lipase is a determinant of oral fat detection. Lingual lipase may only contribute to NEFA generation and oral fat detection of fatty foods that require stronger oral processing effort. PMID:24694384

PPAR Agonists for the Prevention and Treatment of Lung Cancer.

PubMed

Lakshmi, Sowmya P; Reddy, Aravind T; Banno, Asoka; Reddy, Raju C

2017-01-01

Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPAR α , PPAR β / δ , and PPAR γ , display distinct biological activities and varied influences on lung cancer biology. PPAR α activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPAR γ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPAR α and PPAR γ , whether PPAR β / δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria

PubMed Central

Rathinam, Vijay A.K.; Vanaja, Sivapriya Kailasan; Waggoner, Lisa; Sokolovska, Anna; Becker, Christine; Stuart, Lynda M.; Leong, John M.; Fitzgerald, Katherine A.

2013-01-01

SUMMARY Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the “sepsis syndrome,” a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection. PMID:22819539

Measuring and modeling polymer concentration profiles near spindle boundaries argues that spindle microtubules regulate their own nucleation

NASA Astrophysics Data System (ADS)

Kaye, Bryan; Stiehl, Olivia; Foster, Peter J.; Shelley, Michael J.; Needleman, Daniel J.; Fürthauer, Sebastian

2018-05-01

Spindles are self-organized microtubule-based structures that segregate chromosomes during cell division. The mass of the spindle is controlled by the balance between microtubule turnover and nucleation. The mechanisms that control the spatial regulation of microtubule nucleation remain poorly understood. While previous work found that microtubule nucleators bind to pre-existing microtubules in the spindle, it is still unclear whether this binding regulates the activity of those nucleators. Here we use a combination of experiments and mathematical modeling to investigate this issue. We measured the concentration of microtubules and soluble tubulin in and around the spindle. We found a very sharp decay in the concentration of microtubules at the spindle interface. This is inconsistent with a model in which the activity of nucleators is independent of their association with microtubules but consistent with a model in which microtubule nucleators are only active when bound to pre-existing microtubules. This argues that the activity of microtubule nucleators is greatly enhanced when bound to pre-existing microtubules. Thus, microtubule nucleators are both localized and activated by the microtubules they generate.

Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse

PubMed Central

Lasserre, Rémi; Charrin, Stéphanie; Cuche, Céline; Danckaert, Anne; Thoulouze, Maria-Isabel; de Chaumont, Fabrice; Duong, Tarn; Perrault, Nathalie; Varin-Blank, Nadine; Olivo-Marin, Jean-Christophe; Etienne-Manneville, Sandrine; Arpin, Monique; Di Bartolo, Vincenzo; Alcover, Andrés

2010-01-01

T-cell receptor (TCR) signalling is triggered and tuned at immunological synapses by the generation of signalling complexes that associate into dynamic microclusters. Microcluster movement is necessary to tune TCR signalling, but the molecular mechanism involved remains poorly known. We show here that the membrane-microfilament linker ezrin has an important function in microcluster dynamics and in TCR signalling through its ability to set the microtubule network organization at the immunological synapse. Importantly, ezrin and microtubules are important to down-regulate signalling events leading to Erk1/2 activation. In addition, ezrin is required for appropriate NF-AT activation through p38 MAP kinase. Our data strongly support the notion that ezrin regulates immune synapse architecture and T-cell activation through its interaction with the scaffold protein Dlg1. These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. Moreover, they underscore the importance of ezrin and Dlg1 in the regulation of NF-AT activation through p38. PMID:20551903

Self-reported parenting style is associated with children's inflammation and immune activation.

PubMed

Byrne, Michelle L; Badcock, Paul B; Simmons, Julian G; Whittle, Sarah; Pettitt, Adam; Olsson, Craig A; Mundy, Lisa K; Patton, George C; Allen, Nicholas B

2017-04-01

Family environments and parenting have been associated with inflammation and immune activation in children and adolescents; however, it remains unclear which specific aspects of parenting drive this association. In this study, we cross-sectionally examined the association between 5 discrete parenting styles and inflammation and immune activation in late childhood. Data were drawn from 102 families (55 with female children, mean age 9.50 years, SD = 0.34) participating in the Imaging Brain Development in the Childhood to Adolescence Transition Study. Children provided saliva samples from which inflammation (C-reactive protein) and immune competence/activation (secretory immunoglobulin A) were measured. Parents completed the Alabama Parenting Questionnaire, which measures 5 aspects of parenting style-positive parental involvement, positive disciplinary techniques, consistency in disciplinary techniques, corporal punishment, and monitoring and supervision. Results showed that higher scores on the poor parental monitoring scale were associated with higher levels of both inflammation and immune activation in children. This study highlights parental monitoring and supervision as a specific aspect of parenting behavior that may be important for children's physical and mental health. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

The role of fast and slow EEG activity during sleep in males and females with Major Depressive Disorder

PubMed Central

Cheng, Philip; Goldschmied, Jennifer; Deldin, Patricia; Hoffmann, Robert; Armitage, Roseanne

2015-01-01

Sleep difficulties are highly prevalent in depression, and appears to be a contributing factor in the development and maintenance of symptoms. However, despite the generally acknowledged relationship between sleep and depression, the neurophysiological substrates underlying this relationship still remain unclear. Two main hypotheses were tested in this study. The first hypothesis states that sleep in depression is characterized by inadequate generation of restorative sleep, as indexed by reduced amounts of slow-wave activity. Conversely, the second hypothesis states that poor sleep in depression is due to intrusions of fast-frequency activity that may be reflective of a hyperaroused central nervous system. This study aimed to test both hypotheses in a large sample of individuals with clinically validated depression, as well as examine sex as a moderator. Results suggest that depression is better characterized by an overall decrease in slow-wave activity, which is related to elevated anxious and depressed mood the following morning. Results also suggest that females may be more likely to experience fast frequency activity related to depression symptom severity. PMID:26175101

Synthesis, characterization, stereochemistry and biological investigation of certain N-dichloroacetyl-bis(2-chlorophenyl)piperidin-4-ones

NASA Astrophysics Data System (ADS)

Kayalvizhi, R.; Ponnuswamy, S.; Gomathi, K.; Ezhilarasi, K. S.; Usha, G.

2018-02-01

A new series of N-dichloroacetyl-bis(2-chlorophenyl)piperidin-4-ones 4-6 has been synthesized and characterized using IR, 1H, 13C, DEPT and 2D (COSY and HSQC) NMR spectral techniques. The NMR spectral data indicate that the N-acylpiperidin-4-ones 4-6 prefer to exist in an equilibrium between the twist boat conformations with coplanar orientation of Nsbnd Cdbnd O moiety. Furthermore, the antibacterial and antifungal studies have been carried out for compounds 1-6 and the results show that they possess significant activity towards the bacterial organisms Staphylococcus aureus and Salmoneela paratyphi and better activity against the remaining bacterial organisms. All the compounds 1-6 possess moderate antifungal activity. The compounds 4-6 have been docked with the structure of MRSA and the results demonstrate that the compounds 4-6 have similar docking score and glide energy when compared to each other and thus having equal binding affinity. The antioxidant studies show greater activity for compound 4 and poor activity for compounds 5 &6 when compared to the standard drug.

Tonic-Clonic Activity at Subarachnoid Hemorrhage Onset: Impact on Complications and Outcome

PubMed Central

De Marchis, Gian Marco; Pugin, Deborah; Lantigua, Hector; Zammit, Christopher; Tadi, Prasanna; Schmidt, J. Michael; Falo, M. Cristina; Agarwal, Sachin; Mayer, Stephan A.; Claassen, Jan

2013-01-01

Objective Tonic-clonic activity (TCA) at onset complicates 3% to 21% of cases of subarachnoid hemorrhage (SAH). The impact of onset TCA on in-hospital complications, including seizures, remains unclear. One study associated onset TCA with poor clinical outcome at 6 weeks after SAH, but to our knowledge no other studies have confirmed this relationship. This study aims to assess the impact of onset TCA on in-hospital complications, poor functional outcome, mortality, and epilepsy at 3 months. Methods Analysis of a prospective study cohort of 1479 SAH patients admitted to Columbia University Medical Center between 1996 and 2012. TCA within 6 hours of hemorrhage onset was identified based on accounts of emergency care providers or family witnesses. Results TCA at onset was described in 170 patients (11%). Patients with onset TCA were younger (P = 0.002), presented more often with poor clinical grade (55% vs. 26%, P<0.001) and had larger amounts of cisternal, intraventricular, and intracerebral blood than those without onset TCA (all, P<0.001). After adjusting for known confounders, onset TCA was significantly associated with in-hospital seizures (OR 3.80, 95%-CI: 2.43–5.96, P<0.001), in-hospital pneumonia (OR 1.56, 95%-CI: 1.06–2.31, p = 0.02), and delayed cerebral ischemia (OR 1.77, 95%-CI: 1.21–2.58, P = 0.003). At 3 months, however, onset TCA was not associated with poor functional outcome, mortality, and epilepsy after adjusting for age, admission clinical grade, and cisternal blood volume. Conclusions Onset TCA is not a rare event as it complicates 11% of cases of SAH. New and clinically relevant findings are the association of onset TCA with in-hospital seizures, pneumonia and delayed cerebral ischemia. Despite the increased risk of in-hospital complications, onset TCA is not associated with disability, mortality, and epilepsy at 3 months. PMID:23951155

Variation in Older Adult Characteristics by Residence Type and Use of Home- and Community-Based Services.

PubMed

Ewen, Heidi H; Washington, Tiffany R; Emerson, Kerstin G; Carswell, Andrew T; Smith, Matthew Lee

2017-03-22

Background: The majority of older adults prefer to remain in their homes, or to "age-in-place." To accomplish this goal, many older adults will rely upon home- and community-based services (HCBS) for support. However, the availability and accessibility of HCBS may differ based on whether the older adult lives in the community or in a senior housing apartment facility. Methods: This paper reports findings from the Pathways to Life Quality study of residential change and stability among seniors in upstate New York. Data were analyzed from 663 older adults living in one of three housing types: service-rich facilities, service-poor facilities, and community-dwelling in single-family homes. A multinomial logistic regression model was used to examine factors associated with residence type. A linear regression model was fitted to examine factors associated with HCBS utilization. Results : When compared to community-dwelling older adults, those residing in service-rich and service-poor facilities were more likely to be older, report more activity limitations, and provide less instrumental assistance to others. Those in service-poor facilities were more likely to have poorer mental health and lower perceived purpose in life. The three leading HCBS utilized were senior centers (20%), homemaker services (19%), and transportation services (18%). More HCBS utilization was associated with participants who resided in service-poor housing, were older, were female, and had more activity limitations. More HCBS utilization was also associated with those who received instrumental support, had higher perceived purpose in life, and poorer mental health. Conclusions : Findings suggest that older adults' residential environment is associated with their health status and HCBS utilization. Building upon the Person-Environment Fit theories, dedicated efforts are needed to introduce and expand upon existing HCBS available to facility residents to address physical and mental health needs as well as facilitate aging-in-place.

Variation in Older Adult Characteristics by Residence Type and Use of Home- and Community-Based Services

PubMed Central

Ewen, Heidi H.; Washington, Tiffany R.; Emerson, Kerstin G.; Carswell, Andrew T.; Smith, Matthew Lee

2017-01-01

Background: The majority of older adults prefer to remain in their homes, or to “age-in-place.” To accomplish this goal, many older adults will rely upon home- and community-based services (HCBS) for support. However, the availability and accessibility of HCBS may differ based on whether the older adult lives in the community or in a senior housing apartment facility. Methods: This paper reports findings from the Pathways to Life Quality study of residential change and stability among seniors in upstate New York. Data were analyzed from 663 older adults living in one of three housing types: service-rich facilities, service-poor facilities, and community-dwelling in single-family homes. A multinomial logistic regression model was used to examine factors associated with residence type. A linear regression model was fitted to examine factors associated with HCBS utilization. Results: When compared to community-dwelling older adults, those residing in service-rich and service-poor facilities were more likely to be older, report more activity limitations, and provide less instrumental assistance to others. Those in service-poor facilities were more likely to have poorer mental health and lower perceived purpose in life. The three leading HCBS utilized were senior centers (20%), homemaker services (19%), and transportation services (18%). More HCBS utilization was associated with participants who resided in service-poor housing, were older, were female, and had more activity limitations. More HCBS utilization was also associated with those who received instrumental support, had higher perceived purpose in life, and poorer mental health. Conclusions: Findings suggest that older adults’ residential environment is associated with their health status and HCBS utilization. Building upon the Person–Environment Fit theories, dedicated efforts are needed to introduce and expand upon existing HCBS available to facility residents to address physical and mental health needs as well as facilitate aging-in-place. PMID:28327507

Inequality in the use of maternal and child health services in the Philippines: do pro-poor health policies result in more equitable use of services?

PubMed

Paredes, Karlo Paolo P

2016-11-10

The Philippines failed to achieve its Millennium Development Goal (MDG) commitment to reduce maternal deaths by three quarters. This, together with the recently launched Sustainable Development Goals (SDGs), reinforces the need for the country to keep up in improving reach of maternal and child health (MCH) services. Inequitable use of health services is a risk factor for the differences in health outcomes across socio-economic groups. This study aims to explore the extent of inequities in the use of MCH services in the Philippines after pro-poor national health policy reforms. This paper uses data from the 2008 and 2013 Demographic and Health Survey (DHS) in the Philippines. Socio-economic inequality in MCH services use was measured using the concentration index. The concentration index was also decomposed in order to examine the contribution of different factors to the inequalities in the use of MCH services. In absolute figures, women who delivered in facilities increased from 2008 to 2013. Little change was noted for women who received complete antenatal care and caesarean births. Facility deliveries remain pro-rich although a pro-poor shift was noted. Women who received complete antenatal care services also remain concentrated to the rich. Further, there is a highly pro-rich inequality in caesarean deliveries which did not change much from 2008 to 2013. Household income remains as the most important contributor to the resulting inequalities in health services use, followed by maternal education. For complete antenatal care use and deliveries in government facilities, regional differences also showed to have important contribution. The findings suggest inequality in the use of MCH services had limited pro-poor improvements. Household income remains to be the major driver of inequities in MCH services use in the Philippines. This is despite the recent national government-led subsidy for the health insurance of the poor. The highly pro-rich caesarean deliveries may also warrant the need for future studies to determine the prevalence of medically unindicated caesarean births among high-income women. Not applicable.

Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling

PubMed Central

Stephen, Terri-Leigh; Higgs, Nathalie F.; Sheehan, David F.; Al Awabdh, Sana; López-Doménech, Guillermo; Arancibia-Carcamo, I. Lorena

2015-01-01

It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca2+. Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca2+-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca2+ in astrocytic processes. Thus, the regulation of intracellular Ca2+ signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca2+ wave propagation, gliotransmission, and ultimately neuronal function. SIGNIFICANCE STATEMENT Mitochondria are key cellular organelles that play important roles in providing cellular energy and buffering intracellular calcium ions. The mechanisms that control mitochondrial distribution within the processes of glial cells called astrocytes and the impact this may have on calcium signaling remains unclear. We show that activation of glutamate receptors or increased neuronal activity leads to the altered transport of mitochondria and their positioning at synapses dependent on a key mitochondrial trafficking protein called Miro1. We also show that, the control of mitochondrial movement and stopping by Miro plays an important role in regulating astrocyte calcium responses. Thus the regulation of intracellular calcium signaling, by Miro-mediated mitochondrial positioning, could have important consequences for astrocyte signaling and neuron–glial interactions. PMID:26631479

Outcomes in the management of esophageal cancer.

PubMed

Paul, Subroto; Altorki, Nasser

2014-10-01

Esophageal cancer rates have continued to rise in the Western World. Esophageal cancer will be responsible for an estimated 15,450 deaths in the United States in 2014 alone. Esophageal resection with or without preoperative therapy remains the mainstay of treatment. Advances in surgical technique and perioperative care have improved short-term outcomes considerably by decreasing operative mortality. Despite these advances though, esophagectomy remains a procedure associated with considerable morbidity from a wide range of complications. Prompt recognition and treatment of complications can lower overall morbidity and mortality. Unfortunately, long-term outcomes remain poor as the vast majority of patients present with loco-regionally advanced or metastatic disease. Surgery by itself provides poor loco-regional control and fails to address micrometastatic disease. Neoadjuvant chemotherapy or chemoradiation provides a modest survival advantage compared to surgical resection alone. Future gains in understanding the molecular biology of esophageal cancer will hopefully lead to improved therapeutics and resultant outcomes. © 2014 Wiley Periodicals, Inc.

Physiological responses of juvenile rainbow trout to fasting and swimming activity: Effects on body composition and condition indices

USGS Publications Warehouse

Simpkins, D.G.; Hubert, W.A.; Del Rio, C.M.; Rule, D.C.

2003-01-01

The physiological traits that allow fish to survive periods of limited food resources are poorly understood. We assessed changes in proximate body composition, relative organ mass, blood metabolites, and relative weight (Wr) of sedentary and actively swimming (15 cm/s) juvenile rainbow trout (154-182 mm total length) over 147 d of fasting. Fasting caused measurable responses that were augmented when fish were swimming. Lipids and plasma triacylglycerides declined over time. Proteins were catabolized simultaneously with lipid reserves, but ammonia concentrations in plasma did not increase. The liver somatic index (LSI) did not change substantially over 105 d, suggesting that gluconeogenesis maintained blood glucose concentrations and hepatic glycogen reserves for a substantial period of fasting. The gut somatic index (GSI) and Wr declined linearly during fasting, but the LSI did not decline until after 105 d of fasting. Consequently, the use of different body condition indices could lead to different conclusions about the condition of juvenile rainbow trout. Swimming activity caused fish to have lower lipid and protein reserves than those of sedentary fish. No mortalities were observed among sedentary fish, but mortalities occurred among actively swimming fish after 97 d of fasting when 3.2% or less lipid remained in their bodies. Body condition indices did not account for differences in proximate body composition between sedentary and actively swimming fish and were relatively poor predictors of lipid content and risk of mortality. The probability of mortality was most accurately predicted by percent lipid content. Therefore, we suggest that fisheries scientists consider using percent lipid content when evaluating the physiological status and risk of mortality due to starvation among juvenile rainbow trout.

Disability Transitions and Health Expectancies among Adults 45 Years and Older in Malawi: A Cohort-Based Model

PubMed Central

Payne, Collin F.; Mkandawire, James; Kohler, Hans-Peter

2013-01-01

Background Falling fertility and increasing life expectancy contribute to a growing elderly population in sub-Saharan Africa (SSA); by 2060, persons aged 45 y and older are projected to be 25% of SSA's population, up from 10% in 2010. Aging in SSA is associated with unique challenges because of poverty and inadequate social supports. However, despite its importance for understanding the consequences of population aging, the evidence about the prevalence of disabilities and functional limitations due to poor physical health among older adults in SSA continues to be very limited. Methods and Findings Participants came from 2006, 2008, and 2010 waves of the Malawi Longitudinal Survey of Families and Health, a study of the rural population in Malawi. We investigate how poor physical health results in functional limitations that limit the day-to-day activities of individuals in domains relevant to this subsistence-agriculture context. These disabilities were parameterized based on questions from the SF-12 questionnaire about limitations in daily living activities. We estimated age-specific patterns of functional limitations and the transitions over time between different disability states using a discrete-time hazard model. The estimated transition rates were then used to calculate the first (to our knowledge) microdata-based health expectancies calculated for SSA. The risks of experiencing functional limitations due to poor physical health are high in this population, and the onset of disabilities happens early in life. Our analyses show that 45-y-old women can expect to spend 58% (95% CI, 55%–64%) of their remaining 28 y of life (95% CI, 25.7–33.5) with functional limitations; 45-y-old men can expect to live 41% (95% CI, 35%–46%) of their remaining 25.4 y (95% CI, 23.3–28.8) with such limitations. Disabilities related to functional limitations are shown to have a substantial negative effect on individuals' labor activities, and are negatively related to subjective well-being. Conclusions Individuals in this population experience a lengthy struggle with disabling conditions in adulthood, with high probabilities of remitting and relapsing between states of functional limitation. Given the strong association of disabilities with work efforts and subjective well-being, this research suggests that current national health policies and international donor-funded health programs in SSA inadequately target the physical health of mature and older adults. Please see later in the article for the Editors' Summary PMID:23667343

Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease.

PubMed

Pienaar, Ilse S; Gartside, Sarah E; Sharma, Puneet; De Paola, Vincenzo; Gretenkord, Sabine; Withers, Dominic; Elson, Joanna L; Dexter, David T

2015-09-23

Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.

Recovery of contractile and metabolic phenotypes in regenerating slow muscle after notexin-induced or crush injury.

PubMed

Fink, E; Fortin, D; Serrurier, B; Ventura-Clapier, R; Bigard, A X

2003-01-01

The recovery of metabolic pathways after muscle damage has been poorly studied. We investigated the myosin heavy chain (MHC) isoform transitions and the recovery of citrate synthase (CS) activity, isoform distribution of lactate dehydrogenase (LDH) and creatine kinase (CK) in slow muscles after two types of injury. Muscle degeneration was induced in left soleus muscles of male Wistar rats by either notexin injection or crushing and the regenerative process was examined from 2 to 56 days after injury. Myosin transition occurred earlier after notexin than after crush injury. Fast-type IIx and more particularly type IIa MHC isoform disappeared by day 28 after notexin inoculation, while they were still detected long after in crushed muscles. A full recovery of both the CS activity and the specific activity of the H-LDH subunit was observed from day 42 in notexin-treated muscles, while values measured in crushed muscles remained significantly lower than in non-injured muscles (P < 0.05). The activity of the mitochondrial isoform of CK (mi-CK) was markedly affected by the type of injury (P < 0.001), and failed to reach normal levels after crush injury (P < 0.05). The results of this study show that the relatively rapid MHC transitions during regeneration contrasts with the slow recovery in the oxidative capacity. The recovery of the oxidative capacity remained incomplete after crush injury, a model of injury known to lead to disruption of the basal lamina and severe interruption of the vascular and nerve supply.

Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.

PubMed

Lamarthée, B; Malard, F; Gamonet, C; Bossard, C; Couturier, M; Renauld, J-C; Mohty, M; Saas, P; Gaugler, B

2016-03-01

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation.

PubMed

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-08-15

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms.

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation

PubMed Central

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-01-01

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms. PMID:22641778

Comparison of ultrastructural and nanomechanical signature of platelets from acute myocardial infarction and platelet activation

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

Li, Aiqun; Chen, Jianwei; Liang, Zhi-Hong

Acute myocardial infarction (AMI) initiation and progression follow complex molecular and structural changes in the nanoarchitecture of platelets. However, it remains poorly understood how the transformation from health to AMI alters the ultrastructural and biomechanical properties of platelets within the platelet activation microenvironment. Here, we show using an atomic force microscope (AFM) that platelet samples, including living human platelets from the healthy and AMI patient, activated platelets from collagen-stimulated model, show distinct ultrastructural imaging and stiffness profiles. Correlative morphology obtained on AMI platelets and collagen-activated platelets display distinct pseudopodia structure and nanoclusters on membrane. In contrast to normal platelets, AMImore » platelets have a stiffer distribution resulting from complicated pathogenesis, with a prominent high-stiffness peak representative of platelet activation using AFM-based force spectroscopy. Similar findings are seen in specific stages of platelet activation in collagen-stimulated model. Further evidence obtained from different force measurement region with activated platelets shows that platelet migration is correlated to the more elasticity of pseudopodia while high stiffness at the center region. Overall, ultrastructural and nanomechanical profiling by AFM provides quantitative indicators in the clinical diagnostics of AMI with mechanobiological significance.« less

Activation of hypothalamic RIP-Cre neurons promotes beiging of WAT via sympathetic nervous system.

PubMed

Wang, Baile; Li, Ang; Li, Xiaomu; Ho, Philip Wl; Wu, Donghai; Wang, Xiaoqi; Liu, Zhuohao; Wu, Kelvin Kl; Yau, Sonata Sy; Xu, Aimin; Cheng, Kenneth Ky

2018-04-01

Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat-insulin-promoter-Cre (RIP-Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT Genetic ablation of APPL2 in RIP-Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP-Cre neurons, inactivation of VMH AMPK, or treatment with a β3-adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP-Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP-Cre neurons, in which the APPL2-AMPK signaling axis is crucial for this defending mechanism to cold and obesity. © 2018 The Authors.

What does productivity really mean? Towards an integrative paradigm in the search for biodiversity-productivity relationships

Treesearch

Liangjun Hu; Qinfeng Guo

2013-01-01

How species diversity relates to productivity remains a major debate. To date, however, the underlying mechanisms that regulate the ecological processes involved are still poorly understood. Three major issues persist in early efforts at resolution. First, in the context that productivity drives species diversity, how the pathways operate is poorly-explained. Second,...

An Effective Programme Is Not Enough: A Review of Factors Associated with Poor Attendance and Engagement with Parenting Support Programmes

ERIC Educational Resources Information Center

Whittaker, Karen A.; Cowley, Sarah

2012-01-01

The provision of parenting support is a key feature of wealthier nations' health and social care services. However, attendance and engagement by the neediest parents remains poor. Barriers experienced by parents include personal life factors (beliefs, lifestyles and limited resources) and programme-specific factors (delivery, content and support…

Early childhood growth failure and the developmental origins of adult disease: Do enteric infections and malnutrition increase risk for the metabolic syndrome?

PubMed Central

DeBoer, Mark D.; Lima, Aldo A. M.; Oría, Reinaldo B.; Scharf, Rebecca J.; Moore, Sean R.; Luna, Max A.; Guerrant, Richard L.

2012-01-01

Hypotheses regarding the developmental origins of health and disease postulate that developing fetuses–and potentially young children—undergo adaptive epigenetic changes with longstanding effects on metabolism and other processes. Ongoing research explores whether these adaptations occur during early life following malnutrition. In the developing world there remains a high degree of nutritional stunting—linear growth failure due to inadequate calories that may be exacerbated by inflammation from ongoing infections. In areas with poor sanitation children experience vicious cycles of enteric infections and malnutrition, resulting in poor nutrient absorption from intestinal mucosa changes now termed “environmental enteropathy.” Emerging evidence links early childhood diarrhea and/or growth failure with increased CVD risk factors in later life, including dyslipidemia, hypertension and glucose intolerance. The mechanisms for these associations remain poorly understood and may relate to epigenetic responses to poor nutrition, increased inflammation or both. Given increases in CVD in developing areas of the world, associations between childhood malnutrition, early life infections and increased CVD risk factors underscore further reasons to improve nutrition and infection-related outcomes for young children worldwide. PMID:23110643

Blockade of cytotoxic T-lymphocyte antigen-4 as a novel therapeutic approach for advanced melanoma

PubMed Central

Wang, Xiang-Yang; Zuo, Daming; Sarkar, Devanand; Fisher, Paul B.

2012-01-01

Introduction The incidence of melanoma continues to rise and prognosis in patients with metastatic melanoma remains poor. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune checkpoints and downregulates T cell activation pathways. Enhancing T cell activation by antibody blockade of the CTLA-4 provides a novel approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefit in patients with metastatic melanoma, which led to the approval of ipilimumab by the Food and Drug Administration in early 2011. Areas covered The fundamental concepts underlying CTLA-4 blockade-potentiated immune activation, the scientific rationale for and the preclinical evidence supporting CTLA-4-targeted cancer immunotherapy are presented. We also provide an update on clinical trials with anti-CTLA-4 inhibitors and discuss the associated autoimmune toxicity. Expert opinion Given that overall survival is the only validated endpoint for the anti-CTLA-4 therapy, the clinical implications of the antigen or tumor-specific immunity in patients remain to be clarified. Additional research is necessary to elucidate the prognostic significance of immune-related side effects and significantly optimize the treatment regimens. An improved understanding of the mechanisms of action of CTLA-4 antibodies may also culminate in wide-ranging clinical applications of this novel therapy for other tumor types. PMID:22077831

Toward the establishment of standardized in vitro tests for lipid-based formulations. 5. Lipolysis of representative formulations by gastric lipase.

PubMed

Bakala-N'Goma, Jean-Claude; Williams, Hywel D; Sassene, Philip J; Kleberg, Karen; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H; Carrière, Frédéric

2015-04-01

Lipid-based formulations (LBF) are substrates for digestive lipases and digestion can significantly alter their properties and potential to support drug absorption. LBFs have been widely examined for their behaviour in the presence of pancreatic enzymes. Here, the impact of gastric lipase on the digestion of representative formulations from the Lipid Formulation Classification System has been investigated. The pHstat technique was used to measure the lipolysis by recombinant dog gastric lipase (rDGL) of eight LBFs containing either medium (MC) or long (LC) chain triglycerides and a range of surfactants, at various pH values [1.5 to 7] representative of gastric and small intestine contents under both fasting and fed conditions. All LBFs were hydrolyzed by rDGL. The highest specific activities were measured at pH 4 with the type II and IIIA MC formulations that contained Tween®85 or Cremophor EL respectively. The maximum activity on LC formulations was recorded at pH 5 for the type IIIA-LC formulation. Direct measurement of LBF lipolysis using the pHstat, however, was limited by poor LC fatty acid ionization at low pH. Since gastric lipase initiates lipid digestion in the stomach, remains active in the intestine and acts on all representative LBFs, its implementation in future standardized in vitro assays may be beneficial. At this stage, however, routine use remains technically challenging.

Altered behavior and neural activity in conspecific cagemates co-housed with mouse models of brain disorders.

PubMed

Yang, Hyunwoo; Jung, Seungmoon; Seo, Jinsoo; Khalid, Arshi; Yoo, Jung-Seok; Park, Jihyun; Kim, Soyun; Moon, Jangsup; Lee, Soon-Tae; Jung, Keun-Hwa; Chu, Kon; Lee, Sang Kun; Jeon, Daejong

2016-09-01

The psychosocial environment is one of the major contributors of social stress. Family members or caregivers who consistently communicate with individuals with brain disorders are considered at risk for physical and mental health deterioration, possibly leading to mental disorders. However, the underlying neural mechanisms of this phenomenon remain poorly understood. To address this, we developed a social stress paradigm in which a mouse model of epilepsy or depression was housed long-term (>4weeks) with normal conspecifics. We characterized the behavioral phenotypes and electrophysiologically investigated the neural activity of conspecific cagemate mice. The cagemates exhibited deficits in behavioral tasks assessing anxiety, locomotion, learning/memory, and depression-like behavior. Furthermore, they showed severe social impairment in social behavioral tasks involving social interaction or aggression. Strikingly, behavioral dysfunction remained in the cagemates 4weeks following co-housing cessation with the mouse models. In an electrophysiological study, the cagemates showed an increased number of spikes in medial prefrontal cortex (mPFC) neurons. Our results demonstrate that conspecifics co-housed with mouse models of brain disorders develop chronic behavioral dysfunctions, and suggest a possible association between abnormal mPFC neural activity and their behavioral pathogenesis. These findings contribute to the understanding of the psychosocial and psychiatric symptoms frequently present in families or caregivers of patients with brain disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Characterization of iron oxide nanoparticle films at the air–water interface in Arctic tundra waters

DOE PAGES

Jubb, Aaron M.; Eskelsen, Jeremy R.; Yin, Xiangping Lisa; ...

2018-04-04

Here, massive amounts of organic carbon have accumulated in Arctic permafrost and soils due to anoxic and low temperature conditions that limit aerobic microbial respiration. Alternative electron acceptors are thus required for microbes to degrade organic carbon in these soils. Iron or iron oxides have been recognized to play an important role in carbon cycle processes in Arctic soils, although the exact form and role as an electron acceptor or donor remain poorly understood. Here, Arctic biofilms collected during the summers of 2016 and 2017 from tundra surface waters on the Seward Peninsula of western Alaska were characterized with amore » suite of microscopic and spectroscopic methods. We hypothesized that these films contain redox-active minerals bound to biological polymers. The major components of the films were found to be iron oxide nanoparticle aggregates associated with extracellular polymeric substances. The observed mineral phases varied between films collected in different years with magnetite (Fe 2+Fe 2 3+O 4) nanoparticles (<5 nm) predominantly identified in the 2016 films, while for films collected in 2017 ferrihydrite-like amorphous iron oxyhydroxides were found. While the exact formation mechanism of these Artic iron oxide films remains to be explored, the presence of magnetite and other iron oxide/oxyhydroxide nanoparticles at the air–water interface may represent a previously unknown source of electron acceptors for continual anaerobic microbial respiration of organic carbon within poorly drained Arctic tundra.« less

Characterization of iron oxide nanoparticle films at the air–water interface in Arctic tundra waters

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

Jubb, Aaron M.; Eskelsen, Jeremy R.; Yin, Xiangping Lisa

Here, massive amounts of organic carbon have accumulated in Arctic permafrost and soils due to anoxic and low temperature conditions that limit aerobic microbial respiration. Alternative electron acceptors are thus required for microbes to degrade organic carbon in these soils. Iron or iron oxides have been recognized to play an important role in carbon cycle processes in Arctic soils, although the exact form and role as an electron acceptor or donor remain poorly understood. Here, Arctic biofilms collected during the summers of 2016 and 2017 from tundra surface waters on the Seward Peninsula of western Alaska were characterized with amore » suite of microscopic and spectroscopic methods. We hypothesized that these films contain redox-active minerals bound to biological polymers. The major components of the films were found to be iron oxide nanoparticle aggregates associated with extracellular polymeric substances. The observed mineral phases varied between films collected in different years with magnetite (Fe 2+Fe 2 3+O 4) nanoparticles (<5 nm) predominantly identified in the 2016 films, while for films collected in 2017 ferrihydrite-like amorphous iron oxyhydroxides were found. While the exact formation mechanism of these Artic iron oxide films remains to be explored, the presence of magnetite and other iron oxide/oxyhydroxide nanoparticles at the air–water interface may represent a previously unknown source of electron acceptors for continual anaerobic microbial respiration of organic carbon within poorly drained Arctic tundra.« less

Modeling fMRI signals can provide insights into neural processing in the cerebral cortex

PubMed Central

Sharifian, Fariba; Heikkinen, Hanna; Vigário, Ricardo

2015-01-01

Every stimulus or task activates multiple areas in the mammalian cortex. These distributed activations can be measured with functional magnetic resonance imaging (fMRI), which has the best spatial resolution among the noninvasive brain imaging methods. Unfortunately, the relationship between the fMRI activations and distributed cortical processing has remained unclear, both because the coupling between neural and fMRI activations has remained poorly understood and because fMRI voxels are too large to directly sense the local neural events. To get an idea of the local processing given the macroscopic data, we need models to simulate the neural activity and to provide output that can be compared with fMRI data. Such models can describe neural mechanisms as mathematical functions between input and output in a specific system, with little correspondence to physiological mechanisms. Alternatively, models can be biomimetic, including biological details with straightforward correspondence to experimental data. After careful balancing between complexity, computational efficiency, and realism, a biomimetic simulation should be able to provide insight into how biological structures or functions contribute to actual data processing as well as to promote theory-driven neuroscience experiments. This review analyzes the requirements for validating system-level computational models with fMRI. In particular, we study mesoscopic biomimetic models, which include a limited set of details from real-life networks and enable system-level simulations of neural mass action. In addition, we discuss how recent developments in neurophysiology and biophysics may significantly advance the modelling of fMRI signals. PMID:25972586

Modeling fMRI signals can provide insights into neural processing in the cerebral cortex.

PubMed

Vanni, Simo; Sharifian, Fariba; Heikkinen, Hanna; Vigário, Ricardo

2015-08-01

Every stimulus or task activates multiple areas in the mammalian cortex. These distributed activations can be measured with functional magnetic resonance imaging (fMRI), which has the best spatial resolution among the noninvasive brain imaging methods. Unfortunately, the relationship between the fMRI activations and distributed cortical processing has remained unclear, both because the coupling between neural and fMRI activations has remained poorly understood and because fMRI voxels are too large to directly sense the local neural events. To get an idea of the local processing given the macroscopic data, we need models to simulate the neural activity and to provide output that can be compared with fMRI data. Such models can describe neural mechanisms as mathematical functions between input and output in a specific system, with little correspondence to physiological mechanisms. Alternatively, models can be biomimetic, including biological details with straightforward correspondence to experimental data. After careful balancing between complexity, computational efficiency, and realism, a biomimetic simulation should be able to provide insight into how biological structures or functions contribute to actual data processing as well as to promote theory-driven neuroscience experiments. This review analyzes the requirements for validating system-level computational models with fMRI. In particular, we study mesoscopic biomimetic models, which include a limited set of details from real-life networks and enable system-level simulations of neural mass action. In addition, we discuss how recent developments in neurophysiology and biophysics may significantly advance the modelling of fMRI signals. Copyright © 2015 the American Physiological Society.

Poverty and behavior problems trajectories from 1.5 to 8 years of age: Is the gap widening between poor and non-poor children?

PubMed

Mazza, Julia Rachel S E; Boivin, Michel; Tremblay, Richard E; Michel, Gregory; Salla, Julie; Lambert, Jean; Zunzunegui, Maria Victoria; Côté, Sylvana M

2016-08-01

Poverty has been associated with high levels of behavior problems across childhood, yet patterns of associations over time remain understudied. This study aims: (a) to examine whether poverty predicts changes in behavior problems between 1.5 and 8 years of age; (b) to estimate potential selection bias for the observed associations. We used the 1998-2006 waves of the Quebec Longitudinal Study of Child Development (N = 2120). Main outcomes were maternal ratings of hyperactivity, opposition and physical aggression from 1.5 to 8 years of age. Linear mixed-effects models were used to assess the longitudinal association between poverty and behavior problems. Models were re-estimated adjusting for wave nonresponse and using multiple imputation to account for attrition. Poverty predicted higher levels of behavior problems between 1.5 and 8 years of age. Poverty predicted hyperactivity and opposition in a time dependent manner. Hyperactivity [Bpoverty*age = 0.052; CI 95 % (0.002; 0.101)] and opposition [Bpoverty*age = 0.049; CI 95 % (0.018; 0.079)] increased at a faster rate up to age 5 years, and then decreased at a slower rate for poor than non-poor children. Physical aggression decreased at a steady rate over time for all children [Bpoverty*age = -0.030; p = 0.064). Estimates remained similar when accounting for attrition. Poverty predicted higher levels of behavior problems between 1.5 and 8 years of age. The difference between poor and non-poor children was stable over time for physical aggression, but increased with age for hyperactivity and opposition. Attrition among poor children did not compromise the validity of results.

Natural History of the Neotropical Arboreal Ant, Odontomachus hastatus: Nest Sites, Foraging Schedule, and Diet

PubMed Central

Camargo, Rafael X.; Oliveira, Paulo S.

2012-01-01

The ecology of most arboreal ants remains poorly documented because of the difficulty in accessing ant nests and foragers in the forest canopy. This study documents the nesting and foraging ecology of a large (∼13 mm total length) arboreal trap—jaw ant, Odontomachus hastatus (Fabricius) (Hymenoptera: Formicidae) in a sandy plain forest on Cardoso Island, off the coast of Southeast Brazil. The results showed that O. hastatus nested in root clusters of epiphytic bromeliads, most commonly Vriesea procera (70% of nest plants). Mature O. hastatus colonies include one to several queens and about 500 workers. Foraging by O. hastatus is primarily nocturnal year—round, with increased foraging activity during the wet/warm season. The foragers hunt singly in the trees, preying on a variety of canopy—dwelling arthropods, with flies, moths, ants, and spiders accounting for > 60% of the prey captured. Although predators often have impacts on prey populations, the ecological importance of O. hastatus remains to be studied. PMID:22957686

The market for precedent: shifting visions of the role of clinical negligence claims and trials.

PubMed

Mulcahy, Linda

2014-01-01

This article considers the interface between the standard setting activity of the NHS Litigation Authority, and the courts and uses the clinical negligence action as a prism through which to examine it. It is suggested that despite its many disadvantages, the clinical negligence action remains an important safety valve when internal regulatory systems fail or are insufficiently transparent to gain full legitimacy. More specifically, it explores the ways in which attitudes about the usefulness of the data contained in claims against the NHS have changed in the aftermath of a number of high profile inquiries which have focused on issues of poor performance. The article concludes that while much greater use is now been made of the data contained in claims when setting standards, strategies for prompting judicial precedent as an alternative way of mobilising standard setting behaviour remain under developed. © The Author 2014. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prevention and management of post-instability glenohumeral arthropathy

PubMed Central

Waterman, Brian R; Kilcoyne, Kelly G; Parada, Stephen A; Eichinger, Josef K

2017-01-01

Post-instability arthropathy may commonly develop in high-risk patients with a history of recurrent glenohumeral instability, both with and without surgical stabilization. Classically related to anterior shoulder instability, the incidence and rates of arthritic progression may vary widely. Radiographic arthritic changes may be present in up to two-thirds of patients after primary Bankart repair and 30% after Latarjet procedure, with increasing rates associated with recurrent dislocation history, prominent implant position, non-anatomic reconstruction, and/or lateralized bone graft placement. However, the presence radiographic arthrosis does not predict poor patient-reported function. After exhausting conservative measures, both joint-preserving and arthroplasty surgical options may be considered depending on a combination of patient-specific and anatomic factors. Arthroscopic procedures are optimally indicated for individuals with focal disease and may yield superior symptomatic relief when combined with treatment of combined shoulder pathology. For more advanced secondary arthropathy, total shoulder arthroplasty remains the most reliable option, although the clinical outcomes, wear characteristics, and implant survivorship remains a concern among active, young patients. PMID:28361016

Iron deposition and inflammation in multiple sclerosis. Which one comes first?

PubMed Central

2011-01-01

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor. PMID:21699686

Deep-biosphere methane production stimulated by geofluids in the Nankai accretionary complex

PubMed Central

Kubo, Yusuke; Hoshino, Tatsuhiko; Sakai, Sanae; Arnold, Gail L.; Case, David H.; Lever, Mark A.; Morita, Sumito; Nakamura, Ko-ichi

2018-01-01

Microbial life inhabiting subseafloor sediments plays an important role in Earth’s carbon cycle. However, the impact of geodynamic processes on the distributions and carbon-cycling activities of subseafloor life remains poorly constrained. We explore a submarine mud volcano of the Nankai accretionary complex by drilling down to 200 m below the summit. Stable isotopic compositions of water and carbon compounds, including clumped methane isotopologues, suggest that ~90% of methane is microbially produced at 16° to 30°C and 300 to 900 m below seafloor, corresponding to the basin bottom, where fluids in the accretionary prism are supplied via megasplay faults. Radiotracer experiments showed that relatively small microbial populations in deep mud volcano sediments (102 to 103 cells cm−3) include highly active hydrogenotrophic methanogens and acetogens. Our findings indicate that subduction-associated fluid migration has stimulated microbial activity in the mud reservoir and that mud volcanoes may contribute more substantially to the methane budget than previously estimated. PMID:29928689

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

PubMed

Prinzing, Brooke L; Gottschalk, Stephen M; Krenciute, Giedre

2018-05-01

The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.

The cleaved FAS ligand activates the Na(+)/H(+) exchanger NHE1 through Akt/ROCK1 to stimulate cell motility.

PubMed

Monet, Michael; Poët, Mallorie; Tauzin, Sébastien; Fouqué, Amélie; Cophignon, Auréa; Lagadic-Gossmann, Dominique; Vacher, Pierre; Legembre, Patrick; Counillon, Laurent

2016-06-15

Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na(+)/H(+) exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways.

ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling

PubMed Central

Chakrabarti, Rumela; Wei, Yong; Hwang, Julie; Hang, Xiang; Blanco, Mario Andres; Choudhury, Abrar; Tiede, Benjamin; Romano, Rose-Anne; DeCoste, Christina; Mercatali, Laura; Ibrahim, Toni; Amadori, Dino; Kannan, Nagarajan; Eaves, Connie J; Sinha, Satrajit; Kang, Yibin

2014-01-01

Emerging evidence suggests that cancer is populated and maintained by tumor initiating cells (TICs) with stem-like properties similar to that of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signaling. Importantly, Fzd7-dependent enhancement of Wnt signaling by ΔNp63 also governs tumor initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms. PMID:25241036

NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations.

PubMed

Mortimer, Leanne; Moreau, France; MacDonald, Justin A; Chadee, Kris

2016-10-01

Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape.

PubMed

Lloret-Fernández, Carla; Maicas, Miren; Mora-Martínez, Carlos; Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter; Flames, Nuria

2018-03-22

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis -regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans . Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. © 2018, Lloret-Fernández et al.

Formal Models of the Network Co-occurrence Underlying Mental Operations.

PubMed

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-06-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition.

Animal behaviour and algal camouflage jointly structure predation and selection.

PubMed

Start, Denon

2018-05-01

Trait variation can structure interactions between individuals, thus shaping selection. Although antipredator strategies are an important component of many aquatic systems, how multiple antipredator traits interact to influence consumption and selection remains contentious. Here, I use a common larval dragonfly (Epitheca canis) and its predator (Anax junius) to test for the joint effects of activity rate and algal camouflage on predation and survival selection. I found that active and poorly camouflaged Epitheca were more likely to be consumed, and thus, survival selection favoured inactive and well-camouflaged individuals. Notably, camouflage dampened selection on activity rate, likely by reducing attack rates when Epitheca encountered a predator. Correlational selection is therefore conferred by the ecological interaction of traits, rather than by opposing selection acting on linked traits. I suggest that antipredator traits with different adaptive functions can jointly structure patterns of consumption and selection. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.

Electrochemically active, crystalline, mesoporous covalent organic frameworks on carbon nanotubes for synergistic lithium-ion battery energy storage

PubMed Central

Xu, Fei; Jin, Shangbin; Zhong, Hui; Wu, Dingcai; Yang, Xiaoqing; Chen, Xiong; Wei, Hao; Fu, Ruowen; Jiang, Donglin

2015-01-01

Organic batteries free of toxic metal species could lead to a new generation of consumer energy storage devices that are safe and environmentally benign. However, the conventional organic electrodes remain problematic because of their structural instability, slow ion-diffusion dynamics, and poor electrical conductivity. Here, we report on the development of a redox-active, crystalline, mesoporous covalent organic framework (COF) on carbon nanotubes for use as electrodes; the electrode stability is enhanced by the covalent network, the ion transport is facilitated by the open meso-channels, and the electron conductivity is boosted by the carbon nanotube wires. These effects work synergistically for the storage of energy and provide lithium-ion batteries with high efficiency, robust cycle stability, and high rate capability. Our results suggest that redox-active COFs on conducting carbons could serve as a unique platform for energy storage and may facilitate the design of new organic electrodes for high-performance and environmentally benign battery devices. PMID:25650133

Formal Models of the Network Co-occurrence Underlying Mental Operations

PubMed Central

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-01-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition. PMID:27310288

Activation of the c-Met pathway mobilizes an inflammatory network in the brain microenvironment to promote brain metastasis of breast cancer

PubMed Central

Xing, Fei; Liu, Yin; Sharma, Sambad; Wu, Kerui; Chan, Michael D.; Lo, Hui-Wen; Carpenter, Richard L.; Metheny-Barlow, Linda J.; Zhou, Xiaobo; Qasem, Shadi A.; Pasche, Boris; Watabe, Kounosuke

2016-01-01

Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remains poorly understood. Here we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL-8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle which generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. PMID:27364556

Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.

PubMed

Petrie, Emma J; Sandow, Jarrod J; Jacobsen, Annette V; Smith, Brian J; Griffin, Michael D W; Lucet, Isabelle S; Dai, Weiwen; Young, Samuel N; Tanzer, Maria C; Wardak, Ahmad; Liang, Lung-Yu; Cowan, Angus D; Hildebrand, Joanne M; Kersten, Wilhelmus J A; Lessene, Guillaume; Silke, John; Czabotar, Peter E; Webb, Andrew I; Murphy, James M

2018-06-21

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.

The tumour suppressor CYLD regulates the p53 DNA damage response

PubMed Central

Fernández-Majada, Vanesa; Welz, Patrick-Simon; Ermolaeva, Maria A.; Schell, Michael; Adam, Alexander; Dietlein, Felix; Komander, David; Büttner, Reinhard; Thomas, Roman K.; Schumacher, Björn; Pasparakis, Manolis

2016-01-01

The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-κB, MAP kinase and Wnt signalling. However, the tumour suppressing mechanisms of CYLD remain poorly understood. Here we show that loss of CYLD catalytic activity causes impaired DNA damage-induced p53 stabilization and activation in epithelial cells and sensitizes mice to chemical carcinogen-induced intestinal and skin tumorigenesis. Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress. Ubiquitin chain-restriction analysis provides evidence that CYLD removes K48 ubiquitin chains from p53 indirectly by cleaving K63 linkages, suggesting that p53 is decorated with complex K48/K63 chains. Moreover, CYLD deficiency also diminishes CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in the nematode Caenorhabditis elegans. Collectively, our results identify CYLD as a deubiquitinase facilitating DNA damage-induced p53 activation and suggest that regulation of p53 responses to genotoxic stress contributes to the tumour suppressor function of CYLD. PMID:27561390

The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility

PubMed Central

Monet, Michael; Poët, Mallorie; Tauzin, Sébastien; Fouqué, Amélie; Cophignon, Auréa; Lagadic-Gossmann, Dominique; Vacher, Pierre; Legembre, Patrick; Counillon, Laurent

2016-01-01

Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na+/H+ exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways. PMID:27302366

Comparison of Collisional and Electron-Based Dissociation Modes for Middle-Down Analysis of Multiply Glycosylated Peptides

NASA Astrophysics Data System (ADS)

Khatri, Kshitij; Pu, Yi; Klein, Joshua A.; Wei, Juan; Costello, Catherine E.; Lin, Cheng; Zaia, Joseph

2018-04-01

Analysis of singly glycosylated peptides has evolved to a point where large-scale LC-MS analyses can be performed at almost the same scale as proteomics experiments. While collisionally activated dissociation (CAD) remains the mainstay of bottom-up analyses, it performs poorly for the middle-down analysis of multiply glycosylated peptides. With improvements in instrumentation, electron-activated dissociation (ExD) modes are becoming increasingly prevalent for proteomics experiments and for the analysis of fragile modifications such as glycosylation. While these methods have been applied for glycopeptide analysis in isolated studies, an organized effort to compare their efficiencies, particularly for analysis of multiply glycosylated peptides (termed here middle-down glycoproteomics), has not been made. We therefore compared the performance of different ExD modes for middle-down glycopeptide analyses. We identified key features among the different dissociation modes and show that increased electron energy and supplemental activation provide the most useful data for middle-down glycopeptide analysis. [Figure not available: see fulltext.

Detailed kinetics of titanium nitride synthesis

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

Rode, H.; Hlavacek, V.

1995-02-01

A thermogravimetric analyzer is used to study the synthesis of TiN from Ti powder over a wide range of temperature, conversion and heating rate, and for two Ti precursor powders with different morphologies. Conversions to TiN up to 99% are obtained with negligible oxygen contamination. Nonisothermal initial rate and isothermal data are used in a nonlinear least-squares minimization to determine the most appropriate rate law. The logarithmic rate law offers an excellent agreement between the experimental and calculated conversions to TiN and can predict afterburning, which is an important experimentally observed phenomenon. Due to the form of the logarithmic ratemore » law, the observed activation energy is a function of effective particle size, extent of conversion, and temperature even when the intrinsic activation energy remains constant. This aspect explains discrepancies among activation energies obtained in previous studies. The frequently used sedimentation particle size is a poor measure of the powder reactivity. The BET surface area indicates the powder reactivity much better.« less

UV-active plasmons in alkali and alkaline-earth intercalated graphene

NASA Astrophysics Data System (ADS)

Despoja, V.; Marušić, L.

2018-05-01

The interband π and π +σ plasmons in pristine graphene and the Dirac plasmon in doped graphene are not applicable, since they are broad or weak, and weakly couple to an external longitudinal or electromagnetic probe. Therefore, the ab initio density functional theory is used to demonstrate that the chemical doping of the graphene by the alkali or alkaline-earth atoms dramatically changes the poor graphene excitation spectrum in the ultraviolet frequency range (4-10 eV). Four prominent modes are detected. Two of them are the intralayer plasmons with square-root dispersion, characteristic of the two-dimensional modes. The remaining two are the interlayer plasmons, very strong in the long-wavelength limit but damped for larger wave vectors. The optical absorption calculations show that the interlayer plasmons are both optically active, which makes these materials suitable for small-organic-molecule sensing. This is particularly intriguing because the optically active two-dimensional plasmons have not been detected in other materials.

Electrochemically active, crystalline, mesoporous covalent organic frameworks on carbon nanotubes for synergistic lithium-ion battery energy storage.

PubMed

Xu, Fei; Jin, Shangbin; Zhong, Hui; Wu, Dingcai; Yang, Xiaoqing; Chen, Xiong; Wei, Hao; Fu, Ruowen; Jiang, Donglin

2015-02-04

Organic batteries free of toxic metal species could lead to a new generation of consumer energy storage devices that are safe and environmentally benign. However, the conventional organic electrodes remain problematic because of their structural instability, slow ion-diffusion dynamics, and poor electrical conductivity. Here, we report on the development of a redox-active, crystalline, mesoporous covalent organic framework (COF) on carbon nanotubes for use as electrodes; the electrode stability is enhanced by the covalent network, the ion transport is facilitated by the open meso-channels, and the electron conductivity is boosted by the carbon nanotube wires. These effects work synergistically for the storage of energy and provide lithium-ion batteries with high efficiency, robust cycle stability, and high rate capability. Our results suggest that redox-active COFs on conducting carbons could serve as a unique platform for energy storage and may facilitate the design of new organic electrodes for high-performance and environmentally benign battery devices.

GGA3 mediates TrkA endocytic recycling to promote sustained Akt phosphorylation and cell survival

PubMed Central

Li, Xuezhi; Lavigne, Pierre; Lavoie, Christine

2015-01-01

Although TrkA postendocytic sorting significantly influences neuronal cell survival and differentiation, the molecular mechanism underlying TrkA receptor sorting in the recycling or degradation pathways remains poorly understood. Here we demonstrate that Golgi-localized, γ adaptin-ear–containing ADP ribosylation factor-binding protein 3 (GGA3) interacts directly with the TrkA cytoplasmic tail through an internal DXXLL motif and mediates the functional recycling of TrkA to the plasma membrane. We find that GGA3 depletion by siRNA delays TrkA recycling, accelerates TrkA degradation, attenuates sustained NGF-induced Akt activation, and reduces cell survival. We also show that GGA3’s effect on TrkA recycling is dependent on the activation of Arf6. This work identifies GGA3 as a key player in a novel DXXLL-mediated endosomal sorting machinery that targets TrkA to the plasma membrane, where it prolongs the activation of Akt signaling and survival responses. PMID:26446845

Passive antibody-mediated immunotherapy for the treatment of malignant gliomas.

PubMed

Mitra, Siddhartha; Li, Gordon; Harsh, Griffith R

2010-01-01

Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury

PubMed Central

Logan, Mary A.; Hackett, Rachel; Doherty, Johnna; Sheehan, Amy; Speese, Sean D.; Freeman, Marc R.

2012-01-01

Neuronal injury elicits potent cellular responses from glia, but molecular pathways modulating glial activation, phagocytic function, and termination of reactive responses remain poorly defined. Here we show that positive or negative regulation of glial reponses to axon injury are molecularly encoded by unique isoforms of the Drosophila engulfment receptor Draper. Draper-I promotes engulfment of axonal debris through an immunoreceptor tyrosine-based activation motif (ITAM). In contrast, Draper-II, an alternative splice variant, potently inhibits glial engulfment function. Draper-II suppresses Draper-I signaling through a novel immunoreceptor tyrosine-based inhibitory motif (ITIM)-like domain and the tyrosine phosphatase Corkscrew (Csw). Intriguingly, loss of Draper-II/Csw signaling prolongs expression of glial engulfment genes after axotomy and reduces the ability of glia to respond to secondary axotomy. Our work highlights a novel role for Draper-II in inhibiting glial responses to neurodegeneration, and indicates a balance of opposing Draper-I/-II signaling events is essential to maintain glial sensitivity to brain injury. PMID:22426252

Multivariate neural biomarkers of emotional states are categorically distinct

PubMed Central

Kragel, Philip A.

2015-01-01

Understanding how emotions are represented neurally is a central aim of affective neuroscience. Despite decades of neuroimaging efforts addressing this question, it remains unclear whether emotions are represented as distinct entities, as predicted by categorical theories, or are constructed from a smaller set of underlying factors, as predicted by dimensional accounts. Here, we capitalize on multivariate statistical approaches and computational modeling to directly evaluate these theoretical perspectives. We elicited discrete emotional states using music and films during functional magnetic resonance imaging scanning. Distinct patterns of neural activation predicted the emotion category of stimuli and tracked subjective experience. Bayesian model comparison revealed that combining dimensional and categorical models of emotion best characterized the information content of activation patterns. Surprisingly, categorical and dimensional aspects of emotion experience captured unique and opposing sources of neural information. These results indicate that diverse emotional states are poorly differentiated by simple models of valence and arousal, and that activity within separable neural systems can be mapped to unique emotion categories. PMID:25813790

Are Stage of Change constructs relevant for subjective oral health in a vulnerable population?

PubMed

Jamieson, L M; Parker, E J; Broughton, J; Lawrence, H P; Armfield, J M

2015-06-01

Stage of Change constructs may be proxy markers of psychosocial health which, in turn, are related to oral health. To determine if Stage of Change constructs were associated with subjective oral health in a population at heightened risk of dental disease. Stage of Change constructs were developed from a validated 18-item scale and categorised into 'Pre-contemplative', 'Contemplative' and 'Active'. A convenience sample of 446 Australian non-Aboriginal women pregnant by an Aboriginal male (age range 14-43 years) provided data to evaluate the outcome variables (self-rated oral health and oral health impairment), the Stage of Change constructs and socio-demographic, behavioural and access-related factors. Factors significant at the p < 0.05 level in bivariate analysis were entered into prevalence regression models. Approximately 54% of participants had fair/poor self-rated oral health and 34% had oral health impairment. Around 12% were 'Pre-contemplative', 46% 'Contemplative' and 42% 'Active'. Being either 'pre-contemplative' or 'contemplative' was associated with poor self-rated oral health after adjusting for socio-demographic factors. 'Pre-contemplative' ceased being significant after adjusting for dentate status and dental behaviour. 'Pre-contemplative' remained significant when adjusting for dental cost, but not 'Contemplative'. The Stages of Change constructs ceased being associated with self-rated oral health after adjusting for all confounders. Only 'Contemplative' (reference: 'Active') was a risk indicator in the null model for oral health impairment which persisted after adding dentate status, dental behaviour and dental cost variables, but not socio-demographics. When adjusting for all confounders, 'Contemplative' was not a risk indicator for oral health impairment. Both the 'Pre-contemplative' and 'Contemplative' Stage of Change constructs were associated with poor self-rated oral health and oral health impairment after adjusting for some, but not all, covariates. When considered as a proxy marker of psychosocial health, Stage of Change constructs may have some relevance for subjective oral health.

Soil Tillage as a Factor of Soil Conservation

NASA Astrophysics Data System (ADS)

Sherer, D. V.; Chumanova, N. N.

2017-05-01

The work describes the question of the soil treatment system influence on agro-physical and microbiological properties of gray forest soils, and yield of barley in Western Siberia. Research works were carried out in 2013-2014 in Yaya region of the Kemerovo region. Tillage affects soil structure. The water stability in zero tillage conditions was poor (15.7%). Soil density corresponding to the optimum rate for barley is formed by the zonal processing system, while at the zero tillage soil remains solid. The best indicators of phosphataze, catalysis and amylase activity are formed with minimum processing system. In the experiment the highest yield of barley was obtained with minimum tillage - 12.1 c/ha.

Analysis of Actin-Based Intracellular Trafficking in Pollen Tubes.

PubMed

Jiang, Yuxiang; Zhang, Meng; Huang, Shanjin

2017-01-01

Underlying rapid and directional pollen tube growth is the active intracellular trafficking system that carries materials necessary for cell wall synthesis and membrane expansion to the expanding point of the pollen tube. The actin cytoskeleton has been shown to control various intracellular trafficking events in the pollen tube, but the underlying cellular and molecular mechanisms remain poorly understood. To better understand how the actin cytoskeleton is involved in the regulation of intracellular trafficking events, we need to establish assays to visualize and quantify the distribution and dynamics of organelles, vesicles, or secreted proteins. In this chapter, we introduce methods regarding the visualization and quantification of the distribution and dynamics of organelles or vesicles in pollen tubes.

Evolutionary traps as keys to understanding behavioral maladaptation

USGS Publications Warehouse

Robertson, Bruce A.; Chalfoun, Anna

2016-01-01

Evolutionary traps are severe cases of behavioral maladaptation that occur when, due to human activity, the cues animals use to guide their behavior become uncoupled from their fitness consequences. The result is that animals can prefer the most dangerous resources or behaviors, even when better options are available. Traps are increasingly common and represent a significant wildlife conservation problem. Understanding of the more proximate sensory-cognitive mechanisms underpinning traps remains poor, which highlights the need for interdisciplinary and collaborative approaches to investigating traps. Key to advancing basic trap theory and its conservation applications will be the development of appropriate and tractable model systems to investigate the mechanisms that cause traps within species, and how mechanisms vary across species.

WntD and Diedel: Two immunomodulatory cytokines in Drosophila immunity.

PubMed

Lamiable, Olivier; Meignin, Carine; Imler, Jean-Luc

2016-10-01

Remarkable progress has been made on the understanding of the basic mechanisms of innate immunity in flies, from sensing infection to production of effector molecules. However, how the immune response is orchestrated at the level of the organism remains poorly understood. While cytokines activating immune responses, such as Spaetzle or Unpaired-3, have been identified and characterized in Drosophila, much less is known regarding immunosuppressor cytokines. In a recent publication, we reported the identification of a novel cytokine, Diedel, which acts as systemic negative regulator of the IMD pathway. Here, we discuss the similarities between Diedel and WntD, another immunomodulatory cytokine and present evidence that the 2 molecules act independently from one another.

The Use of Radiation Response (RR) in Selecting the Method of Treatment of Carcinoma Cervicis Uteri

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

Chesterman, John N.

1963-03-01

Attempts were made to determine the choice treatment of cervical squamous carcinoma (surgery, radiation, or surgery with radiation) in Stages I and II. A study of 50 patients showed good results from surgery in patients with poor radiation response (RR) and that the RR, estimated by a precise and uniform technique, will identify those patients who will not respond well to complete radiation therapy. Moreover, it will do this after a first radium application of moderate dosage, at a time when it is still possible to interrupt this therapy. A radiation dose of at least 1000 r at the cervixmore » will be followed by the maximum RR, in a good response, between the 8th and 14th (especially 10th to 12th) days. A poor RR will reach its maximum earlier than a good one, on about the 10th day after radium implantation. When deciding the definition of good RR, it was found that the radiation changes present in a count of 100 cells were seen in more than 70 cells. There is evidence that age, menopause, and hormonal status influence the radiation reaction. If poor RR is more frequently found with high estrogenic activity, young patients treated by radiation should be expected to have a worse survival rate than old. The survival rate is about 1/3) in the young patient as against 1/2 in the postmenopausal. A good sensitization response (SR) was, in most cases, followed by good RR after radiation. Of 39 patients with good SR, 34 had good RR after one application of radium. However, this correlation was absent when the SR was poor. Of 41 patients with poor SR, 18 remained poor after radiation and 23 developed good RR. Finally, this SR should not be taken alone as a guide to treatment, but all patients should be given the first radium application and the RR assessed.« less

Management of metastatic renal cell carcinoma patients with poor-risk features: current status and future perspectives.

PubMed

Santoni, Matteo; De Tursi, Michele; Felici, Alessandra; Lo Re, Giovanni; Ricotta, Riccardo; Ruggeri, Enzo Maria; Sabbatini, Roberto; Santini, Daniele; Vaccaro, Vanja; Milella, Michele

2013-06-01

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Factors associated with changes in mobility and living arrangements in a comprehensive geriatric outpatient assessment after hip fracture.

PubMed

Nuotio, Maria; Luukkaala, Tiina

2016-01-01

To examine factors associated with changes in mobility and living arrangements in a comprehensive geriatric outpatient assessment after hip fracture. Population-based prospective data on 887 consecutive hip fracture patients aged 65 years and older. The domains of the geriatric assessment were the independent and changes in mobility level and living arrangements 4 months postoperatively the outcome variables. Of the survivors, 499 (73%) attended the assessment. The mobility level had declined in 39% of the attendees and 38% of them had moved to more supported living arrangements 4 months after the hip fracture. In the age-adjusted univariate logistic regression analyses, almost all the domains of the comprehensive geriatric assessment were significantly associated with both outcomes. In the forward stepwise multivariate analysis, disability in activities of daily living, poor performance in Timed Up and Go and comorbidity as measured by the American Society of Anesthesiologists scores remained significantly associated with the outcomes. While comorbidity and disability in activities of daily living and mobility are the major indicators of poor outcomes of mobility and living arrangements after hip fracture, all the domains in the comprehensive geriatric assessment deserve attention during hip fracture care and rehabilitation. In almost half of the patients the mobility level and living arrangements had deteriorated 4 months after the hip fracture, suggesting an urgent need for more effective postoperative rehabilitation. Almost all the domains of the comprehensive geriatric assessment were associated with poor outcomes and require equal attention during the acute and postacute phases of hip fracture care and in the course of rehabilitation. A geriatric outpatient assessment a few months after the hip fracture provides a check-point for the outcomes and an opportunity to target interventions at different domains of the comprehensive assessment.

Influence of iron redox cycling on organo-mineral associations in arctic tundra soils

NASA Astrophysics Data System (ADS)

Herndon, E.; AlBashaireh, A.; Duroe, K.; Singer, D. M.

2016-12-01

Geochemical interactions between soil organic matter and minerals influence decomposition in many environments but remain poorly understood in arctic tundra systems. In tundra soils that are periodically to persistently saturated, the accumulation of iron oxyhydroxides and organo-iron precipitates at redox interfaces may inhibit decomposition by binding organic molecules and protecting them from microbial degradation. Here, we couple synchrotron-source spectroscopic techniques with chemical sequential extractions and physical density fractionations to evaluate the spatial distribution and speciation of Fe-bearing phases and associated organic matter in organic and mineral horizons of the seasonally thawed active layer in tundra soils from northern Alaska. Mineral-associated organic matter comprised 63 ± 9% of soil organic carbon stored in the active layer of ice wedge polygons. Ferrous iron produced in anoxic mineral horizons diffused upwards and precipitated as poorly-crystalline oxyhydroxides and organic-bound Fe(III) in the organic horizons. Ferrihydrite and goethite were present as coatings on mineral grains and plant debris and in aggregates with clays and particulate organic matter. Organic matter released through acid-dissolution of iron oxides may represent a small pool of readily-degradable organic molecules temporarily stabilized by sorption to iron oxyhydroxide surfaces, while larger quantities of particulate organic carbon and humic-like substances may be physically protected from decomposition by Fe-oxide coatings and aggregation. We conclude that formation of poorly-crystalline and crystalline iron oxides at redox interfaces contributes to mineral protection of organic matter through sorption, aggregation, and co-precipitation reactions. Further study of organo-mineral associations is necessary to determine the net impact of mineral-stabilization on carbon storage in rapidly warming arctic ecosystems.

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

PubMed

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

Problems Caused by Microbes and Treatment Strategies Anaerobic Hydrocarbon Biodegradation and Biocorrosion: A Case Study

NASA Astrophysics Data System (ADS)

Suflita, Joseph M.; Duncan, Kathleen E.

The anaerobic biodegradation of petroleum hydrocarbons is important for the intrinsic remediation of spilt fuels (Gieg and Suflita, 2005), for the conversion of hydrocarbons to clean burning natural gas (Gieg et al., 2008; Jones et al., 2008) and for the fundamental cycling of carbon on the planet (Caldwell et al., 2008). However, the same process has also been implicated in a host of difficult problems including reservoir souring (Jack and Westlake, 1995), oil viscosity alteration (Head et al., 2003), compromised equipment performance and microbiologically influenced corrosion (Duncan et al., 2009). Herein, we will focus on the role of anaerobic microbial communities in catalysing biocorrosion activities in oilfield facilities. Biocorrosion is a costly problem that remains relatively poorly understood. Understanding of the underlying mechanisms requires reliable information on the carbon and energy sources supporting biofilm microorganisms capable of catalysing such activities.

Microtubule-dependent regulation of mitotic protein degradation

PubMed Central

Song, Ling; Craney, Allison; Rape, Michael

2014-01-01

Accurate cell division depends on tightly regulated ubiquitylation events catalyzed by the anaphase-promoting complex. Among its many substrates, the APC/C triggers the degradation of proteins that stabilize the mitotic spindle, and loss or accumulation of such spindle assembly factors can result in aneuploidy and cancer. Although critical for cell division, it has remained poorly understood how the timing of spindle assembly factor degradation is established during mitosis. Here, we report that active spindle assembly factors are protected from APC/C-dependent degradation by microtubules. In contrast, those molecules that are not bound to microtubules are highly susceptible to proteolysis and turned over immediately after APC/C-activation. The correct timing of spindle assembly factor degradation, as achieved by this regulatory circuit, is required for accurate spindle structure and function. We propose that the localized stabilization of APC/C-substrates provides a mechanism for the selective disposal of cell cycle regulators that have fulfilled their mitotic roles. PMID:24462202

Transition from direct to inverted charge transport Marcus regions in molecular junctions via molecular orbital gating

NASA Astrophysics Data System (ADS)

Yuan, Li; Wang, Lejia; Garrigues, Alvar R.; Jiang, Li; Annadata, Harshini Venkata; Anguera Antonana, Marta; Barco, Enrique; Nijhuis, Christian A.

2018-04-01

Solid-state molecular tunnel junctions are often assumed to operate in the Landauer regime, which describes essentially activationless coherent tunnelling processes. In solution, on the other hand, charge transfer is described by Marcus theory, which accounts for thermally activated processes. In practice, however, thermally activated transport phenomena are frequently observed also in solid-state molecular junctions but remain poorly understood. Here, we show experimentally the transition from the Marcus to the inverted Marcus region in a solid-state molecular tunnel junction by means of intra-molecular orbital gating that can be tuned via the chemical structure of the molecule and applied bias. In the inverted Marcus region, charge transport is incoherent, yet virtually independent of temperature. Our experimental results fit well to a theoretical model that combines Landauer and Marcus theories and may have implications for the interpretation of temperature-dependent charge transport measurements in molecular junctions.

From Embryonic Development to Human Diseases: The Functional Role of Caveolae/Caveolin

PubMed Central

Sohn, Jihee; Brick, Rachel M.; Tuan, Rocky S.

2017-01-01

Caveolae, an almost ubiquitous, structural component of the plasma membrane, play a critical role in many functions essential for proper cell function, including membrane trafficking, signal transduction, extracellular matrix remodeling, and tissue regeneration. Three main types of caveolin proteins have been identified from caveolae since the discovery of caveolin-1 in the early 1990s. All three (Cav-1, Cav-2, and Cav-3) play crucial roles in mammalian physiology, and can effect pathogenesis in a wide range of human diseases. While many biological activities of caveolins have been uncovered since its discovery, their role and regulation in embryonic develop remain largely poorly understood, although there is increasing evidence that caveolins may be linked to lung and brain birth defects. Further investigations are clearly needed to decipher how caveolae/caveolins mediate cellular functions and activities of normal embryogenesis and how their perturbations contribute to developmental disorders. PMID:26991990

Role of the superior colliculus in choosing mixed-strategy saccades.

PubMed

Thevarajah, Dhushan; Mikulić, Areh; Dorris, Michael C

2009-02-18

Game theory outlines optimal response strategies during mixed-strategy competitions. The neural processes involved in choosing individual strategic actions, however, remain poorly understood. Here, we tested whether the superior colliculus (SC), a brain region critical for generating sensory-guided saccades, is also involved in choosing saccades under strategic conditions. Monkeys were free to choose either of two saccade targets as they competed against a computer opponent during the mixed-strategy game "matching pennies." The accuracy with which presaccadic SC activity predicted upcoming choice gradually increased in the time leading up to the saccade. Probing the SC with suprathreshold stimulation demonstrated that these evolving signals were functionally involved in preparing strategic saccades. Finally, subthreshold stimulation of the SC increased the likelihood that contralateral saccades were selected. Together, our results suggest that motor regions of the brain play an active role in choosing strategic actions rather than passively executing those prespecified by upstream executive regions.

Nuclear Matrix Association: Switching to the Invasive Cytotrophoblast

PubMed Central

Drennan, Kathryn J.; Linnemann, Amelia K.; Platts, Adrian E.; Heng, Henry H.; Armant, D. Randall; Krawetz, Stephen A.

2010-01-01

Abnormal trophoblast invasion is associated with the most common and most severe complications of human pregnancy. The biology of invasion, as well as the etiology of abnormal invasion remains poorly understood. The aim of this study was to characterize the transcriptome of the HTR-8/SVneo human cytotrophoblast cell line which displays well characterized invasive and non-invasive behavior, and to correlate the activity of the transcriptome with nuclear matrix attachment and cell phenotype. Comparison of the invasive to non-invasive HTR transcriptomes was unremarkable. In contrast, comparison of the MARs on chromosomes 14–18 revealed an increased number of MARs associated with the invasive phenotype. These attachment areas were more likely to be associated with silent rather than actively transcribed genes. This study supports that view that that nuclear matrix attachment may play an important role in cytotrophoblast invasion by ensuring specific silencing that facilitates invasion. PMID:20346505

POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation.

PubMed

Ma, Xianjue; Guo, Xiaowei; Richardson, Helena E; Xu, Tian; Xue, Lei

2018-02-27

The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in Drosophila POSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila .

Membrane potential correlates of sensory perception in mouse barrel cortex.

PubMed

Sachidhanandam, Shankar; Sreenivasan, Varun; Kyriakatos, Alexandros; Kremer, Yves; Petersen, Carl C H

2013-11-01

Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50-400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.

Prospects for TIM3-Targeted Antitumor Immunotherapy.

PubMed

Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J

2011-11-01

New insights into the control of T-cell activation and proliferation have led to the identification of checkpoint proteins that either up- or downmodulate T-cell reactivity. Monoclonal antibody immunotherapies that are reactive with cytotoxic T lymphocyte antigen 4 or programmed death receptor 1 have shown promising therapeutic outcomes in mice and humans with established cancer, highlighting the fact that cancer immunotherapy using T-cell checkpoint inhibitors is one of the most promising new therapeutic approaches. T-cell immunoglobulin and mucin domain 3 (TIM3) is one of many similar inhibitory molecules that are gaining attention as targets, but it remains relatively poorly studied in oncology. This review discusses our recent probing of the mechanism of action of anti-TIM3 antibody against established spontaneous and experimental tumors in mice, in the context of the exciting possibility of rationally combining agents that promote tumor-specific T-cell activation, proliferation, effector function, and survival. ©2011 AACR.

Regulation of mRNA translation during mitosis.

PubMed

Tanenbaum, Marvin E; Stern-Ginossar, Noam; Weissman, Jonathan S; Vale, Ronald D

2015-08-25

Passage through mitosis is driven by precisely-timed changes in transcriptional regulation and protein degradation. However, the importance of translational regulation during mitosis remains poorly understood. Here, using ribosome profiling, we find both a global translational repression and identified ~200 mRNAs that undergo specific translational regulation at mitotic entry. In contrast, few changes in mRNA abundance are observed, indicating that regulation of translation is the primary mechanism of modulating protein expression during mitosis. Interestingly, 91% of the mRNAs that undergo gene-specific regulation in mitosis are translationally repressed, rather than activated. One of the most pronounced translationally-repressed genes is Emi1, an inhibitor of the anaphase promoting complex (APC) which is degraded during mitosis. We show that full APC activation requires translational repression of Emi1 in addition to its degradation. These results identify gene-specific translational repression as a means of controlling the mitotic proteome, which may complement post-translational mechanisms for inactivating protein function.

Tumor infiltrating lymphocytes in ovarian cancer

PubMed Central

Santoiemma, Phillip P; Powell, Daniel J

2015-01-01

The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. PMID:25894333

Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

PubMed Central

Bartsch, Julia C; Fidzinski, Pawel; Huck, Jojanneke HJ; Hörtnagl, Heide; Kovács, Richard; Liotta, Agustin; Priller, Josef; Wozny, Christian; Behr, Joachim

2015-01-01

Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage-gated Ca2+ channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system. PMID:25315194

Phenformin inhibits cell proliferation and induces cell apoptosis and autophagy in cholangiocarcinoma.

PubMed

Hu, Shuyang; Ouyang, Qing; Cheng, Qingbao; Wang, Jinghan; Feng, Feiling; Qiao, Liang; Gan, Wei; Shi, Yang; Wu, Demin; Jiang, Xiaoqing

2018-04-01

Cholangiocarcinoma (CCA) is an aggressive malignant tumor and the prognosis of patients with advanced stage disease remains poor. Therefore, the identification of novel treatment agents for CCA is required. In the present study, the biological effects of the diabetes therapeutic agent, phenformin, in CCA cell lines was investigated. Cell Counting Kit‑8 cell viability, cellular clone formation and subcutaneous tumor formation assays were performed, which revealed that phenformin inhibited CCA cell proliferation and growth both in vitro and in vivo. In addition, phenformin induced CCA cell apoptosis and autophagy. Phenformin partly activated the liver kinase B1 (LKB1)/5' AMP‑activated protein kinase signaling pathway to exert its biological effects on CCA cell lines, as demonstrated by knockdown of LKB1, which reversed these effects. In conclusion, the present study demonstrated the biological effects of phenformin in CCA and suggested that phenformin may be a potential novel agent for CCA treatment.

The interplay between immunity and aging in Drosophila.

PubMed

Garschall, Kathrin; Flatt, Thomas

2018-01-01

Here, we provide a brief review of the mechanistic connections between immunity and aging-a fundamental biological relationship that remains poorly understood-by considering two intertwined questions: how does aging affect immunity, and how does immunity affect aging? On the one hand, aging contributes to the deterioration of immune function and predisposes the organism to infections ("immuno-senescence"). On the other hand, excessive activation of the immune system can accelerate degenerative processes, cause inflammation and immunopathology, and thus promote aging ("inflammaging"). Interestingly, several recent lines of evidence support the hypothesis that restrained or curbed immune activity at old age (that is, optimized age-dependent immune homeostasis) might actually improve realized immune function and thereby promote longevity. We focus mainly on insights from Drosophila , a powerful genetic model system in which both immunity and aging have been extensively studied, and conclude by outlining several unresolved questions in the field.

Advances in immunotherapy for the treatment of glioblastoma.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Lavelle, Ed C; Prehn, Jochen H M

2017-01-01

Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host's immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic. However, as detailed in this review, strategies aimed at circumventing these challenges are showing promise for GBM treatment; including identification of glioma specific antigens and endogenous immune cell activation in an attempt to overcome the immunosuppressive environment which is associated with GBM tumours. An up-to-date summary of current Phase I/II and ongoing Phase III GBM immunotherapy clinical trials is provided in addition to insights into promising preclinical approaches which are focused predominantly on increased induction of Type 1 helper T cell (T h 1) immune responses within patients.

The nature of the hydroxyapatite-binding site in salivary acidic proline-rich proteins.

PubMed

Bennick, A; Cannon, M; Madapallimattam, G

1979-10-01

Protein A and C, which are major components of the acidic proline-rich proteins in human saliva, were digested, before or after adsorption to hydroxyapatite, with alkaline phosphatase, trypsin, thermolysin and a proteinase preparation from salivary sediment. The results demonstrate that the binding site is located in the proline-poor N-terminal part of the protein, possibly between residues 3 and 25. Phosphoserine is necessary for maximal adsorption of the proteins to hydroxyapatite. When proteins A and C are adsorbed to hydroxyapatite before proteolytic digestion there is a protection of some of the susceptible bonds in the N-terminal part of the proteins and a gradual removal of the proline-rich C-terminal part. Thermolysin can cleave susceptible bonds in the part of the protein that remains bound to hydroxyapatite, but at least some of the resulting peptides are retained on the mineral. Since the ability of the proteins to inhibit hydroxyapatite formation and to bind calcium is located in the N-terminal proline-poor part, it is possible that these activities are retained after proteolytic digestion of the adsorbed proteins.

Photomorphogenic responses to ultraviolet-B light.

PubMed

Jenkins, Gareth I

2017-11-01

Exposure to ultraviolet B (UV-B) light regulates numerous aspects of plant metabolism, morphology and physiology through the differential expression of hundreds of genes. Photomorphogenic responses to UV-B are mediated by the photoreceptor UV RESISTANCE LOCUS8 (UVR8). Considerable progress has been made in understanding UVR8 action: the structural basis of photoreceptor function, how interaction with CONSTITUTIVELY PHOTOMORPHOGENIC 1 initiates signaling and how REPRESSOR OF UV-B PHOTOMORPHOGENESIS proteins negatively regulate UVR8 action. In addition, recent research shows that UVR8 mediates several responses through interaction with other signaling pathways, in particular auxin signaling. Nevertheless, many aspects of UVR8 action remain poorly understood. Most research to date has been undertaken with Arabidopsis, and it is important to explore the functions and regulation of UVR8 in diverse plant species. Furthermore, it is essential to understand how UVR8, and UV-B signaling in general, regulates processes under natural growth conditions. Ultraviolet B regulates the expression of many genes through UVR8-independent pathways, but the activity and importance of these pathways in plants growing in sunlight are poorly understood. © 2017 John Wiley & Sons Ltd.

Constructions and experiences of sexual health among young, heterosexual, unmarried Muslim women immigrants in Australia.

PubMed

Wray, Anneke; Ussher, Jane M; Perz, Janette

2014-01-01

Minority ethnic immigrant women are frequently vulnerable to poor sexual health outcomes, due to poor use of sexual health services, lack of knowledge and social stigma associated with the discussion of sexuality. This paper explores the sexual health accounts provided by a group of young, unmarried heterosexual Muslim women immigrants residing and studying in Sydney, an under-researched group in the Australian context. Ten semi-structured interviews were conducted, focusing on sex before marriage, spouse selection and contraceptive use. Feminist discourse analysis identified 'purity versus corruption' as the primary construction of women's sexuality, where women positioned their sexual behaviour as that of purity and uninvolvement or corruption through unwedded participation. The subthemes 'maintaining ignorance and naivety', 'remaining virginal', 'sex segregation' and 'the fallen woman' capture women's personal sexuality-related experiences and values within the context of their religious and cultural communities. Additional research with this community is needed to examine the effects of negative social constructions of sex on young sexually active Muslim women, as well as further research on young women's sexual health within immigrant communities.

Advances in IBS 2016: A Review of Current and Emerging Data.

PubMed

Schoenfeld, Philip S

2016-08-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide.

Advances in IBS 2016: A Review of Current and Emerging Data

PubMed Central

Schoenfeld, Philip S.

2016-01-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide. PMID:28070176

Identifying sources of acidity and spatial distribution of acid sulfate soils in the Anglesea River catchment, southern Australia

NASA Astrophysics Data System (ADS)

Wong, Vanessa; Yau, Chin; Kennedy, David

2015-04-01

Globally, coastal and estuarine floodplains are frequently underlain by sulfidic sediments. When exposed to oxygen, sulfidic sediments oxidise to form acid sulfate soils, adversely impacting on floodplain health and adjacent aquatic ecoystems. In eastern Australia, our understanding of the formation of these coastal and estuarine floodplains, and hence, spatial distribution of acid sulfate soils, is relatively well established. These soils have largely formed as a result of sedimentation of coastal river valleys approximately 6000 years BP when sea levels were one to two metres higher. However, our understanding of the evolution of estuarine systems and acid sulfate soil formation, and hence, distribution, in southern Australia remains limited. The Anglesea River, in southern Australia, is subjected to frequent episodes of poor water quality and low pH resulting in closure of the river and, in extreme cases, large fish kill events. This region is heavily reliant on tourism and host to a number of iconic features, including the Great Ocean Road and Twelve Apostles. Poor water quality has been linked to acid leakage from mining activities and Tertiary-aged coal seams, peat swamps and acid sulfate soils in the region. However, our understanding of the sources of acidity and distribution of acid sulfate soils in this region remains poor. In this study, four sites on the Anglesea River floodplain were sampled, representative of the main vegetation communities. Peat swamps and intertidal marshes were both significant sources of acidity on the floodplain in the lower catchment. However, acid neutralising capacity provided by carbonate sands suggests that there are additional sources of acidity higher in the catchment. This pilot study has highlighted the complexity in the links between the floodplain, upper catchment and waterways with further research required to understand these links for targeted acid management strategies.

Mechanisms of morphine enhancement of spontaneous seizure activity.

PubMed

Saboory, Ehsan; Derchansky, Miron; Ismaili, Mohammed; Jahromi, Shokrollah S; Brull, Richard; Carlen, Peter L; El Beheiry, Hossam

2007-12-01

High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect. The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.

Stellar activity for every TESS star in the Southern sky

NASA Astrophysics Data System (ADS)

Howard, Ward S.; Law, Nicholas; Fors, Octavi; Corbett, Henry T.; Ratzloff, Jeff; del Ser, Daniel

2018-01-01

Although TESS will search for Earths around more than 200,000 nearby stars, the life-impacting superflare occurrence of these stars remains poorly characterized. We monitor long-term stellar flare occurrence for every TESS star in the accessible sky at 2-minute cadence with the CTIO-based Evryscope, a combination of twenty-four telescopes, together giving instantaneous sky coverage of 8000 square degrees. In collaboration with Owens Valley Long Wavelength Array (LWA) all-sky monitoring, Evryscope also provides optical counterparts to radio flare, CME, and exoplanet-magnetosphere stellar activity searches. A Northern Evryscope will be installed at Mount Laguna Observatory, CA in collaboration with SDSU later this year, enabling stellar activity characterization for the full TESS target list and both continuous viewing zones, as well as providing 100% overlap with LWA radio activity. Targets of interest (e.g. Proxima Cen, TRAPPIST-1) are given special focus. We are currently sensitive to stellar activity down to 1% precision at g' ~ 10 and about 0.2 of a magnitude at g' ~ 15. With 2-minute cadence and a projected 5-year timeline, with 2+ years already recorded, we present preliminary results from an activity characterization of every Southern TESS target.

Keyhole limpet hemocyanin induces innate immunity via Syk and Erk phosphorylation

PubMed Central

Yasuda, Kyoko; Ushio, Hideki

2016-01-01

Hemocyanin is an extracellular respiratory protein containing copper in hemolymph of invertebrates, such as Mollusk and Arthropod. Keyhole limpet hemocyanin (KLH) is one of hemocyanins and has many years of experience for vaccine developments and immunological studies in mammals including human. However, the association between KLH and the immune systems, especially the innate immune systems, remains poorly understood. The aim of this study is to clarify the direct effects of KLH on the innate immune systems. KLH activated an inflammation-related transcription factor NF-κB as much as lipopolysaccharide (LPS) in a human monocytic leukemia THP-1 reporter cell line. We have found that the KLH-induced NF-κB activation is partially involved in a spleen tyrosine kinase (Syk) pathway. We have also successfully revealed that an extracellular signal-regulated kinase (Erk), a member of mitogen-activated protein kinases, is located in an upstream of NF-κB activation induced by KLH. Furthermore, a Syk phosphorylation inhibitor partially suppressed the Erk activation in KLH-stimulated THP-1. These results suggest that both Syk and Erk associate with the KLH-induced NF-κB activation in the human monocyte. PMID:27822175

RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth

PubMed Central

Zindy, Pierre-Joachim; Saba-El-Leil, Marc; Lavoie, Geneviève; Dandachi, Farah; Baptissart, Marine; Borden, Katherine L. B.; Meloche, Sylvain; Roux, Philippe P.

2015-01-01

The Ras/mitogen-activated protein kinase (MAPK) signalling cascade regulates various biological functions, including cell growth, proliferation and survival. As such, this pathway is often deregulated in cancer, including melanomas, which frequently harbour activating mutations in the NRAS and BRAF oncogenes. Hyperactive MAPK signalling is known to promote protein synthesis, but the mechanisms by which this occurs remain poorly understood. Here, we show that expression of oncogenic forms of Ras and Raf promotes the constitutive activation of the mammalian target of rapamycin (mTOR). Using pharmacological inhibitors and RNA interference we find that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) is partly required for these effects. Using melanoma cell lines carrying activating BRAF mutations we show that ERK/RSK signalling regulates assembly of the translation initiation complex and polysome formation, as well as the translation of growth-related mRNAs containing a 5’ terminal oligopyrimidine (TOP) motif. Accordingly, we find that RSK inhibition abrogates tumour growth in mice. Our findings indicate that RSK may be a valuable therapeutic target for the treatment of tumours characterized by deregulated MAPK signalling, such as melanoma. PMID:22797077

Active and passive compliance in an enhanced recovery programme.

PubMed

Thorn, Christopher C; White, Ian; Burch, Jennie; Malietzis, George; Kennedy, Robin; Jenkins, John T

2016-07-01

Enhanced recovery after surgery (ERAS) is a well-established and accepted practice following colorectal surgery and has been demonstrated to reduce hospital length of stay (LOS) and 30-day morbidity. Despite evidence to support the individual elements on which the programme is based, there remains uncertainty as to how many and which of these are required to realise its benefits. Furthermore, elements of an ERAS programme might either precipitate or reflect recovery, in which case compliance could have a role in the improvement or prediction of outcome. A multidimensional prospective database of 799 consecutive patients undergoing colorectal surgery within an established ERAS programme at a single institution was interrogated. After application of exclusion criteria, 614 patients were studied. The novel concept of 'active compliance' is introduced. An ERAS element is classified as 'active' if the participation of the patient is required to achieve its compliance. This contrasts with 'passive' compliance, where an intervention is delivered to the patient without their direct contribution. The short-term surgical outcomes of this cohort are reported with reference to ERAS protocol compliance. Compliance with the passive elements of the programme was higher than with the active elements. Univariate and multivariate analyses demonstrate that poor compliance with active but not passive elements of the programme was significantly associated with major morbidity. Receiver operator characteristic curve analysis demonstrated active compliance to be a stronger predictor of both major morbidity (AUC 0.71 vs. AUC 0.56) and length of stay (AUC 0.83 vs. 0.57) when compared with passive compliance. The results suggest that poor active compliance may be a surrogate marker of morbidity which can be recognised in the early post-operative period. This implies the potential for timely diagnosis and intervention. This aspect of ERAS compliance is clinically relevant yet has achieved scant attention. Independent validation of our observations is required.

Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy.

PubMed

Diamond, E; Molina, A M; Carbonaro, M; Akhtar, N H; Giannakakou, P; Tagawa, S T; Nanus, D M

2015-12-01

Renal cell carcinoma (RCC) is a heterogeneous disease with regards to histology, progression, and response to treatment. Cytotoxic chemotherapy has been extensively studied in metastatic RCC (mRCC). Responses in most studies are modest and the mechanisms of resistance remain poorly understood. Targeted therapies have significantly improved outcomes in mRCC; however, most patients eventually relapse and die of their disease. Early clinical data suggest that combinations of chemotherapy and targeted agents are clinically active and are well tolerated. We reviewed the available literature for published clinical trials incorporating traditional chemotherapeutic agents in the treatment of mRCC. These papers were identified through a Medline search and were included if they employed at least one chemotherapeutic agent in the treatment of mRCC. The literature was also reviewed for information regarding mechanisms of chemotherapy resistance. The data regarding the use of cytotoxic chemotherapy in mRCC consist of small, non-randomized phase I and II studies. The major response proportions with single agent chemotherapies are low but combination regimens either with other cytotoxic agents, cytokines, or targeted agents have demonstrated moderate activity. Disparate trial designs and lack of head to head clinical trials make it difficult to compare the efficacy of chemotherapy with that of immunotherapy or targeted agents. Chemotherapy is particularly useful in patients with collecting duct histology and predominantly sarcomatoid differentiation. Chemotherapy resistance may be mediated by overexpression of p-glycoprotein efflux pumps and the dysregulation of the microtubule-hypoxia inducible factor signaling axis. The role of cytotoxic chemotherapy in the treatment for clear cell RCC remains poorly defined. Cytotoxic chemotherapy is considered a standard of care in patients with mRCC with predominantly sarcomatoid differentiation and collecting duct RCC variants (Motzer et al., 2014). Early trials combining chemotherapy with targeted therapies are generally well tolerated and show clinical activity. A better understanding of the biology of aggressive subsets of RCC and mechanisms of resistance will help elucidate the role of cytotoxic agents in the current treatment paradigm of RCC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

How will melting of ice affect volcanic hazards in the twenty-first century?

PubMed

Tuffen, Hugh

2010-05-28

Glaciers and ice sheets on many active volcanoes are rapidly receding. There is compelling evidence that melting of ice during the last deglaciation triggered a dramatic acceleration in volcanic activity. Will melting of ice this century, which is associated with climate change, similarly affect volcanic activity and associated hazards? This paper provides a critical overview of the evidence that current melting of ice will increase the frequency or size of hazardous volcanic eruptions. Many aspects of the link between ice recession and accelerated volcanic activity remain poorly understood. Key questions include how rapidly volcanic systems react to melting of ice, whether volcanoes are sensitive to small changes in ice thickness and how recession of ice affects the generation, storage and eruption of magma at stratovolcanoes. A greater frequency of collapse events at glaciated stratovolcanoes can be expected in the near future, and there is strong potential for positive feedbacks between melting of ice and enhanced volcanism. Nonetheless, much further research is required to remove current uncertainties about the implications of climate change for volcanic hazards in the twenty-first century.

A landscape-based reconnaissance survey of estrogenic activity in streams of the upper Potomac, upper James, and Shenandoah Rivers, USA.

PubMed

Young, John; Iwanowicz, Luke; Sperry, Adam; Blazer, Vicki

2014-09-01

Endocrine-disrupting compounds (EDCs) are becoming of increasing concern in waterways of the USA and worldwide. What remains poorly understood, however, is how prevalent these emerging contaminants are in the environment and what methods are best able to determine landscape sources of EDCs. We describe the development of a spatially structured sampling design and a reconnaissance survey of estrogenic activity along gradients of land use within sub-watersheds. We present this example as a useful approach for state and federal agencies with an interest in identifying locations potentially impacted by EDCs that warrant more intensive, focused research. Our study confirms the importance of agricultural activities on levels of a measured estrogenic equivalent (E2Eq) and also highlights the importance of other potential sources of E2Eq in areas where intensive agriculture is not the dominant land use. Through application of readily available geographic information system (GIS) data, coupled with spatial statistical analysis, we demonstrate the correlation of specific land use types to levels of estrogenic activity across a large area in a consistent and unbiased manner.

Three-dimensional mapping of microcircuit correlation structure

PubMed Central

Cotton, R. James; Froudarakis, Emmanouil; Storer, Patrick; Saggau, Peter; Tolias, Andreas S.

2013-01-01

Great progress has been made toward understanding the properties of single neurons, yet the principles underlying interactions between neurons remain poorly understood. Given that connectivity in the neocortex is locally dense through both horizontal and vertical connections, it is of particular importance to characterize the activity structure of local populations of neurons arranged in three dimensions. However, techniques for simultaneously measuring microcircuit activity are lacking. We developed an in vivo 3D high-speed, random-access two-photon microscope that is capable of simultaneous 3D motion tracking. This allows imaging from hundreds of neurons at several hundred Hz, while monitoring tissue movement. Given that motion will induce common artifacts across the population, accurate motion tracking is absolutely necessary for studying population activity with random-access based imaging methods. We demonstrate the potential of this imaging technique by measuring the correlation structure of large populations of nearby neurons in the mouse visual cortex, and find that the microcircuit correlation structure is stimulus-dependent. Three-dimensional random access multiphoton imaging with concurrent motion tracking provides a novel, powerful method to characterize the microcircuit activity in vivo. PMID:24133414

GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury.

PubMed

Zhou, Xiaogang; Zhou, Jian; Li, Xilei; Guo, Chang'an; Fang, Taolin; Chen, Zhengrong

2011-07-29

Previous studies have shown that GSK-3β inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3β inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3β inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3β inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3β inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury. Copyright © 2011 Elsevier Inc. All rights reserved.

Activating Akt1 mutations alter DNA double strand break repair and radiosensitivity

PubMed Central

Oeck, S.; Al-Refae, K.; Riffkin, H.; Wiel, G.; Handrick, R.; Klein, D.; Iliakis, G.; Jendrossek, V.

2017-01-01

The survival kinase Akt has clinical relevance to radioresistance. However, its contributions to the DNA damage response, DNA double strand break (DSB) repair and apoptosis remain poorly defined and often contradictory. We used a genetic approach to explore the consequences of genetic alterations of Akt1 for the cellular radiation response. While two activation-associated mutants with prominent nuclear access, the phospho-mimicking Akt1-TDSD and the clinically relevant PH-domain mutation Akt1-E17K, accelerated DSB repair and improved survival of irradiated Tramp-C1 murine prostate cancer cells and Akt1-knockout murine embryonic fibroblasts in vitro, the classical constitutively active membrane-targeted myrAkt1 mutant had the opposite effects. Interestingly, DNA-PKcs directly phosphorylated Akt1 at S473 in an in vitro kinase assay but not vice-versa. Pharmacological inhibition of DNA-PKcs or Akt restored radiosensitivity in tumour cells expressing Akt1-E17K or Akt1-TDSD. In conclusion, Akt1-mediated radioresistance depends on its activation state and nuclear localization and is accessible to pharmacologic inhibition. PMID:28209968

NLRP3 Inflammasome Activation Mediates Zika Virus-Associated Inflammation.

PubMed

He, Zhenjian; Chen, Jiahui; Zhu, Xun; An, Shu; Dong, Xinhuai; Yu, Jianchen; Zhang, Shihao; Wu, Yun; Li, Ge; Zhang, Yu; Wu, Jueheng; Li, Mengfeng

2018-05-25

Zika virus (ZIKV) is a mosquito-borne virus that has been identified as a cause of several severe disease manifestations, including congenital microcephaly and Guillain-Barré syndrome, meningoencephalitis, and myelitis. Previous studies showed that ZIKV-infected patients exhibited elevated plasma levels of interleukin 1β (IL-1β), indicating that ZIKV may activate inflammasomes. However, the molecular basis for its viral pathogenesis remains poorly understood. In this current study, we found that ZIKV infection caused severe inflammatory pathological changes and promoted IL-1β production in vitro and in vivo. We here demonstrate that the maturation and secretion of IL-1β during ZIKV infection was mediated by NLRP3 inflammasome activation and that ZIKV nonstructural protein 5 (NS5) facilitated the assembly of the NLRP3 inflammasome complex, leading to IL-1β activation through interaction with NLRP3 and induction of reactive oxygen species production. Collectively, our data identify NLRP3 inflammasome-derived IL-1β production as a critical feature of inflammation during ZIKV infection. These findings offer new insights into inflammasome-mediated diseases and may provide new therapeutic options for ZIKV-associated diseases.

Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci

PubMed Central

Philippe, Claude; Vargas-Landin, Dulce B; Doucet, Aurélien J; van Essen, Dominic; Vera-Otarola, Jorge; Kuciak, Monika; Corbin, Antoine; Nigumann, Pilvi; Cristofari, Gaël

2016-01-01

LINE-1 (L1) retrotransposons represent approximately one sixth of the human genome, but only the human-specific L1HS-Ta subfamily acts as an endogenous mutagen in modern humans, reshaping both somatic and germline genomes. Due to their high levels of sequence identity and the existence of many polymorphic insertions absent from the reference genome, the transcriptional activation of individual genomic L1HS-Ta copies remains poorly understood. Here we comprehensively mapped fixed and polymorphic L1HS-Ta copies in 12 commonly-used somatic cell lines, and identified transcriptional and epigenetic signatures allowing the unambiguous identification of active L1HS-Ta copies in their genomic context. Strikingly, only a very restricted subset of L1HS-Ta loci - some being polymorphic among individuals - significantly contributes to the bulk of L1 expression, and these loci are differentially regulated among distinct cell lines. Thus, our data support a local model of L1 transcriptional activation in somatic cells, governed by individual-, locus-, and cell-type-specific determinants. DOI: http://dx.doi.org/10.7554/eLife.13926.001 PMID:27016617

Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation.

PubMed

Yan, Yiqing; Jiang, Wei; Spinetti, Thibaud; Tardivel, Aubry; Castillo, Rosa; Bourquin, Carole; Guarda, Greta; Tian, Zhigang; Tschopp, Jurg; Zhou, Rongbin

2013-06-27

Omega-3 fatty acids (ω-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with ω-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1β secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein β-arrestin-2 were shown to be involved in inflammasome inhibition induced by ω-3 FAs. Importantly, ω-3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which ω-3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of ω-3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

Waves of Cdk1 Activity in S Phase Synchronize the Cell Cycle in Drosophila Embryos.

PubMed

Deneke, Victoria E; Melbinger, Anna; Vergassola, Massimo; Di Talia, Stefano

2016-08-22

Embryos of most metazoans undergo rapid and synchronous cell cycles following fertilization. While diffusion is too slow for synchronization of mitosis across large spatial scales, waves of Cdk1 activity represent a possible process of synchronization. However, the mechanisms regulating Cdk1 waves during embryonic development remain poorly understood. Using biosensors of Cdk1 and Chk1 activities, we dissect the regulation of Cdk1 waves in the Drosophila syncytial blastoderm. We show that Cdk1 waves are not controlled by the mitotic switch but by a double-negative feedback between Cdk1 and Chk1. Using mathematical modeling and surgical ligations, we demonstrate a fundamental distinction between S phase Cdk1 waves, which propagate as active trigger waves in an excitable medium, and mitotic Cdk1 waves, which propagate as passive phase waves. Our findings show that in Drosophila embryos, Cdk1 positive feedback serves primarily to ensure the rapid onset of mitosis, while wave propagation is regulated by S phase events. Copyright © 2016 Elsevier Inc. All rights reserved.

Idiosyncratic Brain Activation Patterns Are Associated with Poor Social Comprehension in Autism

PubMed Central

Tyszka, J. Michael; Adolphs, Ralph; Kennedy, Daniel P.

2015-01-01

Autism spectrum disorder (ASD) features profound social deficits but neuroimaging studies have failed to find any consistent neural signature. Here we connect these two facts by showing that idiosyncratic patterns of brain activation are associated with social comprehension deficits. Human participants with ASD (N = 17) and controls (N = 20) freely watched a television situation comedy (sitcom) depicting seminaturalistic social interactions (“The Office”, NBC Universal) in the scanner. Intersubject correlations in the pattern of evoked brain activation were reduced in the ASD group—but this effect was driven entirely by five ASD subjects whose idiosyncratic responses were also internally unreliable. The idiosyncrasy of these five ASD subjects was not explained by detailed neuropsychological profile, eye movements, or data quality; however, they were specifically impaired in understanding the social motivations of characters in the sitcom. Brain activation patterns in the remaining ASD subjects were indistinguishable from those of control subjects using multiple multivariate approaches. Our findings link neurofunctional abnormalities evoked by seminaturalistic stimuli with a specific impairment in social comprehension, and highlight the need to conceive of ASD as a heterogeneous classification. PMID:25855192

Who is food-insecure in California? Findings from the California Women's Health Survey, 2004.

PubMed

Kaiser, Lucia; Baumrind, Nikki; Dumbauld, Sheila

2007-06-01

To identify factors associated with food insecurity in California women. The California Women's Health Survey is an ongoing annual telephone survey that collects data about health-related attitudes and behaviours from a randomly selected sample of women. Food insecurity of the women was measured by a 6-item subset of the Food Security Module. Statistical procedures included chi-square tests, t-tests, logistic regression analysis and analysis of covariance. California, USA. Four thousand and thirty-seven women (18 years or older). Prevalence of food insecurity was 25.7%. After controlling for income, factors associated with greater food insecurity were Hispanic or Black race/ethnicity; less than a 12th grade education; being unmarried; less than 55 years old; being Spanish-speaking; having spent less than half of one's life in the USA; sadness/depression; feeling overwhelmed; poor physical/mental health interfering with activities; and fair to poor general health. Among Food Stamp Program (FSP) participants, 71% were food-insecure. Among FSP-eligible women who had not applied for the programme, the prevalence of food insecurity was lower among women responding that they did not need food stamps than in women giving other reasons for not applying (23.9% vs. 66.9%, P < 0.001). Factors associated with food insecurity in FSP recipients included being unable to make food stamps last for 30 days, feeling overwhelmed, and having a birthplace in Mexico or Central America. Along with several socio-economic variables, poor physical and mental health is associated with food insecurity. Whether food insecurity is a cause or effect of poor health remains in question.

Is poor mental health a risk factor for retirement? Findings from a longitudinal population survey.

PubMed

Olesen, Sarah C; Butterworth, Peter; Rodgers, Bryan

2012-05-01

Poor mental health may influence people's decisions about, and ability to, keep working into later adulthood. The identification of factors that drive retirement provides valuable information for policymakers attempting to mitigate the effects of population ageing. This study examined whether mental health predicts subsequent retirement in a general population sample, and whether this association varied with the timing of retirement. Longitudinal data from 2,803 people aged 45-75 years were drawn from five waves of the Household Income and Labour Dynamics in Australia (HILDA) survey. Discrete-time survival analyses were used to estimate the association between mental health and retirement. Mental health was measured using the Mental Health Index (MHI-5). The relative influences of other health, social, financial, and work-related predictors of retirement were considered to determine the unique contribution of mental health to retirement behaviour. Poor mental health was associated with higher rates of retirement in men (hazard rate ratio, HRR 1.19, 95% CI 1.01-1.29), and workforce exit more generally in women (HRR 1.14, 95% CI 1.07-1.22). These associations varied with the timing of retirement and were driven by early retirees specifically. Physical functioning, income, social activity, job conditions (including job stress for women and job control for men), and aspects of job satisfaction also predicted subsequent retirement. Poor mental and physical health predict workforce departure in mid-to-late adulthood, particularly early retirement. Strategies to accommodate health conditions in the workplace may reduce rates of early retirement and encourage people to remain at work into later adulthood.

A cross-sectional cluster analysis of the combined association of physical activity and sleep with sociodemographic and health characteristics in mid-aged and older adults.

PubMed

Rayward, Anna T; Duncan, Mitch J; Brown, Wendy J; Plotnikoff, Ronald C; Burton, Nicola W

2017-08-01

This study aimed to identify how different patterns of physical activity, sleep duration and sleep quality cluster together, and to examine how the identified clusters differ in terms of socio-demographic and health characteristics. Participants were adults from Brisbane, Australia, aged 42-72 years who reported their physical activity, sleep duration, sleep quality, socio-demographic and health characteristics in 2011 (n=5854). Two-step Cluster Analyses were used to identify clusters. Cluster differences in socio-demographic and health characteristics were examined using chi square tests (p<0.05). Four clusters were identified: 'Poor Sleepers' (31.2%), 'Moderate Sleepers' (30.7%), 'Mixed Sleepers/Highly Active' (20.5%), and 'Excellent Sleepers/Mixed Activity' (17.6%). The 'Poor Sleepers' cluster had the highest proportion of participants with less-than-recommended sleep duration and poor sleep quality, had the poorest health characteristics and a high proportion of participants with low physical activity. Physical activity, sleep duration and sleep quality cluster together in distinct patterns and clusters of poor behaviours are associated with poor health status. Multiple health behaviour change interventions which target both physical activity and sleep should be prioritised to improve health outcomes in mid-aged adults. Copyright © 2017 Elsevier B.V. All rights reserved.

High triglycerides and low high-density lipoprotein cholesterol lipid profile in rheumatoid arthritis: A potential link among inflammation, oxidative status, and dysfunctional high-density lipoprotein.

PubMed

Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; López-Mejías, Raquel; Alonso-Castro, Sara; Abal, Francisco; Ballina-García, Francisco J; González-Gay, Miguel Á; Suárez, Ana

The interactions between inflammation and lipid profile in rheumatoid arthritis (RA) are poorly understood. The lipid profile study in RA has been biased toward lipoprotein levels, whereas those of triglycerides (TGs) and lipoprotein functionality have been underestimated. Since recent findings suggest a role for TG and TG-rich lipoproteins (TRL) on inflammation, we aimed to evaluate a combined lipid profile characterized by high TG and low high-density lipoprotein cholesterol levels (TG high HDL low ) in RA. Lipid profiles were analyzed in 113 RA patients, 113 healthy controls, and 27 dyslipemic subjects. Levels of inflammatory mediators, paraoxonase-1 (PON1) activity, and total antioxidant capacity were quantified in serum. PON1-rs662 status was evaluated by real-time polymerase chain reaction. The TG high HDL low profile was detected in 29/113 RA patients. Although no differences in prevalence compared with healthy controls or dyslipemic subjects were observed, this profile was associated with increased tumor necrosis factor α (P = .004), monocyte chemotactic protein (P = .004), interferon-gamma-inducible protein-10 (P = .018), and leptin (P < .001) serum levels in RA, where decreased PON1 activity and total antioxidant capacity were found. TG high HDL low prevalence was lower among anti-TNFα-treated patients (P = .004). When RA patients were stratified by PON1-rs662 status, these associations remained in the low-activity genotype (QQ). Finally, a poor clinical response on TNFα blockade was related to an increasing prevalence of the TG high HDL low profile over treatment (P = .021) and higher TRL levels at baseline (P = .042). The TG high HDL low profile is associated with systemic inflammation, decreased PON1 activity, and poor clinical outcome on TNFα blockade in RA, suggesting a role of TRL and HDL dysfunction as the missing link between inflammation and lipid profile. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Expansion of Kes 73, a shell supernova remnant containing a magnetar

NASA Astrophysics Data System (ADS)

Borkowski, Kazimierz

2014-09-01

Formation and evolution of highly magnetized neutron stars (magnetars) remain poorly understood. We can learn about magnetars by studying their remnants. Kes 73 is a young supernova remnant containing a magnetar. But basic properties of Kes 73, including its age, remain poorly known. We propose a third-epoch observation of Kes 73 with Chandra. When combined with the 2000 and 2006 observations, this will allow for determination of the remnant's age through expansion rate measurements. We will also search for spatial variations in expansion rate that will help in understanding of the remnant's dynamics. New observations will also be used to determine abundances of heavy-element supernova ejecta, placing further constraints on the supernova that produced Kes 73.

How much more exposed are the poor to natural disasters? Global and regional measurement.

PubMed

Kim, Namsuk

2012-04-01

This paper proposes a simple indicator to measure the exposure to natural disasters for the poor and non-poor population, in order to assess the global and regional trend of natural hazard and poverty. Globally, poor people are two times more exposed to natural disasters than the non-poor in the twenty-first century. The time trend varies across regions, with poor people in East Asia and Pacific being most exposed to natural disasters, followed by those in South Asia and Sub-Saharan Africa. The change of exposure measure over time is decomposed into two factors: a pure exposure change, which could be fuelled by climate change; and a concentration component. The result shows that the total net increase of exposure between the 1970s and the 2000s is driven significantly by the increased concentration of the poor (26 per cent) in disaster-prone areas, whereas the contribution of that factor remains very small for the non-poor (six per cent). © 2012 The Author(s). Disasters © Overseas Development Institute, 2012.

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway.

PubMed

Zhang, Yi; Wei, Yangchao; Li, Xuan; Liang, Xingsi; Wang, Liming; Song, Jun; Zhang, Xiuzhong; Zhang, Chong; Niu, Jian; Zhang, Pengbo; Ren, Zeqiang; Tang, Bo

2018-01-26

The δ opioid receptor (DOR) is involved in the regulation of malignant transformation and tumor progression of hepatocellular carcinoma (HCC). However, regulation of the DOR in HCC remains poorly defined. We found that miR-874 was identified as a negative regulator of the DOR, which is a direct and functional target of miR-874 via its 3' untranslated region (UTR). Moreover, miR-874 was downregulated in HCC and its expression was inversely correlated with DOR expression. Downregulation of miR-874 was also associated with larger tumor size, more vascular invasion, a poor TNM stage, poor tumor differentiation, and inferior patient outcomes. Functionally, overexpression of miR-874 in the HCC cell line SK-hep-1 inhibited cell growth, migration, in vitro invasion, and in vivo tumorigenicity. Furthermore, miR-874 overexpression suppressed the DOR, resulting in a downregulated epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation. The EGFR activator-epidermal growth factor (EGF)-can rescue the proliferation and migration suppression induced by miR-874 overexpression, and the rescue effects of the EGF were blocked by an ERK inhibitor. Our study results suggest that miRNA-874 is a negative regulator of the DOR that can suppress tumor proliferation and metastasis in HCC by targeting the DOR/EGFR/ERK pathway, which may be a potential target for HCC treatment.

Molecular characterization of the acquisition of longevity during seed maturation in soybean

PubMed Central

Lalanne, David; Rossi, Rubiana Falopa; Pelletier, Sandra; da Silva, Edvaldo Aparecido Amaral

2017-01-01

Seed longevity, defined as the ability to remain alive during storage, is an important agronomic factor. Poor longevity negatively impacts seedling establishment and consequently crop yield. This is particularly problematic for soybean as seeds have a short lifespan. While the economic importance of soybean has fueled a large number of transcriptome studies during embryogenesis and seed filling, the mechanisms regulating seed longevity during late maturation remain poorly understood. Here, a detailed physiological and molecular characterization of late seed maturation was performed in soybean to obtain a comprehensive overview of the regulatory genes that are potentially involved in longevity. Longevity appeared at physiological maturity at the end of seed filling before maturation drying and progressively doubled until the seeds reached the dry state. The increase in longevity was associated with the expression of genes encoding protective chaperones such as heat shock proteins and the repression of nuclear and chloroplast genes involved in a range of chloroplast activities, including photosynthesis. An increase in the raffinose family oligosaccharides (RFO)/sucrose ratio together with changes in RFO metabolism genes was also associated with longevity. A gene co-expression network analysis revealed 27 transcription factors whose expression profiles were highly correlated with longevity. Eight of them were previously identified in the longevity network of Medicago truncatula, including homologues of ERF110, HSF6AB, NFXL1 and members of the DREB2 family. The network also contained several transcription factors associated with auxin and developmental cell fate during flowering, organ growth and differentiation. A transcriptional transition occurred concomitant with seed chlorophyll loss and detachment from the mother plant, suggesting the activation of a post-abscission program. This transition was enriched with AP2/EREBP and WRKY transcription factors and genes associated with growth, germination and post-transcriptional processes, suggesting that this program prepares the seed for the dry quiescent state and germination. PMID:28700604

Taking the pulse of Mars via dating of a plume-fed volcano.

PubMed

Cohen, Benjamin E; Mark, Darren F; Cassata, William S; Lee, Martin R; Tomkinson, Tim; Smith, Caroline L

2017-10-03

Mars hosts the solar system's largest volcanoes. Although their size and impact crater density indicate continued activity over billions of years, their formation rates are poorly understood. Here we quantify the growth rate of a Martian volcano by 40 Ar/ 39 Ar and cosmogenic exposure dating of six nakhlites, meteorites that were ejected from Mars by a single impact event at 10.7 ± 0.8 Ma (2σ). We find that the nakhlites sample a layered volcanic sequence with at least four discrete eruptive events spanning 93 ± 12 Ma (1416 ± 7 Ma to 1322 ± 10 Ma (2σ)). A non-radiogenic trapped 40 Ar/ 36 Ar value of 1511 ± 74 (2σ) provides a precise and robust constraint for the mid-Amazonian Martian atmosphere. Our data show that the nakhlite-source volcano grew at a rate of ca. 0.4-0.7 m Ma -1 -three orders of magnitude slower than comparable volcanoes on Earth, and necessitating that Mars was far more volcanically active earlier in its history.Mars hosts the solar system's largest volcanoes, but their formation rates remain poorly constrained. Here, the authors have measured the crystallization and ejection ages of meteorites from a Martian volcano and find that its growth rate was much slower than analogous volcanoes on Earth.

Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.

PubMed

Gallipoli, Paolo; Giotopoulos, George; Tzelepis, Konstantinos; Costa, Ana S H; Vohra, Shabana; Medina-Perez, Paula; Basheer, Faisal; Marando, Ludovica; Di Lisio, Lorena; Dias, Joao M L; Yun, Haiyang; Sasca, Daniel; Horton, Sarah J; Vassiliou, George; Frezza, Christian; Huntly, Brian J P

2018-04-12

FLT3 internal tandem duplication (FLT3 ITD ) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3 ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3 ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3 ITD and other TK activating mutation-driven leukemias. © 2018 by The American Society of Hematology.

Active Nuclear Import of Membrane Proteins Revisited

PubMed Central

Laba, Justyna K.; Steen, Anton; Popken, Petra; Chernova, Alina; Poolman, Bert; Veenhoff, Liesbeth M.

2015-01-01

It is poorly understood how membrane proteins destined for the inner nuclear membrane pass the crowded environment of the Nuclear Pore Complex (NPC). For the Saccharomyces cerevisiae proteins Src1/Heh1 and Heh2, a transport mechanism was proposed where the transmembrane domains diffuse through the membrane while the extralumenal domains encoding a nuclear localization signal (NLS) and intrinsically disordered linker (L) are accompanied by transport factors and travel through the NPC. Here, we validate the proposed mechanism and explore and discuss alternative interpretations of the data. First, to disprove an interpretation where the membrane proteins become membrane embedded only after nuclear import, we present biochemical and localization data to support that the previously used, as well as newly designed reporter proteins are membrane-embedded irrespective of the presence of the sorting signals, the specific transmembrane domain (multipass or tail anchored), independent of GET, and also under conditions that the proteins are trapped in the NPC. Second, using the recently established size limit for passive diffusion of membrane proteins in yeast, and using an improved assay, we confirm active import of polytopic membrane protein with extralumenal soluble domains larger than those that can pass by diffusion on similar timescales. This reinforces that NLS-L dependent active transport is distinct from passive diffusion. Thirdly, we revisit the proposed route through the center of the NPC and conclude that the previously used trapping assay is, unfortunately, poorly suited to address the route through the NPC, and the route thus remains unresolved. Apart from the uncertainty about the route through the NPC, the data confirm active, transport factor dependent, nuclear transport of membrane-embedded mono- and polytopic membrane proteins in baker’s yeast. PMID:26473931

In Vitro Killing of Colorectal Carcinoma Cells by Autologous Activated NK Cells is Boosted by Anti-Epidermal Growth Factor Receptor-induced ADCC Regardless of RAS Mutation Status.

PubMed

Turin, Ilaria; Delfanti, Sara; Ferulli, Federica; Brugnatelli, Silvia; Tanzi, Matteo; Maestri, Marcello; Cobianchi, Lorenzo; Lisini, Daniela; Luinetti, Ombretta; Paulli, Marco; Perotti, Cesare; Todisco, Elisabetta; Pedrazzoli, Paolo; Montagna, Daniela

2018-05-01

Treatment of advanced metastatic colorectal cancer (mCRC) patients is associated with a poor prognosis and significant morbidity. Moreover, targeted therapies such as anti-epidermal growth factor receptor (EGFR) have no effect in metastatic patients with tumors harboring a mutation in the RAS gene. The failure of conventional treatment to improve outcomes in mCRC patients has prompted the development of adoptive immunotherapy approaches including natural killer (NK)-based therapies. In this study, after confirmation that patients' NK cells were not impaired in their cytotoxic activity, evaluated against long-term tumor cell lines, we evaluated their interactions with autologous mCRC cells. Molecular and phenotypical evaluation of mCRC cells, expanded in vitro from liver metastasis, showed that they expressed high levels of polio virus receptor and Nectin-2, whereas UL16-binding proteins were less expressed in all tumor samples evaluated. Two different patterns of MICA/B and HLA class I expression on the membrane of mCRC were documented; approximately half of mCRC patients expressed high levels of these molecules on the membrane surface, whereas, in the remaining, very low levels were documented. Resting NK cells were unable to display sizeable levels of cytotoxic activity against mCRC cells, whereas their cytotoxic activity was enhanced after overnight or 5-day incubation with IL-2 or IL-15. The susceptibility of NK-mediated mCRC lysis was further significantly enhanced after coating with cetuximab, irrespective of their RAS mutation and HLA class I expression. These data open perspectives for combined NK-based immunotherapy with anti-epidermal growth factor receptor antibodies in a cohort of mCRC patients with a poor prognosis refractory to conventional therapies.

Upregulation of CD94 on CD8+T Cells in Anterior Chamber-Associated Immune Deviation

PubMed Central

He, Hao; Yang, Peizeng; Jiang, Liqiong; Zhang, Junfeng; Zhao, Changlin; Chen, Lina; Lin, Xiaomin; Zhou, Hongyan; Kijlstra, Aize

2008-01-01

Background CD8+ regulatory T cells (Treg) have been considered to be involved in a model of ocular-induced tolerance, known as anterior chamber-associated immune deviation (ACAID). The phenotype and characteristics of CD8+Treg in ACAID remain only poorly understood. Recent studies have reported that the CD94-Qa-1 system is implicated in the induction of ACAID CD8+Treg, but the functions and characteristics of CD8+CD94+T cells remain unclear. Results Both mRNA and protein of CD94 and NKG2A were markedly up-regulated on splenic CD8+T cells of ACAID mice compared with controls. Flow cytometric analysis showed that very few CD8+CD94+T cells express granzyme B, perforin and Foxp3. CD8+CD94+T cells, but not CD8+CD94-T cells, magnetically isolated from the spleens of ACAID mice, produced large amounts of TGF-beta1 and exhibited suppressive activity in vitro. Neutralization of TGF-beta1 caused reversal of suppression mediated by CD8+CD94+T cells. Conclusion CD8+CD94+T cells from ACAID mice exhibited suppressive activity in association with enhanced expression of TGF-beta1, suggesting that CD8+Treg are mainly distributed in CD94+T cell subpopulations. PMID:18816417

Liposomal Amphotericin B (AmBisome®): A review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions

PubMed Central

Stone, Neil RH; Bicanic, Tihana; Salim, Rahuman; Hope, William

2016-01-01

Liposomal amphotericin B (AmBisome®; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients. PMID:26818726

Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype

PubMed Central

Bleau, Anne-Marie; Zandueta, Carolina; Redrado, Miriam; Martínez-Canarias, Susana; Larzábal, Leyre; Montuenga, Luis M.

2015-01-01

The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo, despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications. PMID:26318423

Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca2+ binding and protein dimerization

PubMed Central

2012-01-01

Background As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood. Results When Phe65 of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr69 with Arg69 made dimers unstable. When Glu106 was changed to Gly106, the resultant mutant protein completely lost Ca2+ binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3. Conclusion These results show that in P. misakiensis, the cytostatic activity of TC14-3 is mediated by PmEed and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca2+-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells. PMID:22296827

Dog Ownership, Physical Activity, and Health-Related Quality of Life in Veterinary Students: A Cross-Sectional Study.

PubMed

Corrigan, Virginia K; Pierce, Bess J; Hosig, Kathy

The primary objective of this cross-sectional study was to examine the relationship between dog ownership and physical activity in veterinary students. The secondary objective was to gain an understanding of veterinary students' health-related quality of life (HRQOL), and whether dog ownership and/or physical activity were associated with HRQOL measures. Veterinary students were invited to complete surveys between September and November 2015. The primary outcome for multivariate analyses was self-reported physical activity. Bivariate analyses and descriptive statistics were performed to assess student HRQOL. The survey response rate was 33% (152/460). Self-efficacy to exercise (p<.001, OR 2.24, 95% CI 1.46-3.44) and dog ownership (p=.01, OR 3.38, 95% CI 1.31-8.71) independently predicted meeting physical activity guidelines when controlling for other variables. About two thirds of respondents met physical activity guidelines. Veterinary students had significantly worse self-reported mental health scores when compared to both national and state averages. Neither dog ownership nor meeting physical activity guidelines were significantly associated with measures of HRQOL. The poor mental health status of veterinary students remains a significant issue for the profession to address. Longitudinal studies are needed that examine the relationship between physical activity and mental health outcomes in this population.

Aeromonas caviae alters the cytosolic and mitochondrial creatine kinase activities in experimentally infected silver catfish: Impairment on renal bioenergetics.

PubMed

Baldissera, Matheus D; Souza, Carine F; Júnior, Guerino B; Verdi, Camila Marina; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Vizzotto, Bruno S; Baldisserotto, Bernardo

2017-09-01

Cytosolic and mitochondrial creatine kinases (CK), through the creatine kinase-phosphocreatine (CK/PCr) system, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. However, the effects of bacterial infections on the kidney remain poorly understood and are limited only to histopathological analyses. Thus, the aim of this study was to investigate the involvement of cytosolic and mitochondrial CK activities in renal energetic homeostasis in silver catfish experimentally infected with Aeromonas caviae. Cytosolic CK activity decreased in infected animals, while mitochondrial CK activity increased compared to uninfected animals. Moreover, the activity of the sodium-potassium pump (Na + , K + -ATPase) decreased in infected animals compared to uninfected animals. Based on this evidence, it can be concluded that the inhibition of cytosolic CK activity by A. caviae causes an impairment on renal energy homeostasis through the depletion of adenosine triphosphate (ATP) levels. This contributes to the inhibition of Na + , K + -ATPase activity, although the mitochondrial CK activity acted in an attempt to restore the cytosolic ATP levels through a feedback mechanism. In summary, A. caviae infection causes a severe energetic imbalance in infected silver catfish, which may contribute to disease pathogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation.

PubMed

Dong, Hongquan; Zhang, Xiang; Wang, Yiming; Zhou, Xiqiao; Qian, Yanning; Zhang, Shu

2017-03-01

Brain inflammation has a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells are the "first responder" in the injury rather than microglia. Functional aspects of mast cell-microglia interactions remain poorly understood. Our results demonstrated that site-directed injection of the "mast cell degranulator" compound 48/80 (C48/80) in the hypothalamus induced mast cell degranulation, microglial activation, and inflammatory factor production, which initiated the acute brain inflammatory response. "Mast cell stabilizer" disodium cromoglycate (cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced microglial activation, inhibition of MAPK and AKT pathways, and repression of protein expression of histamine receptor 1 (H 1 R), histamine receptor 4 (H 4 R), protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. We also demonstrated that C48/80 had no effect on microglial activation in mast cell-deficient Kit W-sh/W-sh mice. These results implicate that activated brain mast cells trigger microglial activation and stabilization of mast cell inhibits microglial activation-induced central nervous system (CNS) inflammation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.

Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex

PubMed Central

Shaikhouni, Ammar

2017-01-01

Converging evidence suggests that reinstatement of neural activity underlies our ability to successfully retrieve memories. However, the temporal dynamics of reinstatement in the human cortex remain poorly understood. One possibility is that neural activity during memory retrieval, like replay of spiking neurons in the hippocampus, occurs at a faster timescale than during encoding. We tested this hypothesis in 34 participants who performed a verbal episodic memory task while we recorded high gamma (62–100 Hz) activity from subdural electrodes implanted for seizure monitoring. We show that reinstatement of distributed patterns of high gamma activity occurs faster than during encoding. Using a time-warping algorithm, we quantify the timescale of the reinstatement and identify brain regions that show significant timescale differences between encoding and retrieval. Our data suggest that temporally compressed reinstatement of cortical activity is a feature of cued memory retrieval. SIGNIFICANCE STATEMENT We show that cued memory retrieval reinstates neural activity on a faster timescale than was present during encoding. Our data therefore provide a link between reinstatement of neural activity in the cortex and spontaneous replay of cortical and hippocampal spiking activity, which also exhibits temporal compression, and suggest that temporal compression may be a universal feature of memory retrieval. PMID:28336569

Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments.

PubMed

Martin, Alissa; Morgan, Elaine; Hijiya, Nobuko

2012-12-01

Relapsed acute lymphoblastic leukemia (ALL) represents a major cause of morbidity and mortality in pediatrics. With contemporary chemotherapy, >85% of patients with newly diagnosed ALL survive. Unfortunately, 20% of these patients will relapse and for these children, outcomes remain poor despite our best known chemotherapy protocols. Most of these children will achieve a second complete remission, but maintaining this remission remains difficult. Because relapsed ALL is such a significant cause of morbidity and mortality, it is the focus of much research interest. Efforts have been made and continue to focus on understanding the underlying biology that drives relapse. The role of hematopoietic stem cell transplantation in relapsed ALL remains unclear, but many clinicians still favor this for high-risk patients given the poor prognosis with current chemotherapy alone. It is important to use new drugs with little cross-resistance in the treatment of relapsed ALL. New classes of agents are currently being studied. We also discuss prognostic factors and the biology of relapsed ALL.

Does the risk of reprisal prevent nurses blowing the whistle on bad practice?

PubMed

Whitehead, Bill; Barker, Denise

Despite the introduction of legislation to protect people who report poor or unsafe practice, whistleblowing can still have serious consequences for nurses. To review the literature on whistleblowing in healthcare, and explore the barriers to reporting poor practice. Studies focusing on whistleblowing in healthcare were used to assess the safety of incident reporting, and to determine what prevented nurses from reporting poor practice. Four major themes were identified as the main barriers to whistleblowing in healthcare: experience of the nurse; confidentiality and reporting processes; incident severity; and personal beliefs. Reprisal for whistleblowing remains a major concern for nurses. Patient safety could be improved by prioritising confidentiality and creating an environment where nurses feel safe to report poor practice.

Residents of poor nations have a greater sense of meaning in life than residents of wealthy nations.

PubMed

Oishi, Shigehiro; Diener, Ed

2014-02-01

Using Gallup World Poll data, we examined the role of societal wealth for meaning in life across 132 nations. Although life satisfaction was substantially higher in wealthy nations than in poor nations, meaning in life was higher in poor nations than in wealthy nations. In part, meaning in life was higher in poor nations because people in those nations were more religious. The mediating role of religiosity remained significant after we controlled for potential third variables, such as education, fertility rate, and individualism. As Frankl (1963) stated in Man's Search for Meaning, it appears that meaning can be attained even under objectively dire living conditions, and religiosity plays an important role in this search.

Improving outcome in schizophrenia: the potential importance of EPS and neuroleptic dysphoria.

PubMed

Gerlach, Jes

2002-03-01

Despite half a century of antipsychotic drug treatment, the outcome of therapy in schizophrenia remains disappointing. Relapse, rehospitalization, limited fulfilment of social roles, and suicide remain frequent, and the economic costs are high. Current relapse rates may be two to three times higher than those that could be achieved with optimal use of therapy. Poor compliance with treatment is considered to be a significant preventable cause of poor outcome and is in turn likely to be influenced by the patient's experience of drug treatment. There is some evidence that extrapyramidal symptoms (EPS), particularly akathisia and neuroleptic dysphoria, are associated with poor compliance and poor treatment outcome. Atypical antipsychotics have a lower risk of EPS than do standard antipsychotics. Some (risperidone, olanzapine, and ziprasidone) show evidence of a dose-related increase in EPS, but clozapine and quetiapine have demonstrated a placebo-level incidence of EPS across the dose range. Quetiapine does not require the regular blood monitoring mandated for clozapine, and results from a patient survey indicate a high degree of patient satisfaction with treatment. While further research is needed, it is possible that wider use of medications with low EPS and high patient acceptability could promote better compliance and improve the outcome of schizophrenia treatment.

Nonspatial Sequence Coding in CA1 Neurons

PubMed Central

Allen, Timothy A.; Salz, Daniel M.; McKenzie, Sam

2016-01-01

The hippocampus is critical to the memory for sequences of events, a defining feature of episodic memory. However, the fundamental neuronal mechanisms underlying this capacity remain elusive. While considerable research indicates hippocampal neurons can represent sequences of locations, direct evidence of coding for the memory of sequential relationships among nonspatial events remains lacking. To address this important issue, we recorded neural activity in CA1 as rats performed a hippocampus-dependent sequence-memory task. Briefly, the task involves the presentation of repeated sequences of odors at a single port and requires rats to identify each item as “in sequence” or “out of sequence”. We report that, while the animals' location and behavior remained constant, hippocampal activity differed depending on the temporal context of items—in this case, whether they were presented in or out of sequence. Some neurons showed this effect across items or sequence positions (general sequence cells), while others exhibited selectivity for specific conjunctions of item and sequence position information (conjunctive sequence cells) or for specific probe types (probe-specific sequence cells). We also found that the temporal context of individual trials could be accurately decoded from the activity of neuronal ensembles, that sequence coding at the single-cell and ensemble level was linked to sequence memory performance, and that slow-gamma oscillations (20–40 Hz) were more strongly modulated by temporal context and performance than theta oscillations (4–12 Hz). These findings provide compelling evidence that sequence coding extends beyond the domain of spatial trajectories and is thus a fundamental function of the hippocampus. SIGNIFICANCE STATEMENT The ability to remember the order of life events depends on the hippocampus, but the underlying neural mechanisms remain poorly understood. Here we addressed this issue by recording neural activity in hippocampal region CA1 while rats performed a nonspatial sequence memory task. We found that hippocampal neurons code for the temporal context of items (whether odors were presented in the correct or incorrect sequential position) and that this activity is linked with memory performance. The discovery of this novel form of temporal coding in hippocampal neurons advances our fundamental understanding of the neurobiology of episodic memory and will serve as a foundation for our cross-species, multitechnique approach aimed at elucidating the neural mechanisms underlying memory impairments in aging and dementia. PMID:26843637

Anticipatory anxiety disrupts neural valuation during risky choice.

PubMed

Engelmann, Jan B; Meyer, Friederike; Fehr, Ernst; Ruff, Christian C

2015-02-18

Incidental negative emotions unrelated to the current task, such as background anxiety, can strongly influence decisions. This is most evident in psychiatric disorders associated with generalized emotional disturbances. However, the neural mechanisms by which incidental emotions may affect choices remain poorly understood. Here we study the effects of incidental anxiety on human risky decision making, focusing on both behavioral preferences and their underlying neural processes. Although observable choices remained stable across affective contexts with high and low incidental anxiety, we found a clear change in neural valuation signals: during high incidental anxiety, activity in ventromedial prefrontal cortex and ventral striatum showed a marked reduction in (1) neural coding of the expected subjective value (ESV) of risky options, (2) prediction of observed choices, (3) functional coupling with other areas of the valuation system, and (4) baseline activity. At the same time, activity in the anterior insula showed an increase in coding the negative ESV of risky lotteries, and this neural activity predicted whether the risky lotteries would be rejected. This pattern of results suggests that incidental anxiety can shift the focus of neural valuation from possible positive consequences to anticipated negative consequences of choice options. Moreover, our findings show that these changes in neural value coding can occur in the absence of changes in overt behavior. This suggest a possible pathway by which background anxiety may lead to the development of chronic reward desensitization and a maladaptive focus on negative cognitions, as prevalent in affective and anxiety disorders. Copyright © 2015 the authors 0270-6474/15/353085-15$15.00/0.

Immunostimulative Activity of Low Molecular Weight Chitosans in RAW264.7 Macrophages

PubMed Central

Wu, Ning; Wen, Zheng-Shun; Xiang, Xing-Wei; Huang, Yan-Na; Gao, Yang; Qu, You-Le

2015-01-01

Chitosan and its derivatives such as low molecular weight chitosans (LMWCs) have been reported to exert many biological activities, such as antioxidant and antitumor effects. However, complex and molecular weight dependent effects of chitosan remain controversial and the mechanisms that mediate these complex effects are still poorly defined. This study was carried out to investigate the immunostimulative effect of different molecular weight chitosan in RAW264.7 macrophages. Our data suggested that two LMWCs (molecular weight of 3 kDa and 50 kDa) both possessed immunostimulative activity, which was dependent on dose and, at the higher doses, also on the molecular weight. LMWCs could significantly enhance the the pinocytic activity, and induce the production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon-γ (IFN-γ), nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in a molecular weight and concentration-dependent manner. LMWCs were further showed to promote the expression of the genes including iNOS, TNF-α. Taken together, our findings suggested that LMWCs elicited significantly immunomodulatory response through up-regulating mRNA expression of proinflammatory cytokines and activated RAW264.7 macrophage in a molecular weight- and concentration-dependent manner. PMID:26437419

The Physical Mechanism for Retinal Discrete Dark Noise: Thermal Activation or Cellular Ultraweak Photon Emission?

PubMed

Salari, Vahid; Scholkmann, Felix; Bokkon, Istvan; Shahbazi, Farhad; Tuszynski, Jack

2016-01-01

For several decades the physical mechanism underlying discrete dark noise of photoreceptors in the eye has remained highly controversial and poorly understood. It is known that the Arrhenius equation, which is based on the Boltzmann distribution for thermal activation, can model only a part (e.g. half of the activation energy) of the retinal dark noise experimentally observed for vertebrate rod and cone pigments. Using the Hinshelwood distribution instead of the Boltzmann distribution in the Arrhenius equation has been proposed as a solution to the problem. Here, we show that the using the Hinshelwood distribution does not solve the problem completely. As the discrete components of noise are indistinguishable in shape and duration from those produced by real photon induced photo-isomerization, the retinal discrete dark noise is most likely due to 'internal photons' inside cells and not due to thermal activation of visual pigments. Indeed, all living cells exhibit spontaneous ultraweak photon emission (UPE), mainly in the optical wavelength range, i.e., 350-700 nm. We show here that the retinal discrete dark noise has a similar rate as UPE and therefore dark noise is most likely due to spontaneous cellular UPE and not due to thermal activation.

Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion

PubMed Central

Marshall, Wallace F.; Fung, Jennifer C.

2016-01-01

The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by un-attached chromosomes, but that randomly-directed active forces applied to the telomeres speeds up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions. PMID:27046097

Effects of Resource Chemistry on the Composition and Function of Stream Hyporheic Biofilms

PubMed Central

Hall, E. K.; Besemer, K.; Kohl, L.; Preiler, C.; Riedel, K.; Schneider, T.; Wanek, W.; Battin, T. J.

2012-01-01

Fluvial ecosystems process large quantities of dissolved organic matter as it moves from the headwater streams to the sea. In particular, hyporheic sediments are centers of high biogeochemical reactivity due to their elevated residence time and high microbial biomass and activity. However, the interaction between organic matter and microbial dynamics in the hyporheic zone remains poorly understood. We evaluated how variance in resource chemistry affected the microbial community and its associated activity in experimentally grown hyporheic biofilms. To do this we fed beech leaf leachates that differed in chemical composition to a series of bioreactors filled with sediment from a sub-alpine stream. Differences in resource chemistry resulted in differences in diversity and phylogenetic origin of microbial proteins, enzyme activity, and microbial biomass stoichiometry. Specifically, increased lignin, phenolics, and manganese in a single leachate resulted in increased phenoloxidase and peroxidase activity, elevated microbial biomass carbon:nitrogen ratio, and a greater proportion of proteins of Betaproteobacteria origin. We used this model system to attempt to link microbial form (community composition and metaproteome) with function (enzyme activity) in order to better understand the mechanisms that link resource heterogeneity to ecosystem function in stream ecosystems. PMID:22347877

Effects of resource chemistry on the composition and function of stream hyporheic biofilms.

USGS Publications Warehouse

Hall, E.K.; Besemer, K.; Kohl, L.; Preiler, C.; Reidel, K.; Schneider, T.; Wanek, W.; Battin, T.J.

2012-01-01

Fluvial ecosystems process large quantities of dissolved organic matter as it moves from the headwater streams to the sea. In particular, hyporheic sediments are centers of high biogeochemical reactivity due to their elevated residence time and high microbial biomass and activity. However, the interaction between organic matter and microbial dynamics in the hyporheic zone remains poorly understood. We evaluated how variance in resource chemistry affected the microbial community and its associated activity in experimentally grown hyporheic biofilms. To do this we fed beech leaf leachates that differed in chemical composition to a series of bioreactors filled with sediment from a sub-alpine stream. Differences in resource chemistry resulted in differences in diversity and phylogenetic origin of microbial proteins, enzyme activity, and microbial biomass stoichiometry. Specifically, increased lignin, phenolics, and manganese in a single leachate resulted in increased phenoloxidase and peroxidase activity, elevated microbial biomass carbon:nitrogen ratio, and a greater proportion of proteins of Betaproteobacteria origin. We used this model system to attempt to link microbial form (community composition and metaproteome) with function (enzyme activity) in order to better understand the mechanisms that link resource heterogeneity to ecosystem function in stream ecosystems.

Allatostatin-A neurons inhibit feeding behavior in adult Drosophila.

PubMed

Hergarden, Anne Christina; Tayler, Timothy D; Anderson, David J

2012-03-06

How the brain translates changes in internal metabolic state or perceived food quality into alterations in feeding behavior remains poorly understood. Studies in Drosophila larvae have yielded information about neuropeptides and circuits that promote feeding, but a peptidergic neuron subset whose activation inhibits feeding in adult flies, without promoting metabolic changes that mimic the state of satiety, has not been identified. Using genetically based manipulations of neuronal activity, we show that activation of neurons (or neuroendocrine cells) expressing the neuropeptide allatostatin A (AstA) inhibits or limits several starvation-induced changes in feeding behavior in adult Drosophila, including increased food intake and enhanced behavioral responsiveness to sugar. Importantly, these effects on feeding behavior are observed in the absence of any measurable effects on metabolism or energy reserves, suggesting that AstA neuron activation is likely a consequence, not a cause, of metabolic changes that induce the state of satiety. These data suggest that activation of AstA-expressing neurons promotes food aversion and/or exerts an inhibitory influence on the motivation to feed and implicate these neurons and their associated circuitry in the mechanisms that translate the state of satiety into alterations in feeding behavior.

Allatostatin-A neurons inhibit feeding behavior in adult Drosophila

PubMed Central

Hergarden, Anne Christina; Tayler, Timothy D.; Anderson, David J.

2012-01-01

How the brain translates changes in internal metabolic state or perceived food quality into alterations in feeding behavior remains poorly understood. Studies in Drosophila larvae have yielded information about neuropeptides and circuits that promote feeding, but a peptidergic neuron subset whose activation inhibits feeding in adult flies, without promoting metabolic changes that mimic the state of satiety, has not been identified. Using genetically based manipulations of neuronal activity, we show that activation of neurons (or neuroendocrine cells) expressing the neuropeptide allatostatin A (AstA) inhibits or limits several starvation-induced changes in feeding behavior in adult Drosophila, including increased food intake and enhanced behavioral responsiveness to sugar. Importantly, these effects on feeding behavior are observed in the absence of any measurable effects on metabolism or energy reserves, suggesting that AstA neuron activation is likely a consequence, not a cause, of metabolic changes that induce the state of satiety. These data suggest that activation of AstA-expressing neurons promotes food aversion and/or exerts an inhibitory influence on the motivation to feed and implicate these neurons and their associated circuitry in the mechanisms that translate the state of satiety into alterations in feeding behavior. PMID:22345563

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats.

PubMed

An, Yan; Chen, Chong; Inoue, Takeshi; Nakagawa, Shin; Kitaichi, Yuji; Wang, Ce; Izumi, Takeshi; Kusumi, Ichiro

2016-10-03

The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Inferior Frontal Gyrus Activation Underlies the Perception of Emotions, While Precuneus Activation Underlies the Feeling of Emotions during Music Listening.

PubMed

Tabei, Ken-ichi

2015-01-01

While music triggers many physiological and psychological reactions, the underlying neural basis of perceived and experienced emotions during music listening remains poorly understood. Therefore, using functional magnetic resonance imaging (fMRI), I conducted a comparative study of the different brain areas involved in perceiving and feeling emotions during music listening. I measured fMRI signals while participants assessed the emotional expression of music (perceived emotion) and their emotional responses to music (felt emotion). I found that cortical areas including the prefrontal, auditory, cingulate, and posterior parietal cortices were consistently activated by the perceived and felt emotional tasks. Moreover, activity in the inferior frontal gyrus increased more during the perceived emotion task than during a passive listening task. In addition, the precuneus showed greater activity during the felt emotion task than during a passive listening task. The findings reveal that the bilateral inferior frontal gyri and the precuneus are important areas for the perception of the emotional content of music as well as for the emotional response evoked in the listener. Furthermore, I propose that the precuneus, a brain region associated with self-representation, might be involved in assessing emotional responses.

Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion

NASA Astrophysics Data System (ADS)

Marshall, Wallace F.; Fung, Jennifer C.

2016-04-01

The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by unattached chromosomes, but that randomly directed active forces applied to the telomeres speed up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions.

Comparison of obese adults with poor versus good sleep quality during a functional neuroimaging delay discounting task: A pilot study.

PubMed

Martin, Laura E; Pollack, Lauren; McCune, Ashley; Schulte, Erica; Savage, Cary R; Lundgren, Jennifer D

2015-10-30

This study aimed to determine if obese adults with poor versus good sleep quality demonstrate reduced self-regulatory capacity and different patterns of neural activation when making impulsive monetary choices. Six obese, good quality sleepers (M age=44.7 years, M BMI=38.1 kg/m(2)) were compared to 13 obese, poor quality sleepers (M age=42.6, M BMI=39.2 kg/m(2)) on sleep and eating behavior and brain activation in prefrontal and insular regions while engaging in a delay discounting task during functional magnetic resonance imaging (fMRI). Poor quality sleepers demonstrated significantly lower brain activation in the right inferior frontal gyrus, right middle frontal gyrus, and bilateral insula when making immediate and smaller (impulsive) monetary choices compared to the baseline condition. Behaviorally, poor compared to good quality sleepers reported higher scores in the night eating questionnaire. Obese adults with poor sleep quality demonstrate decreased brain activation in multiple regions that regulate cognitive control and interceptive awareness, possibly reducing self-regulatory capacity when making immediately gratifying decisions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The treatment of psychogenic polydipsia with risperidone in two children diagnosed with schizophrenia.

PubMed

Dogangün, Burak; Hergüner, Sabri; Atar, Murat; Kara, Bülent; Aksoy, M Umut; Kayaalp, Levent; Tüzün, Umran

2006-08-01

Polydipsia is a well-known phenomenon in adult psychiatry, but the literature regarding children is very limited. Just as the pathogenesis remains poorly understood, so does its management remain a clinical challenge. Data regarding the effect of risperidone on polydipsia are contradictory. We present case studies of remission of severe polydipsia with risperidone in two children.

An analytical model of prominence dynamics

NASA Astrophysics Data System (ADS)

Routh, Swati; Saha, Snehanshu; Bhat, Atul; Sundar, M. N.

2018-01-01

Solar prominences are magnetic structures incarcerating cool and dense gas in an otherwise hot solar corona. Prominences can be categorized as quiescent and active. Their origin and the presence of cool gas (∼104 K) within the hot (∼106K) solar corona remains poorly understood. The structure and dynamics of solar prominences was investigated in a large number of observational and theoretical (both analytical and numerical) studies. In this paper, an analytic model of quiescent solar prominence is developed and used to demonstrate that the prominence velocity increases exponentially, which means that some gas falls downward towards the solar surface, and that Alfvén waves are naturally present in the solar prominences. These theoretical predictions are consistent with the current observational data of solar quiescent prominences.

The challenge of annotating protein sequences: The tale of eight domains of unknown function in Pfam.

PubMed

Goonesekere, Nalin C W; Shipely, Krysten; O'Connor, Kevin

2010-06-01

The Pfam database is an important tool in genome annotation, since it provides a collection of curated protein families. However, a subset of these families, known as domains of unknown function (DUFs), remains poorly characterized. We have related sequences from DUF404, DUF407, DUF482, DUF608, DUF810, DUF853, DUF976 and DUF1111 to homologs in PDB, within the midnight zone (9-20%) of sequence identity. These relationships were extended to provide functional annotation by sequence analysis and model building. Also described are examples of residue plasticity within enzyme active sites, and change of function within homologous sequences of a DUF. Copyright 2010 Elsevier Ltd. All rights reserved.

Mutations that alter the equilibrium between open and closed conformations of Escherichia coli maltose-binding protein impede its ability to enhance the solubility of passenger proteins

PubMed Central

Nallamsetty, Sreedevi; Waugh, David S.

2007-01-01

Certain highly soluble proteins, such as Escherichia coli maltose-binding protein (MBP), have the ability to enhance the solubility of their fusion partners, making them attractive vehicles for the production of recombinant proteins, yet the mechanism of solubility enhancement remains poorly understood. Here, we report that the solubility-enhancing properties of MBP are dramatically affected by amino acid substitutions that alter the equilibrium between its “open” and “closed” conformations. Our findings indicate that the solubility-enhancing activity of MBP is mediated by its open conformation and point to a likely role for the ligand-binding cleft in the mechanism of solubility enhancement. PMID:17964542

The Interplay of Star formation and Accretion in the Local Universe

NASA Astrophysics Data System (ADS)

Green, Paul

2010-09-01

Galaxy evolution and supermassive black hole growth are closely linked, but the inter-relationships between active accretion and star formation, AGN outflows, and host morphological trends remain poorly understood. We propose to study an unprecedented sample of 615 low redshift SDSS galaxies and AGN detected in archival Chandra fields. We will measure diverse optical and X-ray spectroscopic properties spanning the artificial galaxy/AGN divide, and provide detailed results of our model fitting. We highlight tests of (1) an evolutionary sequence from star-forming through AGN to passive galaxy modes (2) narrow line Sy1 galaxies and new parallels between the accretion modes of AGN and stellar mass X-ray binaries and (3) the relationship of host morphology and mergers to accretion.

Astrocytic calcium activation in a mouse model of tDCS—Extended discussion

PubMed Central

Monai, Hiromu; Hirase, Hajime

2016-01-01

ABSTRACT Transcranial direct current stimulation (tDCS) has been reported to be effective for alleviation of neuropsychiatric and neurological conditions as well as enhancement of memory and cognition. Despite the positive effects of tDCS in humans, its mechanism of action remains poorly understood. Recently, we reported that astrocytes, a major glial cell type in the brain, show an increase in intracellular Ca2+ levels during tDCS in the cerebral cortex of the awake mouse. This tDCS-induced elevation in astrocytic Ca2+ has subsequently been demonstrated to be important for cortical plasticity. In this commentary article, we discuss possible interpretations and implications of our findings from the viewpoint of neuron-glia interactions. PMID:27830161

Apollo XVI TV TRANSMISSION - POOR QUALITY

NASA Image and Video Library

1972-04-22

S72-35611 (21 April 1972) --- Astronaut John W. Young, commander of the Apollo 16 lunar landing mission, leaps from the lunar surface as he salutes the U.S. flag, during the first Apollo 16 extravehicular activity (EVA) on the moon, as seen in this reproduction taken from a color television transmission made by the color television camera mounted on the Lunar Roving Vehicle (LRV). Astronaut Charles M. Duke Jr., lunar module pilot, is standing in the background. While astronauts Young and Duke descended in the Apollo 16 Lunar Module (LM) "Orion" to explore the Descartes highlands landing site on the moon, astronaut Thomas K. Mattingly II, command module pilot, remained with the Command and Service Modules (CSM) "Casper" in lunar orbit.

Pathogenesis and Management of Sarcopenia

PubMed Central

Dhillon, Robinder JS; Hasni, Sarfaraz

2016-01-01

SYNOPSIS Sarcopenia represents a loss of muscle strength and mass in older individuals and is a major determinant of fall risk and impaired ability to perform activities of daily living, often leading to disability, loss of independence and death. Sarcopenia in the elderly has now become a major focus of research and public policy debate due to its impact on morbidity, mortality and healthcare expenditure. Despite its clinical importance, sarcopenia remains under recognized and poorly managed in routine clinical practice. This is, in part, due to a lack of available diagnostic testing and uniform diagnostic criteria. The management of sarcopenia is primarily focused on physical therapy for muscle strengthening and gait training. There are no pharmacological agents currently approved for the treatment of sarcopenia. PMID:27886695

An Interesting Presentation About Cyclical Menstrual Psychosis with an Updated Review of Literature.

PubMed

Thippaiah, Srinagesh Mannekote; Nagaraja, Soumya; Birur, Badari; Cohen, Arnold W

2018-03-13

Cyclical menstrual psychosis is an uncommon, generally a self-limiting mental illness that occurs only in females. It is associated with other menstruation-related disorders and stressful psychogenic factors. Nonetheless, many cases remain unrecognized due to poor awareness of its presence. A young female who presented with psychotic and mood symptoms during each cycle of menstruation was admitted to the psychiatric inpatient unit. There was severe disruption in her activities of daily living and socio-occupational functioning. Treatment involved bio-psycho-social approach in collaboration with Ob-Gyn team with symptoms responding well to a combination of valproic acid and risperidone. Severe affective instability with evident psychosis during menstrual cycle should be evaluated for cyclical menstrual psychosis.

Senescence-like Phenotypes in Human Nevi

PubMed Central

Joselow, Andrew; Lynn, Darren; Terzian, Tamara; Box, Neil F.

2016-01-01

Summary Cellular senescence is an irreversible arrest of cell proliferation at the G1 stage of the cell cycle in which cells become refractory to growth stimuli. Senescence is a critical and potent defense mechanism that mammalian cells have to suppress tumors. While there are many ways to induce a senescence response, oncogene-induced senescence (OIS) remains key to inhibiting progression of cells that have acquired oncogenic mutations. In primary cells in culture, OIS induces a set of measurable phenotypic and behavioral changes, in addition to cell cycle exit. Senescence-associated β-Galactosidase (SA-β-Gal) activity is a main hallmark of senescent cells, along with morphological changes that may depend on the oncogene that is activated, or on the primary cell type. Characteristic cellular changes of senescence include increased size, flattening, multi-nucleation, and extensive vacuolation. At the molecular level, tumor suppressor genes such as p53 and p16INK4a may play a role in initiation or maintenance of OIS. Activation of a DNA damage response and a senescence-associated secretory phenotype could delineate the onset of senescence. Despite advances in our understanding of how OIS suppresses some tumor types, the in vivo role of OIS in melanocytic nevi and melanoma remains poorly understood and not validated. In an effort to stimulate research in this field, we review in this chapter the known markers of senescence and provide experimental protocols for their identification by immunofluorescent staining in melanocytic nevi and malignant melanoma. PMID:27812879

CALIPSO Borehole Monitoring Project at Soufriere Hills Volcano, Montserrat, BWI: Overview, and Response of Magma Reservoir to Prodigious Dome Collapse

NASA Astrophysics Data System (ADS)

Voight, B.; Mattioli, G. S.; Linde, A. T.; Sacks, I. S.; Young, S. R.; Malin, P. E.; Shalev, E.; Hidayat, D.; Elsworth, D.; Widiwijayanti, C.; Miller, V.; McWhorter, N.; Schleigh, B.; Johnston, W.; Sparks, R.; Neuberg, J.; Bass, V.; Dunkley, P.; Herd, R.; Jolly, A.; Norton, G.; Syers, T.; Thompson, G.; Williams, C.; Williams, D.; Clarke, A. B.

2004-12-01

Project CALIPSO (Caribbean Andesite Lava Island Precision Seismo-geodetic Observatory) aims to investigate the magmatic system at the active Soufriere Hills Volcano (SHV), Montserrat. The collaborative project involves several institutions acting in partnership with the Montserrat Volcano Observatory (MVO), and is funded by NSF with assistance by NERC. SHV remains active after 9 years, displaying cyclic activity on several scales. Many aspects of andesite system dynamics remain poorly understood, and CALIPSO is expected to improve our understanding of SHV and andesite systems generally. Drilling was carried out Nov 02 to Mar 03. CALIPSO comprises an integrated array of four strategically located 200-m boreholes, plus several shallower holes and surface installations. The borehole instruments are designed to have long life (decades). Each site includes a very broad-band Sacks-Evertson strainmeter, three-component seismometer, tiltmeter, and surface cGPS station. At one site a hot-hole strainmeter design, involving hydraulic sensors and no downhole electronics, has been used for the first time anywhere. FreeWave telemetry is coupled with Quanterra A/D converters. These instruments are intended to probe changes in the andesitic volcanic system and underlying mafic sources with unprecedented sensitivity. Early data from the July 2003 dome collapse suggest remarkable insights about the depth, shape and nature of the volatile-saturated magmatic reservoir, gleaned from the magnitude of dilatation pulses accompanying the collapse, and their change in sign of with radial distance.

Recent advances in the pathophysiology of arterial hypertension: potential implications for clinical practice.

PubMed

Hering, Dagmara; Trzebski, Andrzej; Narkiewicz, Krzysztof

2017-03-01

Hypertension remains a major and growing public health problem associated with the greatest global rate of cardiovascular morbidity and mortality. Although numerous factors contribute to poor control of blood pressure (BP) and to pseudoresistance (eg, unawareness, lifestyle habits, nonadherence to medication, insufficient treatment, drug‑induced hypertension, undiagnosed secondary causes), true resistant hypertension (RH) is reported in 10.1% of patients treated for elevated BP. While the mechanisms underlying RH remain complex and not entirely understood, sympathetic activation involved in the pathophysiology of hypertension, disease progression, and adverse complications is further augmented in patients with drug‑resistant hypertension. The well‑established contribution of neurogenic component of hypertension has led to the introduction of new alternative therapies aimed specifically at modulating central and neural reflexes mechanisms involved in BP control. Although clinical benefits of lowering BP with renal denervation, baroreflex activation therapy, carotid body denervation, central arteriovenous anastomosis, and deep brain stimulation have advanced our knowledge on uncontrolled hypertension, the variable BP response has prompted extensive ongoing research to define predictors of treatment effectiveness and further investigation of pathophysiology of RH. Very recently, research on the role of vasopressinergic neurons, masked tachycardia, and impaired brain neural activity has provided novel insights into hypertension. This review briefly summarizes the role of the centrally mediated sympathetic nervous system in hypertension, the therapeutic strategies that distinctively target impaired neural reflex mechanisms, and potential implications for future clinical research and therapies.

Neural correlates and network connectivity underlying narrative production and comprehension: a combined fMRI and PET study.

PubMed

AbdulSabur, Nuria Y; Xu, Yisheng; Liu, Siyuan; Chow, Ho Ming; Baxter, Miranda; Carson, Jessica; Braun, Allen R

2014-08-01

The neural correlates of narrative production and comprehension remain poorly understood. Here, using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), contrast and functional network connectivity analyses we comprehensively characterize the neural mechanisms underlying these complex behaviors. Eighteen healthy subjects told and listened to fictional stories during scanning. In addition to traditional language areas (e.g., left inferior frontal and posterior middle temporal gyri), both narrative production and comprehension engaged regions associated with mentalizing and situation model construction (e.g., dorsomedial prefrontal cortex, precuneus and inferior parietal lobules) as well as neocortical premotor areas, such as the pre-supplementary motor area and left dorsal premotor cortex. Narrative comprehension alone showed marked bilaterality, activating right hemisphere homologs of perisylvian language areas. Narrative production remained predominantly left lateralized, uniquely activating executive and motor-related regions essential to language formulation and articulation. Connectivity analyses revealed strong associations between language areas and the superior and middle temporal gyri during both tasks. However, only during storytelling were these same language-related regions connected to cortical and subcortical motor regions. In contrast, during story comprehension alone, they were strongly linked to regions supporting mentalizing. Thus, when employed in a more complex, ecologically-valid context, language production and comprehension show both overlapping and idiosyncratic patterns of activation and functional connectivity. Importantly, in each case the language system is integrated with regions that support other cognitive and sensorimotor domains. Copyright © 2014. Published by Elsevier Ltd.

Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas.

PubMed

Schneider, Hannah; Lohmann, Birthe; Wirsching, Hans-Georg; Hasenbach, Kathy; Rushing, Elisabeth J; Frei, Karl; Pruschy, Martin; Tabatabai, Ghazaleh; Weller, Michael

2017-10-20

The poor prognosis associated with advanced age in patients with glioblastoma remains poorly understood. Glioblastoma in the elderly has been particularly associated with vascular endothelial growth factor (VEGF)-dependent angiogenesis, and early uncontrolled studies suggested that the anti-angiogenic agent bevacizumab (BEV), an antibody to VEGF, might be preferentially active in this patient population. Accordingly, we explored host age-dependent differences in survival and benefit from radiotherapy (RT) or BEV in syngeneic mouse glioma models. Survival was inferior in older mice in the SMA-540 and and less so in SMA-560, but not in the SMA-497 or GL-261 models. Detailed flow cytometric studies revealed increased myeloid and decreased effector T cell population frequencies in SMA-540 tumors of old compared to young mice, but no such difference in the SMA-497 model. Bone marrow transplantation (BMT) from young to old mice had no effect, whereas survival was reduced with BMT from old to young mice. BEV significantly decreased vessel densities in gliomas of old, but not young mice. Accordingly, old, but not young SMA-540 tumor-bearing mice benefited from BEV alone or in combination with RT. End-stage tumors of old BEV- and BEV/RT-treated mice exhibited increased infiltration of T helper and cytotoxic T cells compared to tumors of young mice. The SMA-540 model may provide a valuable tool to evaluate the influence of host age on glioblastoma progression and treatment response. The biological host factors that modulate glioma growth in old as opposed to young mice remain to be identified.

Elevated venous thromboembolism risk in preeclampsia: molecular mechanisms and clinical impact.

PubMed

Egan, Karl; Kevane, Barry; Ní Áinle, Fionnuala

2015-08-01

Venous thromboembolism (VTE) remains a leading cause of maternal death and morbidity in the developed world. Strategies for prevention of VTE in pregnancy have been the subject of recent guidelines and consensus statements. These guidelines recommend thrombosis prevention in women who have risk factors associated with an elevated VTE risk. Preeclampsia is characterized by maternal hypertension and proteinuria developing after 20 weeks gestation, complicating up to 7% of pregnancies and is associated with a massive annual morbidity and mortality burden. Women with preeclampsia have been shown to be at increased risk of VTE with studies to date suggesting that this risk may be up to 5-fold greater than the risk of pregnancy-associated VTE in the general population. Despite the fact that preeclampsia is so common and potentially devastating, our understanding of its pathogenesis and potential therapeutic strategies remain poor. In addition, the mechanisms underlying the prothrombotic phenotype in preeclampsia are also poorly characterized although a number of potential mechanisms have been postulated. Derangements of platelet and endothelial activation and impairment of endogenous anti-coagulant pathways have been reported and may contribute to the observed VTE risk. Recently, evidence for the role of neutrophil extracellular traps (NETs) and cell-free DNA in the pathogenesis of VTE has emerged and some evidence exists to suggest that this may be of relevance in preeclampsia. Future studies aimed at understanding the diagnostic and potential therapeutic relevance of this procoagulant state are likely to be of enormous clinical benefit for pregnant women affected with this potentially devastating condition. © 2015 Authors; published by Portland Press Limited.

Household exposure and animal-bite surveillance following human rabies detection in Southern Ghana.

PubMed

Afakye, Kofi; Kenu, Ernest; Nyarko, Kofi Mensah; Johnson, Sherry Ama Mawuko; Wongnaah, Florence; Bonsu, George Kwame

2016-01-01

Rabies remains a neglected tropical zoonotic disease with 100% case fatality rate and estimated 6,000 global mortality annually, and yet vaccine preventable. In Ghana, rabies outbreaks receive poor response. We investigated rabies in a 5-year old boy to find the source of infection, identify exposed persons for post-exposure prophylaxis and describe animal-bite surveillance in Manya-Krobo District of Ghana. We actively searched for cases and exposures by interviewing household members of the victim, schoolmates, and health professionals using WHO case definition, interview guide and checklist. We reviewed health and veterinary records and reports, and interviewed stakeholders. Descriptive data analyses were carried out and presented using tables and charts. Recorded responses were transcribed into thematic areas and analysed. Child had dog-bite at the wrist, and developed hyperactivity, hydrophobia and hyperventilation 2 months post bite. He was hospitalised and died from respiratory failure day 3 after admission. Thirty-three persons were exposed to rabies infectious material. Females were 66%, age-groups 5-15yrs and 30-59 yrs were 33.3% and 39.4% respectively. A third (11/33) were category II exposure by WHO classification and were recommended for post-exposure prophylaxis. Surveillance records showed ninety-two animal-bite cases were reported for past 12 months. Half were females, and 18-59yrs age-group was 43%. Surveillance data quality was poor. Rabies remains a public health burden inGhana with domestic dog as reservoir of the virus and females more vulnerable to secondary exposures. Health education on rabies should be intensified, and robust animal-bite surveillance system put in place.

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors.

PubMed

Lee, Carol M; Tannock, Ian F

2010-06-03

Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity. Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with ERBB2 (231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2. The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly. Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors.

The RhoA-ROCK-PTEN pathway as a molecular switch for anchorage dependent cell behavior.

PubMed

Yang, Seungwon; Kim, Hyun-Man

2012-04-01

The proliferation of anchorage-dependent cells of mesenchymal origin requires the attachment of the cells to substrates. Thus, cells that are poorly attached to substrates exhibit retarded cell cycle progression or apoptotic death. A major disadvantage of most polymers used in tissue engineering is their hydrophobicity; hydrophobic surfaces do not allow cells to attach firmly and, therefore, do not allow normal proliferation rates. In this study, we investigated the molecular mechanism underlying the reduced proliferation rate of cells that are poorly attached to substrates. There was an inverse relationship between the activity of the small GTPase RhoA (RhoA) and the cell proliferation rate. RhoA activity correlated inversely with the strength of cell adhesion to the substrates. The high RhoA activity in the cells poorly attached to substrates caused an increase in the activity of Rho-associated kinase (ROCK), a well-known effector of RhoA that upregulated the activity of phosphatase and tensin homolog (PTEN). The resulting activated PTEN downregulated Akt activity, which is essential for cell proliferation. Thus, the cells that were poorly attached to substrates showed low levels of cell proliferation because the RhoA-ROCK-PTEN pathway was hyperactive. In addition, RhoA activity seemed to be related to focal adhesion kinase (FAK) activity. Weak FAK activity in these poorly attached cells failed to downregulate the high RhoA activity that restrained cell proliferation. Interestingly, reducing the expression of any component of the RhoA-ROCK-PTEN pathway rescued the proliferation rate without physico-chemical surface modifications. Based on these results, we suggest that the RhoA-ROCK-PTEN pathway acts as a molecular switch to control cell proliferation and determine anchorage dependence. In cells that are poorly attached to substrates, its inhibition is sufficient to restore cell proliferation without the need for physico-chemical modification of the material surface. Copyright © 2012 Elsevier Ltd. All rights reserved.

[A PARADIGM SHIFT IN THE PERCEPTION OF HEALTH MAINTENANCE FROM INCREASING PHYSICAL ACTIVITY TO DECREASING PHYSICAL INACTIVITY].

PubMed

Rotman, Dani; Constantini, Naama

2016-06-01

Modern man spends most of his waking hours (50-70%) in one form or another of sedentary behavior, defined as activity conducted in a sitting or reclining position involving low energy expenditure. The remaining waking hours are spent performing low intensity physical activity (25-45%) and medium-high intensity physical activity (less than 5%): Despite this distribution, medical research has focused on the impact of increasing medium-high intensity physical activity and many health organizations' recommendations are in accordance. In recent years, research conducted has begun to examine the effect inactivity has on health and has shown that excess sedentary behaviour is an independent risk factor for a wide range of medical problems such as obesity, metabolic syndrome, poor cardiovascular health profile, diabetes mellitus, and possibly cancer. Although the higher risk brought on by sedentary behaviour is partially reduced by increasing medium-high intensity physical activity, it is not completely neutralized. One way to diminish the harm caused by long hours of sitting is to take short breaks during periods of prolonged sitting in order to walk. According to these findings, it is worthwhile to recommend reducing the hours spent in sedentary behaviour, or at least to take frequent short breaks ("activity snacks") during periods of prolonged sitting to get up and walk around.

IL-17A and Serum Amyloid A Are Elevated in a Cigarette Smoke Cessation Model Associated with the Persistence of Pigmented Macrophages, Neutrophils and Activated NK Cells

PubMed Central

Hansen, Michelle J.; Chan, Sheau Pyng J.; Langenbach, Shenna Y.; Dousha, Lovisa F.; Jones, Jessica E.; Yatmaz, Selcuk; Seow, Huei Jiunn; Vlahos, Ross; Anderson, Gary P.; Bozinovski, Steven

2014-01-01

While global success in cessation advocacy has seen smoking rates fall in many developed countries, persistent lung inflammation in ex-smokers is an increasingly important clinical problem whose mechanistic basis remains poorly understood. In this study, candidate effector mechanisms were assessed in mice exposed to cigarette smoke (CS) for 4 months following cessation from long term CS exposure. BALF neutrophils, CD4+ and CD8+ T cells and lung innate NK cells remained significantly elevated following smoking cessation. Analysis of neutrophil mobilization markers showed a transition from acute mediators (MIP-2α, KC and G-CSF) to sustained drivers of neutrophil and macrophage recruitment and activation (IL-17A and Serum Amyoid A (SAA)). Follicle-like lymphoid aggregates formed with CS exposure and persisted with cessation, where they were in close anatomical proximity to pigmented macrophages, whose number actually increased 3-fold following CS cessation. This was associated with the elastolytic protease, MMP-12 (macrophage metallo-elastase) which remained significantly elevated post-cessation. Both GM-CSF and CSF-1 were significantly increased in the CS cessation group relative to the control group. In conclusion, we show that smoking cessation mediates a transition to accumulation of pigmented macrophages, which may contribute to the expanded macrophage population observed in COPD. These macrophages together with IL-17A, SAA and innate NK cells are identified here as candidate persistence determinants and, we suggest, may represent specific targets for therapies directed towards the amelioration of chronic airway inflammation. PMID:25405776

Perspective: Update on Idiopathic Intracranial Hypertension

PubMed Central

Bruce, Beau B.; Biousse, Valérie; Newman, Nancy J.

2011-01-01

Purpose Provide an update on various features of idiopathic intracranial hypertension. Design Perspective. Methods Selected articles on the epidemiology, clinical and imaging features, natural history, pathophysiology, and treatment of idiopathic intracranial hypertension were reviewed and interpreted in the context of the authors’ clinical and research experience. Results Idiopathic intracranial hypertension is primarily a disease of obese women of childbearing age, but it can affect patients of any weight, sex, and age. Although a relatively rare disorder, idiopathic intracranial hypertension’s associated costs in the U.S. entail hundreds of millions of dollars. Even following treatment, headaches are frequently persistent and may require the continued involvement of a neurologist. Quality of life reductions and depression are common among idiopathic intracranial hypertension patients. However, visual dysfunction, especially visual field abnormalities, represents the major morbidity of this disorder, and serial automated perimetry remains the primary mode of patient monitoring. Patients who are men, black, very obese, or anemic are at higher risk of visual loss. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding idiopathic intracranial hypertension’s pathophysiology. Treatment studies show that lumbar puncture is a valuable treatment (in addition to its crucial diagnostic role) and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, CSF diversion procedures, and cerebral venous stenting. Conclusions Many questions remain unanswered about idiopathic intracranial hypertension. Ongoing studies, especially an ongoing NIH-funded clinical trial of acetazolamide, should provide more insight into this important, yet poorly understood syndrome of isolated intracranial hypertension. PMID:21696699

What's new in perioperative nutritional support?

PubMed

Awad, Sherif; Lobo, Dileep N

2011-06-01

To highlight recent developments in the field of perioperative nutritional support by reviewing clinically pertinent English language articles from October 2008 to December 2010, that examined the effects of malnutrition on surgical outcomes, optimizing metabolic function and nutritional status preoperatively and postoperatively. Recognition of patients with or at risk of malnutrition remains poor despite the availability of numerous clinical aids and clear evidence of the adverse effects of poor nutritional status on postoperative clinical outcomes. Unfortunately, poor design and significant heterogeneity remain amongst many studies of nutritional interventions in surgical patients. Patients undergoing elective surgery should be managed within a multimodal pathway that includes evidence-based interventions to optimize nutritional status perioperatively. The aforementioned should include screening patients to identify those at high nutritional risk, perioperative immuno-nutrition, minimizing 'metabolic stress' and insulin resistance by preoperative conditioning with carbohydrate-based drinks, glutamine supplementation, minimal access surgery and enhanced recovery protocols. Finally gut-specific nutrients and prokinetics should be utilized to improve enteral feed tolerance thereby permitting early enteral feeding. An evidence-based multimodal pathway that includes interventions to optimize nutritional status may improve outcomes following elective surgery.

Aspergillus fumigatus in Poultry

PubMed Central

Arné, Pascal; Thierry, Simon; Wang, Dongying; Deville, Manjula; Le Loc'h, Guillaume; Desoutter, Anaïs; Féménia, Françoise; Nieguitsila, Adélaïde; Huang, Weiyi; Chermette, René; Guillot, Jacques

2011-01-01

Aspergillus fumigatus remains a major respiratory pathogen in birds. In poultry, infection by A. fumigatus may induce significant economic losses particularly in turkey production. A. fumigatus develops and sporulates easily in poor quality bedding or contaminated feedstuffs in indoor farm environments. Inadequate ventilation and dusty conditions increase the risk of bird exposure to aerosolized spores. Acute cases are seen in young animals following inhalation of spores, causing high morbidity and mortality. The chronic form affects older birds and looks more sporadic. The respiratory tract is the primary site of A. fumigatus development leading to severe respiratory distress and associated granulomatous airsacculitis and pneumonia. Treatments for infected poultry are nonexistent; therefore, prevention is the only way to protect poultry. Development of avian models of aspergillosis may improve our understanding of its pathogenesis, which remains poorly understood. PMID:21826144

Molecular mechanism of the Syk activation switch.

PubMed

Tsang, Emily; Giannetti, Anthony M; Shaw, David; Dinh, Marie; Tse, Joyce K Y; Gandhi, Shaan; Ho, Hoangdung; Wang, Sandra; Papp, Eva; Bradshaw, J Michael

2008-11-21

Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an "OR-gate" type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.

Health and the 2008 Economic Recession: Evidence from the United Kingdom

PubMed Central

Astell-Burt, Thomas; Feng, Xiaoqi

2013-01-01

Introduction The economic recession which began in 2008 has resulted in a substantial increase in unemployment across many countries, including the United Kingdom. Strong association between unemployment and poor health status among individuals is widely recognised. We investigated whether the prevalence of poor health at a population level increased concurrent to the rise in unemployment during the economic recession, and whether the impact on health varied by geographical and socioeconomic circumstances. Method Health, demographic and socioeconomic measures on 1.36 million survey responses aged 16–64 were extracted from the Quarterly Labour Force Survey of the United Kingdom, collected every three months, from January 2006 to December 2010. The likelihood of self-reporting poor health status and specific types of health problems (depression, mental illness, cardiovascular and respiratory) across time were estimated separately using logistic regression. Explanatory variables included economic status (International Labour Organization definition), occupational class, age, gender, country of birth, ethnicity, educational qualifications, couple status, household tenure, number of dependents, and geographical region. Results Unemployment (age-gender adjusted) rose from 4.5% in January 2008 to 7.1% by September 2009. The reporting of poor health status increased from 25.7% in July 2009 to 29.5% by December 2010. Similar increases were found for cardiovascular and respiratory health problems; not depression or mental illness. The prevalence of poor health status among the unemployed decreased from 28.8% in July 2008, to 24.9% by March 2009; but this was followed by an increase in poor health experienced across all regions and by all socioeconomic groups, including those who remained employed, regardless of their occupational class. Interpretation Although our study found no exacerbation of pre-recession health inequalities, the rise in poor health status not only for the unemployed, but also among people who remained employed, regardless of their occupational class, justifies concern voiced among many public health commentators. PMID:23437208

Avoiding the Major Causes of Death: Does Childhood Misfortune Reduce the Likelihood of Being Disease Free in Later Life?

PubMed

Williams, Monica M; Kemp, Blakelee R; Ferraro, Kenneth F; Mustillo, Sarah A

2018-04-03

Although previous research reveals the detrimental effects of early misfortune on the development of chronic diseases in later life, few studies have investigated its effects on remaining disease free. This study draws on cumulative inequality theory to investigate whether experiencing childhood misfortune reduces the likelihood of remaining disease free over time. This study utilizes five waves of data from the Health and Retirement Study to test whether five domains of childhood misfortune predict being disease free at baseline (2004) and developing disease over time (2004-2012). Respondents reporting risky parental behaviors during childhood were less likely to be disease free at baseline and had an increased risk of disease onset over time, the latter driven by having a guardian who smoked in combination with more pack-years smoked in adulthood. Furthermore, we find that adult resources, i.e. wealth, help to mitigate the noxious effects of other misfortunes, notably poor socioeconomic conditions. Consistent with cumulative inequality theory, these findings reveal that experiencing multiple types of misfortune during childhood decreases the likelihood of remaining disease free in later life, but engaging in health behaviors, such as physical activity, can help to ameliorate some of the noxious effects of early misfortune.

The scientific challenges to forecasting and nowcasting the magnetospheric response to space weather (Invited)

NASA Astrophysics Data System (ADS)

Hesse, M.; Kuznetsova, M. M.; Birn, J.; Pulkkinen, A. A.

2013-12-01

Space weather is different from terrestrial weather in an essential way. Terrestrial weather has benefitted from a long history of research, which has led to a deep and detailed level of understanding. In comparison, space weather is scientifically in its infancy. Many key processes in the causal chains from processes on the Sun to space weather effects in various locations in the heliosphere remain either poorly understood or not understood at all. Space weather is therefore, and will remain in the foreseeable future, primarily a research field. Extensive further research efforts are needed before we can reasonably expect the precision and fidelity of weather forecasts. For space weather within the Earth's magnetosphere, the coupling between solar wind and magnetosphere is of crucial importance. While past research has provided answers, often on qualitative levels, to some of the most fundamental questions, answers to some of the latter and the ability to predict quantitatively remain elusive. This presentation will provide an overview of pertinent aspects of solar wind-magnetospheric coupling, its importance for space weather near the Earth, and it will analyze the state of our ability to describe and predict its efficiency. It will conclude with a discussion of research activities, which are aimed at improving our ability to quantitatively forecast coupling processes.

Muscle Oxygen Supply Impairment during Exercise in Poorly Controlled Type 1 Diabetes

PubMed Central

TAGOUGUI, SEMAH; LECLAIR, ERWAN; FONTAINE, PIERRE; MATRAN, RÉGIS; MARAIS, GAELLE; AUCOUTURIER, JULIEN; DESCATOIRE, AURÉLIEN; VAMBERGUE, ANNE; OUSSAIDENE, KAHINA; BAQUET, GEORGES; HEYMAN, ELSA

2015-01-01

ABSTRACT Purpose Aerobic fitness, as reflected by maximal oxygen (O2) uptake (V˙O2max), is impaired in poorly controlled patients with type 1 diabetes. The mechanisms underlying this impairment remain to be explored. This study sought to investigate whether type 1 diabetes and high levels of glycated hemoglobin (HbA1c) influence O2 supply including O2 delivery and release to active muscles during maximal exercise. Methods Two groups of patients with uncomplicated type 1 diabetes (T1D-A, n = 11, with adequate glycemic control, HbA1c <7.0%; T1D-I, n = 12 with inadequate glycemic control, HbA1c >8%) were compared with healthy controls (CON-A, n = 11; CON-I, n = 12, respectively) matched for physical activity and body composition. Subjects performed exhaustive incremental exercise to determine V˙O2max. Throughout the exercise, near-infrared spectroscopy allowed investigation of changes in oxyhemoglobin, deoxyhemoglobin, and total hemoglobin in the vastus lateralis. Venous and arterialized capillary blood was sampled during exercise to assess arterial O2 transport and factors able to shift the oxyhemoglobin dissociation curve. Results Arterial O2 content was comparable between groups. However, changes in total hemoglobin (i.e., muscle blood volume) was significantly lower in T1D-I compared with that in CON-I. T1D-I also had impaired changes in deoxyhemoglobin levels and increase during high-intensity exercise despite normal erythrocyte 2,3-diphosphoglycerate levels. Finally, V˙O2max was lower in T1D-I compared with that in CON-I. No differences were observed between T1D-A and CON-A. Conclusions Poorly controlled patients displayed lower V˙O2max and blunted muscle deoxyhemoglobin increase. The latter supports the hypotheses of increase in O2 affinity induced by hemoglobin glycation and/or of a disturbed balance between nutritive and nonnutritive muscle blood flow. Furthermore, reduced exercise muscle blood volume in poorly controlled patients may warn clinicians of microvascular dysfunction occurring even before overt microangiopathy. PMID:24983346

A quantitative analysis of the state of knowledge of turtles of the United States and Canada

USGS Publications Warehouse

Lovich, Jeffrey E.; Ennen, Joshua R.

2013-01-01

The “information age” ushered in an explosion of knowledge and access to knowledge that continues to revolutionize society. Knowledge about turtles, as measured by number of published papers, has been growing at an exponential rate since the early 1970s, a phenomenon mirrored in all scientific disciplines. Although knowledge about turtles, as measured by number of citations for papers in scientific journals, has been growing rapidly, this taxonomic group remains highly imperiled suggesting that knowledge is not always successfully translated into effective conservation of turtles. We reviewed the body of literature on turtles of the United States and Canada and found that: 1) the number of citations is biased toward large-bodied species, 2) the number of citations is biased toward wide-ranging species, and 3) conservation status has little effect on the accumulation of knowledge for a species, especially after removing the effects of body size or range size. The dispersion of knowledge, measured by Shannon Weiner diversity and evenness indices across species, was identical from 1994 to 2009 suggesting that poorly studied species remained poorly-studied species while well-studied species remained well studied. Several species listed as threatened or endangered under the U.S. Endangered Species Act (e.g., Pseudemys alabamensis, Sternotherus depressus, and Graptemys oculifera) remain poorly studied with the estimated number of citations for each ranging from only 13-24. The low number of citations for these species could best be explained by their restricted distribution and/or their smaller size. Despite the exponential increase in knowledge of turtles in the United States and Canada, no species of turtle listed under the Endangered Species Act has ever been delisted for reason of recovery. Therefore, increased knowledge does not necessarily contribute appreciably to recovery of threatened turtles.

Does low workplace social capital have detrimental effect on workers' health?

PubMed

Suzuki, Etsuji; Takao, Soshi; Subramanian, S V; Komatsu, Hirokazu; Doi, Hiroyuki; Kawachi, Ichiro

2010-05-01

While the majority of studies of social capital and health have focused on conceptualizing social capital at the geographic level, evidence remains sparse on workplace social capital. We examined the association between workplace social capital and health status among Japanese private sector employees in a cross-sectional study. By employing a two-stage stratified random sampling procedure, 1147 employees were identified from 46 companies in Okayama in 2007. Workplace social capital was measured based on two components; trust and reciprocity. Company-level social capital was based on aggregating employee responses and calculating the proportion of workers reporting mistrust and lack of reciprocity. Multilevel logistic regression analysis was conducted using Markov Chain Monte Carlo methods to explore whether individual- and company-level mistrust and lack of reciprocity were associated with poor self-rated health. Odds ratios (ORs) and 95% credible intervals (CIs) for poor health were obtained for each variable. Workers reporting individual-level mistrust and lack of reciprocity had approximately double the odds of poor health even after controlling for sex, age, occupation, educational attainment, smoking, alcohol use, physical activity, body mass index, and chronic diseases. While we found some suggestion of a contextual association between company-level mistrust and poor health, no association was found between company-level lack of reciprocity and health. Despite the thorough examination of cross-level interaction terms between company-level social capital and individual characteristics, no clear patterns were observed. Individual perceptions of mistrust and lack of reciprocity at work have adverse effects on self-rated health among Japanese workers. Although the present study possibly suggests the contextual effect of workplace mistrust on workers' health, the contextual effect of workplace lack of reciprocity was not supported. Copyright 2010 Elsevier Ltd. All rights reserved.

Compensating Losses in Bridge Employment? Examining Relations between Compensation Strategies, Health Problems, and Intention to Remain at Work

ERIC Educational Resources Information Center

Muller, Andreas; De Lange, Annet; Weigl, Matthias; Oxfart, Caroline; Van der Heijden, Beatrice

2013-01-01

In order to better understand the precursors of bridge employment, this study aimed to investigate whether individual action strategies in terms of selection, optimization, and compensation (SOC; Baltes & Baltes, 1990) are able to buffer the well-known negative impact of poor health on the intention to remain in the workforce. 784 employees (60-85…

Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells.

PubMed

Yamaguchi, Hiroshi; Maruyama, Toshihiko; Urade, Yoshihiro; Nagata, Shigekazu

2014-03-25

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5'-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a 'calm down' signal. DOI: http://dx.doi.org/10.7554/eLife.02172.001.

Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

PubMed Central

Yamaguchi, Hiroshi; Maruyama, Toshihiko; Urade, Yoshihiro; Nagata, Shigekazu

2014-01-01

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal. DOI: http://dx.doi.org/10.7554/eLife.02172.001 PMID:24668173

The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.

PubMed

Xing, Fan; Luan, Yizhao; Cai, Jing; Wu, Sihan; Mai, Jialuo; Gu, Jiayu; Zhang, Haipeng; Li, Kai; Lin, Yuan; Xiao, Xiao; Liang, Jiankai; Li, Yuan; Chen, Wenli; Tan, Yaqian; Sheng, Longxiang; Lu, Bingzheng; Lu, Wanjun; Gao, Mingshi; Qiu, Pengxin; Su, Xingwen; Yin, Wei; Hu, Jun; Chen, Zhongping; Sai, Ke; Wang, Jing; Chen, Furong; Chen, Yinsheng; Zhu, Shida; Liu, Dongbing; Cheng, Shiyuan; Xie, Zhi; Zhu, Wenbo; Yan, Guangmei

2017-01-10

Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Adolescent Alcohol Drinking Renders Adult Drinking BLA-Dependent: BLA Hyper-Activity as Contributor to Comorbid Alcohol Use Disorder and Anxiety Disorders

PubMed Central

Moaddab, Mahsa; Mangone, Elizabeth; McDannald, Michael A.

2017-01-01

Adolescent alcohol drinking increases the risk for alcohol-use disorder in adulthood. Yet, the changes in adult neural function resulting from adolescent alcohol drinking remain poorly understood. We hypothesized that adolescent alcohol drinking alters basolateral amygdala (BLA) function, making alcohol drinking BLA-dependent in adulthood. Male, Long Evans rats were given voluntary, intermittent access to alcohol (20% ethanol) or a bitter, isocaloric control solution, across adolescence. Half of the rats in each group received neurotoxic BLA lesions. In adulthood, all rats were given voluntary, intermittent access to alcohol. BLA lesions reduced adult alcohol drinking in rats receiving adolescent access to alcohol, but not in rats receiving adolescent access to the control solution. The effect of the BLA lesion was most apparent in high alcohol drinking adolescent rats. The BLA is essential for fear learning and is hyper-active in anxiety disorders. The results are consistent with adolescent heavy alcohol drinking inducing BLA hyper-activity, providing a neural mechanism for comorbid alcohol use disorder and anxiety disorders. PMID:29135933

Imaging auditory representations of song and syllables in populations of sensorimotor neurons essential to vocal communication.

PubMed

Peh, Wendy Y X; Roberts, Todd F; Mooney, Richard

2015-04-08

Vocal communication depends on the coordinated activity of sensorimotor neurons important to vocal perception and production. How vocalizations are represented by spatiotemporal activity patterns in these neuronal populations remains poorly understood. Here we combined intracellular recordings and two-photon calcium imaging in anesthetized adult zebra finches (Taeniopygia guttata) to examine how learned birdsong and its component syllables are represented in identified projection neurons (PNs) within HVC, a sensorimotor region important for song perception and production. These experiments show that neighboring HVC PNs can respond at markedly different times to song playback and that different syllables activate spatially intermingled PNs within a local (~100 μm) region of HVC. Moreover, noise correlations were stronger between PNs that responded most strongly to the same syllable and were spatially graded within and between classes of PNs. These findings support a model in which syllabic and temporal features of song are represented by spatially intermingled PNs functionally organized into cell- and syllable-type networks within local spatial scales in HVC. Copyright © 2015 the authors 0270-6474/15/355589-17$15.00/0.

Tremor in multiple sclerosis: The intriguing role of the cerebellum.

PubMed

Ayache, Samar S; Chalah, Moussa A; Al-Ani, Tarik; Farhat, Wassim H; Zouari, Hela G; Créange, Alain; Lefaucheur, Jean-Pascal

2015-11-15

Tremor is frequently encountered in multiple sclerosis (MS) patients. However, its underlying pathophysiological mechanisms remain poorly understood. Our aim was to assess the potential role of the cerebellum and brain stem structures in the generation of MS tremor.We performed accelerometric (ACC) and electromyographic(EMG) assessment of tremor in 32MS patients with manual clumsiness. In addition to clinical examination, patients underwent a neurophysiological exploration of the brainstem and cerebellar functions,which consisted of blink and masseter inhibitory reflexes, cerebello-thalamo-cortical inhibition (CTCi), and somatosensory evoked potentials. Tremor was clinically visible in 18 patients and absent in 14. Patients with visible tremor had more severe score of ataxia and clinical signs of cerebellar dysfunction, as well as a more reduced CTCi on neurophysiological investigation. However, ACC and EMG recordings confirmed the presence of a real rhythmic activity in only one patient. In most MS patients, the clinically visible tremor corresponded to a pseudorhythmic activity without coupling between ACC and EMG recordings. Cerebellar dysfunction may contribute to the occurrence of this pseudorhythmic activity mimicking tremor during posture and movement execution.

Multivariate neural biomarkers of emotional states are categorically distinct.

PubMed

Kragel, Philip A; LaBar, Kevin S

2015-11-01

Understanding how emotions are represented neurally is a central aim of affective neuroscience. Despite decades of neuroimaging efforts addressing this question, it remains unclear whether emotions are represented as distinct entities, as predicted by categorical theories, or are constructed from a smaller set of underlying factors, as predicted by dimensional accounts. Here, we capitalize on multivariate statistical approaches and computational modeling to directly evaluate these theoretical perspectives. We elicited discrete emotional states using music and films during functional magnetic resonance imaging scanning. Distinct patterns of neural activation predicted the emotion category of stimuli and tracked subjective experience. Bayesian model comparison revealed that combining dimensional and categorical models of emotion best characterized the information content of activation patterns. Surprisingly, categorical and dimensional aspects of emotion experience captured unique and opposing sources of neural information. These results indicate that diverse emotional states are poorly differentiated by simple models of valence and arousal, and that activity within separable neural systems can be mapped to unique emotion categories. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Intravenous immunoglobulin enhances the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria.

PubMed

Matsuo, Hidemasa; Itoh, Hiroshi; Kitamura, Naoko; Kamikubo, Yasuhiko; Higuchi, Takeshi; Shiga, Shuichi; Ichiyama, Satoshi; Kondo, Tadakazu; Takaori-Kondo, Akifumi; Adachi, Souichi

2015-08-14

Intravenous immunoglobulin (IVIG) is periodically administered to immunocompromised patients together with antimicrobial agents. The evidence that supports the effectiveness of IVIG is mostly based on data from randomized clinical trials; the underlying mechanisms are poorly understood. A recent study revealed that killing of multidrug-resistant bacteria and drug-sensitive strains by neutrophils isolated from healthy donors is enhanced by an IVIG preparation. However, the effectiveness of IVIG in immunocompromised patients remains unclear. The present study found that IVIG increased both killing activity and O2(-) release by neutrophils isolated from six patients receiving immune-suppressive drugs after hematopoietic stem cell transplantation (HSCT); these neutrophils killed both multidrug-resistant extended-spectrum β-lactamase-producing Escherichia coli (E. coli) and multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa). Moreover, IVIG increased the autophagy of the neutrophils, which is known to play an important role in innate immunity. These results suggest that IVIG promotes both the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of mTOR in podocyte function and diabetic nephropathy in humans and mice

PubMed Central

Gödel, Markus; Hartleben, Björn; Herbach, Nadja; Liu, Shuya; Zschiedrich, Stefan; Lu, Shun; Debreczeni-Mór, Andrea; Lindenmeyer, Maja T.; Rastaldi, Maria-Pia; Hartleben, Götz; Wiech, Thorsten; Fornoni, Alessia; Nelson, Robert G.; Kretzler, Matthias; Wanke, Rüdiger; Pavenstädt, Hermann; Kerjaschki, Dontscho; Cohen, Clemens D.; Hall, Michael N.; Rüegg, Markus A.; Inoki, Ken; Walz, Gerd; Huber, Tobias B.

2011-01-01

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy. PMID:21606591

The histone code reader SPIN1 controls RET signaling in liposarcoma

PubMed Central

Franz, Henriette; Greschik, Holger; Willmann, Dominica; Ozretić, Luka; Jilg, Cordula Annette; Wardelmann, Eva; Jung, Manfred; Buettner, Reinhard; Schüle, Roland

2015-01-01

The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy. PMID:25749382

MYC Mediates mRNA Cap Methylation of Canonical Wnt/β-catenin Signaling Transcripts by Recruiting CDK7 and RNA Methyltransferase

PubMed Central

Posternak, Valeriya; Ung, Matthew H.; Cheng, Chao; Cole, Michael D.

2016-01-01

MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational capacity, elevated protein levels, and enhanced Wnt signaling activity. Mechanistic evidence indicates that MYC promotes recruitment of RNA methyltransferase (RNMT) to Wnt signaling gene promoters by enhancing phosphorylation of serine 5 on the RNA Polymerase II Carboxy-Terminal Domain, mediated in part through an interaction between the TIP60 acetyltransferase complex and TFIIH. Implications MYC enhances mRNA cap methylation above and beyond transcriptional induction. PMID:27899423

A flavonoid component from Docynia delavayi (Franch.) Schneid represses transplanted H22 hepatoma growth and exhibits low toxic effect on tumor-bearing mice.

PubMed

Zhao, Xiangpei; Shu, Guangwen; Chen, Lvyi; Mi, Xue; Mei, Zhinan; Deng, Xukun

2012-09-01

The fruit of Docynia delavayi (Franch.) Schneid is a kind of popular food in southwestern areas of China. Additionally, its rhizome has been long used as a folk medicine in the treatment of liver cancer by local people. Chrysin is a kind of flavonoid which induces cancer cell death in vitro. However, its anti-tumor activity in vivo and toxicological effects on the tumor-bearing animals still remain poorly understood. In this study, we obtained four flavonoids from this herb. Among them, chrysin showed the strongest cytotoxic effect on an array of cultured tumor cells. Further investigations revealed that it significantly repressed transplanted H22 ascitic hepatic tumor cell growth in vivo. Moreover, this compound displayed little toxic effects. Additionally, we demonstrated that in transplanted tumor tissues, chrysin not only activated caspase-3 and induced apoptosis, but also inhibited the production of vascular endothelial growth factor (VEGF) and suppressed angiogenesis. These data showed that chrysin exhibited prominent anti-tumor activities and low toxic effects in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors.

PubMed

Thevenot, Paul T; Sierra, Rosa A; Raber, Patrick L; Al-Khami, Amir A; Trillo-Tinoco, Jimena; Zarreii, Parisa; Ochoa, Augusto C; Cui, Yan; Del Valle, Luis; Rodriguez, Paulo C

2014-09-18

Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant of their survival and growth. However, the interaction between tumor-linked stress and antitumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

A Scopus-Based Analysis of Publication Activity in Kazakhstan from 2010 to 2015: Positive Trends, Concerns, and Possible Solutions.

PubMed

Yessirkepov, Marlen; Nurmashev, Bekaidar; Anartayeva, Mariya

2015-12-01

The article analyzes the publication activity of scientific authors from Kazakhstan based on Scopus and SCImago Journal & Country Rank data from 2010 to 2015. The number of indexed multidisciplinary and medical articles from the country has been steadily growing from 2011 onward and this can be due to the adoption of the new Law on Science in that year. Several regulatory legal acts have been issued in recent years aimed at improving the quality of local journals and the international recognition of academic degrees and titles. Publication activity of scientific authors from Kazakhstan was found to be higher than that from other countries in the Central Asian region. However, there are still many unresolved issues related to the English language barrier, lack of indexing status of local journals, and poor topical education on science writing and editing. As such, the number of articles published in 'predatory' journals remains sizable, and there are concerns over authors' negligence and plagiarism. The global solution to the discussed problems may be achieved by educating researchers, authors, reviewers, and editors.

Protein Kinase Cδ Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance

PubMed Central

Zikherman, Julie; Lau, Tannia; Leitges, Michael; Weiss, Arthur

2014-01-01

Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca2+-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation. PMID:24515435

Structural and functional analysis of mRNA export regulation by the nuclear pore complex.

PubMed

Lin, Daniel H; Correia, Ana R; Cai, Sarah W; Huber, Ferdinand M; Jette, Claudia A; Hoelz, André

2018-06-13

The nuclear pore complex (NPC) controls the passage of macromolecules between the nucleus and cytoplasm, but how the NPC directly participates in macromolecular transport remains poorly understood. In the final step of mRNA export, the DEAD-box helicase DDX19 is activated by the nucleoporins Gle1, Nup214, and Nup42 to remove Nxf1•Nxt1 from mRNAs. Here, we report crystal structures of Gle1•Nup42 from three organisms that reveal an evolutionarily conserved binding mode. Biochemical reconstitution of the DDX19 ATPase cycle establishes that human DDX19 activation does not require IP 6 , unlike its fungal homologs, and that Gle1 stability affects DDX19 activation. Mutations linked to motor neuron diseases cause decreased Gle1 thermostability, implicating nucleoporin misfolding as a disease determinant. Crystal structures of human Gle1•Nup42•DDX19 reveal the structural rearrangements in DDX19 from an auto-inhibited to an RNA-binding competent state. Together, our results provide the foundation for further mechanistic analyses of mRNA export in humans.

TMEM150C/Tentonin3 Is a Regulator of Mechano-gated Ion Channels.

PubMed

Anderson, Evan O; Schneider, Eve R; Matson, Jon D; Gracheva, Elena O; Bagriantsev, Sviatoslav N

2018-04-17

Neuronal mechano-sensitivity relies on mechano-gated ion channels, but pathways regulating their activity remain poorly understood. TMEM150C was proposed to mediate mechano-activated current in proprioceptive neurons. Here, we studied functional interaction of TMEM150C with mechano-gated ion channels from different classes (Piezo2, Piezo1, and the potassium channel TREK-1) using two independent methods of mechanical stimulation. We found that TMEM150C significantly prolongs the duration of the mechano-current produced by all three channels, decreases apparent activation threshold in Piezo2, and induces persistent current in Piezo1. We also show that TMEM150C is co-expressed with Piezo2 in trigeminal neurons, expanding its role beyond proprioceptors. Finally, we cloned TMEM150C from the trigeminal neurons of the tactile-foraging domestic duck and showed that it functions similarly to the mouse ortholog, demonstrating evolutionary conservation among vertebrates. Our studies reveal TMEM150C as a general regulator of mechano-gated ion channels from different classes. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A Scopus-Based Analysis of Publication Activity in Kazakhstan from 2010 to 2015: Positive Trends, Concerns, and Possible Solutions

PubMed Central

Nurmashev, Bekaidar; Anartayeva, Mariya

2015-01-01

The article analyzes the publication activity of scientific authors from Kazakhstan based on Scopus and SCImago Journal & Country Rank data from 2010 to 2015. The number of indexed multidisciplinary and medical articles from the country has been steadily growing from 2011 onward and this can be due to the adoption of the new Law on Science in that year. Several regulatory legal acts have been issued in recent years aimed at improving the quality of local journals and the international recognition of academic degrees and titles. Publication activity of scientific authors from Kazakhstan was found to be higher than that from other countries in the Central Asian region. However, there are still many unresolved issues related to the English language barrier, lack of indexing status of local journals, and poor topical education on science writing and editing. As such, the number of articles published in 'predatory' journals remains sizable, and there are concerns over authors' negligence and plagiarism. The global solution to the discussed problems may be achieved by educating researchers, authors, reviewers, and editors. PMID:26713071

Resin Glycosides from the Morning Glory Family

NASA Astrophysics Data System (ADS)

Pereda-Miranda, Rogelio; Rosas-Ramírez, Daniel; Castañeda-Gómez, Jhon

Resin glycosides are part of a very extensive family of secondary metabolites known as glycolipids or lipo-oligosaccharides and are constituents of complex resins (glycoresins) (1) unique to the morning glory family, Convolvulaceae (2). These active principles are responsible for the drastic purgative action of all the important Convolvulaceous species used in traditional medicine throughout the world since ancient times. Several commercial purgative crude drugs can be prepared from the roots of different species of Mexican morning glories. Their incorporation as therapeutic agents in Europe is an outstanding example of the assimilation of botanical drugs from the Americas as substitutes for traditional Old World remedies (3). Even though phytochemical investigations on the constituents of these drugs were initiated during the second half of the nineteenth century, the structure of their active ingredients still remains poorly known for some examples of these purgative roots. During the last two decades, the higher resolution capabilities of modern analytical isolation techniques used in conjunction with powerful spectroscopic methods have facilitated the elucidation of the active principles of these relevant herbal products.

A landscape-based reconnaissance survey of estrogenicactivity in streams of the upper Potomac, upper James,and Shenandoah Rivers, USA

USGS Publications Warehouse

Young, John A.; Iwanowicz, Luke R.; Sperry, Adam J.; Blazer, Vicki

2014-01-01

Endocrine-disrupting compounds (EDCs) are becoming of increasing concern in waterways of the USA and worldwide. What remains poorly understood, however, is how prevalent these emerging contaminants are in the environment and what methods are best able to determine landscape sources of EDCs. We describe the development of a spatially structured sampling design and a reconnaissance survey of estrogenic activity along gradients of land use within sub-watersheds.We present this example as a useful approach for state and federal agencies with an interest in identifying locations potentially impacted by EDCs that warrant more intensive, focused research. Our study confirms the importance of agricultural activities on levels of a measured estrogenic equivalent (E2Eq) and also highlights the importance of other potential sources of E2Eq in areas where intensive agriculture is not the dominant land use. Through application of readily available geographic information system (GIS) data, coupled with spatial statistical analysis, we demonstrate the correlation of specific land use types to levels of estrogenic activity across a large area in a consistent and unbiased manner.

Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury

PubMed Central

Overall, Christopher C.

2017-01-01

The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile. After spinal cord injury (SCI), meningeal ILC2s are activated in an IL-33–dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild-type lung-derived ILC2s into the meningeal space of IL-33R−/− animals partially improves recovery after SCI. These data characterize ILC2s as a novel meningeal cell type that responds to SCI and could lead to new therapeutic insights for neuroinflammatory conditions. PMID:27994070

CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling.

PubMed

Lin, C; Liao, W; Jian, Y; Peng, Y; Zhang, X; Ye, L; Cui, Y; Wang, B; Wu, X; Xiong, Z; Wu, S; Li, J; Wang, X; Song, L

2017-06-29

Metastatic relapse remains largely incurable and a major challenge of clinical management in breast cancer, but the underlying mechanisms are poorly understood. Herein, we report that CGI-99 is overexpressed in breast cancer tissues from patients with metastatic recurrence within 5 years. High CGI-99 significantly predicts poorer 5-year metastasis-free patient survival. We find that CGI-99 increases breast cancer stem cell properties, and potentiates efficient tumor lung colonization and outgrowth in vivo. Furthermore, we demonstrate that CGI-99 activates the autocrine interleukin-6 (IL-6)/STAT3 signaling by increasing the accumulation and activity of RNA polymerase II and p300 cofactor at the proximal promoter of IL-6. Importantly, delivery of the IL-6-receptor humanized monoclonal antibody tocilizumab robustly abrogates CGI-99-induced metastasis in vivo. Finally, we find that high levels of CGI-99 are significantly correlated with STAT3 hyperactivation in breast cancer patients. These findings reveal a potential mechanism for constitutive activation of autocrine IL-6/STAT3 signaling and may suggest a novel target for clinical intervention in breast cancer.

Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development

PubMed Central

Stoffel, Wilhelm; Jenke, Britta; Blöck, Barbara; Zumbansen, Markus; Koebke, Jürgen

2005-01-01

Neutral sphingomyelinases sphingomyelin phosphodiesterase (SMPD)2 and -3 hydrolyze sphingomyelin to phosphocholine and ceramide. smpd2 is expressed ubiquitously, and smpd3 is expressed predominantly in neurons of the CNS. Their activation and the functions of the released ceramides have been associated with signaling pathways in cell growth, differentiation, and apoptosis. However, these cellular responses remain poorly understood. Here we describe the generation and characterization of the smpd3–/– and smpd2–/–smpd3–/– double mutant mouse, which proved to be devoid of neutral sphingomyelinase activity. SMPD3 plays a pivotal role in the control of late embryonic and postnatal development: the smpd3-null mouse develops a novel form of dwarfism and delayed puberty as part of a hypothalamus-induced combined pituitary hormone deficiency. Our studies suggest that SMPD3 is segregated into detergent-resistant subdomains of Golgi membranes of hypothalamic neurosecretory neurons, where its transient activation modifies the lipid bilayer, an essential step in the Golgi secretory pathway. The smpd3–/– mouse might mimic a form of human combined pituitary hormone deficiency. PMID:15764706

Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development.

PubMed

Stoffel, Wilhelm; Jenke, Britta; Blöck, Barbara; Zumbansen, Markus; Koebke, Jürgen

2005-03-22

Neutral sphingomyelinases sphingomyelin phosphodiesterase (SMPD)2 and -3 hydrolyze sphingomyelin to phosphocholine and ceramide. smpd2 is expressed ubiquitously, and smpd3 is expressed predominantly in neurons of the CNS. Their activation and the functions of the released ceramides have been associated with signaling pathways in cell growth, differentiation, and apoptosis. However, these cellular responses remain poorly understood. Here we describe the generation and characterization of the smpd3(-/-) and smpd2(-/-)smpd3(-/-) double mutant mouse, which proved to be devoid of neutral sphingomyelinase activity. SMPD3 plays a pivotal role in the control of late embryonic and postnatal development: the smpd3-null mouse develops a novel form of dwarfism and delayed puberty as part of a hypothalamus-induced combined pituitary hormone deficiency. Our studies suggest that SMPD3 is segregated into detergent-resistant subdomains of Golgi membranes of hypothalamic neurosecretory neurons, where its transient activation modifies the lipid bilayer, an essential step in the Golgi secretory pathway. The smpd3(-/-) mouse might mimic a form of human combined pituitary hormone deficiency.

Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

NASA Astrophysics Data System (ADS)

Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

Phylogenetics beyond biology.

PubMed

Retzlaff, Nancy; Stadler, Peter F

2018-06-21

Evolutionary processes have been described not only in biology but also for a wide range of human cultural activities including languages and law. In contrast to the evolution of DNA or protein sequences, the detailed mechanisms giving rise to the observed evolution-like processes are not or only partially known. The absence of a mechanistic model of evolution implies that it remains unknown how the distances between different taxa have to be quantified. Considering distortions of metric distances, we first show that poor choices of the distance measure can lead to incorrect phylogenetic trees. Based on the well-known fact that phylogenetic inference requires additive metrics, we then show that the correct phylogeny can be computed from a distance matrix [Formula: see text] if there is a monotonic, subadditive function [Formula: see text] such that [Formula: see text] is additive. The required metric-preserving transformation [Formula: see text] can be computed as the solution of an optimization problem. This result shows that the problem of phylogeny reconstruction is well defined even if a detailed mechanistic model of the evolutionary process remains elusive.

Between hope and abandonment: black queer collectivity and the affective labour of biomedicalised HIV prevention.

PubMed

van Doorn, Niels

2012-01-01

This paper investigates how current transformations in HIV prevention in the USA are intensifying a logic of viral containment rooted in biomedicine and behavioural science, in order to curb the recent rise in new HIV infections, predominantly among young African-American 'men who have sex with men'. Based on fieldwork in Baltimore, I examine how this paradigm shift is translated into concrete prevention activities that focus on HIV testing and treatment. By attending to the affective labour performed by members of Baltimore's Ballroom scene - a kinship system of black queer youth structured around competitive dance and performance - I show how the emergent 'Test & Treat' approach becomes a polyvalent object that attracts a host of optimistic investments in collective and individual prosperity, which nevertheless threaten to remain unrequited. Finally, I argue that the current move towards a biomedically mediated model of viral management depoliticises the struggle against HIV by suggesting that we can treat our way out of an epidemic that in fact remains intricately interwoven with racialised violence against the queer, the poor and the otherwise dispossessed.

A Spatially Resolved Investigation on the Influence of AGN and Star Formation in a Lensed Main-Sequence Galaxy at z = 2.39

NASA Astrophysics Data System (ADS)

Fischer, Travis; Rigby, Jane; Gladders, Michael; Sharon, Keren q.; Barrientos, L. Felipe; Bayliss, Matt; Dahle, Håkon; Florian, Michael; Johnson, Traci Lin; Wuyts, Eva

2018-01-01

We present rest-frame optical SINFONI integral field spectroscopy and rest-frame UV HST imaging of a lensed galaxy hosting an active galactic nucleus (AGN) at z = 2.39. Galactic wind feedback is widely acknowledged to play a critical role in the evolution of galaxies, however, the physical mechanisms involved and the relative importance of AGN and star formation as the main feedback drivers remain poorly understood. AGN-driven feedback has been evident in very luminous but rare quasars and radio galaxies, but observational evidence remains lacking for less extreme, “normal” star-forming galaxies. We report, for the first time at high redshift, spatially resolved velocity profiles and geometries of an AGN-driven outflow in a normal star-forming galaxy and spatial extents and morphologies of Lyα emission and stellar UV continuum. Analyzing these measurements in tandem, we determine the physical conditions, geometry, and excitation sources of the interstellar medium in a star-forming, AGN-hosting galaxy at cosmic noon.

Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

PubMed Central

Prosper, Boris W.; Marathe, Swanand; Husain, Basma F. A.; Kernie, Steven G.; Bartlett, Perry F.; Vaidya, Vidita A.

2014-01-01

Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis. PMID:24922313

Seasonal divergence in the interannual responses of Northern Hemisphere vegetation activity to variations in diurnal climate.

PubMed

Wu, Xiuchen; Liu, Hongyan; Li, Xiaoyan; Liang, Eryuan; Beck, Pieter S A; Huang, Yongmei

2016-01-11

Seasonal asymmetry in the interannual variations in the daytime and nighttime climate in the Northern Hemisphere (NH) is well documented, but its consequences for vegetation activity remain poorly understood. Here, we investigate the interannual responses of vegetation activity to variations of seasonal mean daytime and nighttime climate in NH (>30 °N) during the past decades using remote sensing retrievals, FLUXNET and tree ring data. Despite a generally significant and positive response of vegetation activity to seasonal mean maximum temperature (Tmax) in ~22-25% of the boreal (>50 °N) NH between spring and autumn, spring-summer progressive water limitations appear to decouple vegetation activity from the mean summer Tmax, particularly in climate zones with dry summers. Drought alleviation during autumn results in vegetation recovery from the marked warming-induced drought limitations observed in spring and summer across 24-26% of the temperate NH. Vegetation activity exhibits a pervasively negative correlation with the autumn mean minimum temperature, which is in contrast to the ambiguous patterns observed in spring and summer. Our findings provide new insights into how seasonal asymmetry in the interannual variations in the mean daytime and nighttime climate interacts with water limitations to produce spatiotemporally variable responses of vegetation growth.

Real-time monitoring prefrontal activities during online video game playing by functional near-infrared spectroscopy.

PubMed

Li, Yue; Zhang, Lei; Long, Kehong; Gong, Hui; Lei, Hao

2018-02-16

A growing body of literature has suggested that video game playing can induce functional and structural plasticity of the brain. The underlying mechanisms, however, remain poorly understood. In this study, functional near-infrared spectroscopy (fNIRS) was used to record prefrontal activities in 24 experienced game players when they played a massively multiplayer online battle arena video game, League of Legends (LOL), under naturalistic conditions. It was observed that game onset was associated with significant activations in the ventrolateral prefrontal cortex (VLPFC) and concomitant deactivations in the dorsolateral prefrontal cortex (DLPFC) and frontal pole area (FPA). Game events, such as slaying an enemy and being slain by an enemy evoked region-specific time-locked hemodynamic/oxygenation responses in the prefrontal cortex (PFC). It was proposed that the VLPFC activities during LOL playing are likely responses to visuo-motor task load of the game, while the DLPFC/FPA activities may be involved in the constant shifts of attentional states and allocation of cognitive resources required by game playing. The present study demonstrated that it is feasible to use fNIRS to monitor real-time prefrontal activity during online video game playing. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Seasonal divergence in the interannual responses of Northern Hemisphere vegetation activity to variations in diurnal climate

PubMed Central

Wu, Xiuchen; Liu, Hongyan; Li, Xiaoyan; Liang, Eryuan; Beck, Pieter S. A.; Huang, Yongmei

2016-01-01

Seasonal asymmetry in the interannual variations in the daytime and nighttime climate in the Northern Hemisphere (NH) is well documented, but its consequences for vegetation activity remain poorly understood. Here, we investigate the interannual responses of vegetation activity to variations of seasonal mean daytime and nighttime climate in NH (>30 °N) during the past decades using remote sensing retrievals, FLUXNET and tree ring data. Despite a generally significant and positive response of vegetation activity to seasonal mean maximum temperature () in ~22–25% of the boreal (>50 °N) NH between spring and autumn, spring-summer progressive water limitations appear to decouple vegetation activity from the mean summer , particularly in climate zones with dry summers. Drought alleviation during autumn results in vegetation recovery from the marked warming-induced drought limitations observed in spring and summer across 24–26% of the temperate NH. Vegetation activity exhibits a pervasively negative correlation with the autumn mean minimum temperature, which is in contrast to the ambiguous patterns observed in spring and summer. Our findings provide new insights into how seasonal asymmetry in the interannual variations in the mean daytime and nighttime climate interacts with water limitations to produce spatiotemporally variable responses of vegetation growth. PMID:26751166

Moderating effects of social engagement on driving cessation in older women.

PubMed

Pachana, Nancy A; Leung, Janni K; Gardiner, Paul A; McLaughlin, Deirdre

2016-08-01

Driving cessation in later life is associated with depression. This study examines if social support can buffer the negative effects of driving cessation on older women's mental health. Participants were drawn from the 1921-1926 cohort of the Australian Longitudinal Study on Women's Health (ALSWH) and included 4,075 older women (aged 76-87 years) who drove at baseline, following them for three years to assess driving cessation. The outcome variable was mental health, measured by the mental health index (MHI) of the SF-36. The explanatory variables were social support factors, including social interaction, whether the women were living alone or with others, and engagement in social activities. Control variables included age, country of birth, area of residence, ability to manage on income, marital status, and general health. Main effect results showed that poor mental health was predicted by driving cessation, low levels of social interaction, and non-engagement in social activities. There was a significant interaction effect of driving status by social activities engagement on mental health. Women who remained active in their engagement of social activities were able to maintain a good level of mental health despite driving cessation. Engagement and participation in social activities can help older women who stopped driving maintain a good level of mental health.

Activation of Gαq subunits up-regulates the expression of the tumor suppressor Fhit.

PubMed

Zuo, Hao; Chan, Anthony S L; Ammer, Hermann; Wong, Yung H

2013-12-01

The tumor suppressor Fhit protein is defective or absent in many tumor cells due to methylation, mutation or deletion of the FHIT gene. Despite numerous attempts to unravel the functions of Fhit, the mechanisms by which the function and expression of Fhit are regulated remain poorly understood. We have recently shown that activated Gαq subunits interact directly with Fhit and enhance its inhibitory effect on cell growth. Here we investigated the regulation of Fhit expression by Gq. Our results showed that Fhit was up-regulated specifically by activating Gα subunits of the Gq subfamily but not by those of the other G protein subfamilies. This up-regulation effect was mediated by a PKC/MEK pathway independent of Src-mediated Fhit Tyr(114) phosphorylation. We further demonstrated that elevated Fhit expression was due to the specific regulation of Fhit protein synthesis in the ribosome by activated Gαq, where the regulations of cap-dependent protein synthesis were apparently not required. Moreover, we showed that activated Gαq could increase cell-cell adhesion through Fhit. These findings provide a possible handle to modulate the level of the Fhit tumor suppressor by manipulating the activity of Gq-coupled receptors. © 2013. Published by Elsevier Inc. All rights reserved.

An investigation of the relationship between subjective sleep quality, loneliness and mood in an Australian sample: can daily routine explain the links?

PubMed

Smith, Simon Squire; Kozak, Nahum; Sullivan, Karen Anne

2012-03-01

Loneliness and low mood are associated with significant negative health outcomes including poor sleep, but the strength of the evidence underlying these associations varies. There is strong evidence that poor sleep quality and low mood are linked, but only emerging evidence that loneliness and poor sleep are associated. To independently replicate the finding that loneliness and poor subjective sleep quality are associated and to extend past research by investigating lifestyle regularity as a possible mediator of relationships, since lifestyle regularity has been linked to loneliness and poor sleep. Using a cross-sectional design, 97 adults completed standardized measures of loneliness, lifestyle regularity, subjective sleep quality and mood. Loneliness was a significant predictor of sleep quality. Lifestyle regularity was not a predictor of, nor associated with, mood, sleep quality or loneliness. This study provides an important independent replication of the association between poor sleep and loneliness. However, the mechanism underlying this link remains unclear. A theoretically plausible mechanism for this link, lifestyle regularity, does not explain the relationship between loneliness and poor sleep. The nexus between loneliness and poor sleep is unlikely to be broken by altering the social rhythm of patients who present with poor sleep and loneliness.

Overt Naming fMRI Pre- and Post- TMS: Two Nonfluent Aphasia Patients, with and without Improved Naming Post- TMS

PubMed Central

Martin, Paula I; Naeser, Margaret A.; Ho, Michael; Doron, Karl W.; Kurland, Jacquie; Kaplan, Jerome; Wang, Yunyan; Nicholas, Marjorie; Baker, Errol H.; Alonso, Miguel; Fregni, Felipe; Pascual-Leone, Alvaro

2009-01-01

Two chronic, nonfluent aphasia patients participated in overt naming fMRI scans, pre- and post- a series of repetitive transcranial magnetic stimulation (rTMS) treatments as part of a TMS study to improve naming. Each patient received ten, 1-Hz rTMS treatments to suppress a part of R pars triangularis. P1 was a ‘good responder’ with improved naming and phrase length; P2 was a ‘poor responder’ without improved naming. Pre- TMS (10 yr. poststroke), P1 had significant activation in R and L sensorimotor cortex, R IFG, and in both L and R SMA during overt naming fMRI (28% pictures named. At 3 mo. post- TMS (42% named), P1 showed continued activation in R and L sensorimotor cortex, R IFG, and in R and L SMA. At 16 mo. post- TMS (58% named), he also showed significant activation in R and L sensorimotor cortex mouth and R IFG. He now showed a significant increase in activation in the L SMA compared to pre- TMS and at 3 mo. post- TMS (p<.02; p<.05, respectively). At 16 mo. there was also greater activation in L than R SMA (p<.08). At 46 mo. post- TMS (42% named), this new LH pattern of activation continued. He improved on the Boston Naming Test from 11 pictures named pre- TMS, to scores ranging from 14-18 pictures, post- TMS (2 mo. to 43 mo. post- TMS). His longest phrase length (Cookie Theft picture) improved from 3 words pre- TMS, to 5-6 words post- TMS. Pre- TMS (1.5 yr. poststroke), P2 had significant activation in R IFG (3% pictures named). At 3 and 6 mo. post- TMS, there was no longer significant activation in R IFG, but significant activation was present in R sensorimotor cortex. On all three fMRI scans, P2 had significant activation in both the L and R SMA. There was no new, lasting perilesional LH activation across sessions for this patient. Over time, there was little or no change in his activation. His naming remained only at 1-2 pictures during all three fMRI scans. His BNT score and longest phrase length remained at 1 word, post- TMS. Lesion site may play a role in each patient’s fMRI activation pattern and response to TMS treatment. P2, the poor responder, had an atypical frontal lesion in the L motor and premotor cortex that extended high, near brain vertex, with deep white matter lesion near L SMA. P2 also had frontal lesion in the posterior middle frontal gyrus, an area important for naming (Duffau et al., 2003); P1 did not. Additionally, P2 had lesion inferior and posterior to Wernicke’s area, in parts of BA 21 and 37, whereas P1 did not. The fMRI data of our patient who had good response following TMS support the notion that restoration of the LH language network is linked in part, to better recovery of naming and phrase length in nonfluent aphasia. PMID:19695692

Overt naming fMRI pre- and post-TMS: Two nonfluent aphasia patients, with and without improved naming post-TMS.

PubMed

Martin, Paula I; Naeser, Margaret A; Ho, Michael; Doron, Karl W; Kurland, Jacquie; Kaplan, Jerome; Wang, Yunyan; Nicholas, Marjorie; Baker, Errol H; Alonso, Miguel; Fregni, Felipe; Pascual-Leone, Alvaro

2009-10-01

Two chronic, nonfluent aphasia patients participated in overt naming fMRI scans, pre- and post-a series of repetitive transcranial magnetic stimulation (rTMS) treatments as part of a TMS study to improve naming. Each patient received 10, 1-Hz rTMS treatments to suppress a part of R pars triangularis. P1 was a 'good responder' with improved naming and phrase length; P2 was a 'poor responder' without improved naming. Pre-TMS (10 years poststroke), P1 had significant activation in R and L sensorimotor cortex, R IFG, and in both L and R SMA during overt naming fMRI (28% pictures named). At 3 mo. post-TMS (42% named), P1 showed continued activation in R and L sensorimotor cortex, R IFG, and in R and L SMA. At 16 mo. post-TMS (58% named), he also showed significant activation in R and L sensorimotor cortex mouth and R IFG. He now showed a significant increase in activation in the L SMA compared to pre-TMS and at 3 mo. post-TMS (p < .02; p < .05, respectively). At 16 mo. there was also greater activation in L than R SMA (p < .08). At 46 mo. post-TMS (42% named), this new LH pattern of activation continued. He improved on the Boston Naming Test from 11 pictures named pre-TMS, to scores ranging from 14 to 18 pictures, post-TMS (2-43 mo. post-TMS). His longest phrase length (Cookie Theft picture) improved from three words pre-TMS, to 5-6 words post-TMS. Pre-TMS (1.5 years poststroke), P2 had significant activation in R IFG (3% pictures named). At 3 and 6 mo. post-TMS, there was no longer significant activation in R IFG, but significant activation was present in R sensorimotor cortex. On all three fMRI scans, P2 had significant activation in both the L and R SMA. There was no new, lasting perilesional LH activation across sessions for this patient. Over time, there was little or no change in his activation. His naming remained only at 1-2 pictures during all three fMRI scans. His BNT score and longest phrase length remained at one word, post-TMS. Lesion site may play a role in each patient's fMRI activation pattern and response to TMS treatment. P2, the poor responder, had an atypical frontal lesion in the L motor and premotor cortex that extended high, near brain vertex, with deep white matter lesion near L SMA. P2 also had frontal lesion in the posterior middle frontal gyrus, an area important for naming (Duffau et al., 2003); P1 did not. Additionally, P2 had lesion inferior and posterior to Wernicke's area, in parts of BA 21 and 37, whereas P1 did not. The fMRI data of our patient who had good response following TMS support the notion that restoration of the LH language network is linked in part, to better recovery of naming and phrase length in nonfluent aphasia.

Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy

PubMed Central

Tsujimura, Shizuyo; Adachi, Tomoko; Saito, Kazuyoshi; Tanaka, Yoshiya

2017-01-01

Introduction P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp+CD4+ cells in organ manifestations in refractory SLE. Methods The proportion of P-gp+CD4+ cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. Results CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4+ cells and CD69-expressing CD4+ cells in peripheral blood was higher in SLE than control. The proportion of P-gp+CD69+CD4+ cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp+CD69+CD4+ cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp+CD69+CD4+ cells. Marked accumulation of P-gp+CD4+ cells in renal interstitial tissue and high proportion of peripheral P-gp+CD69+CD4+ cells were noted in patients with proliferative LN. Conclusions The results showed high proportion of P-gp+CD69+CD4+ cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4+ T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment. PMID:29225917

Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy.

PubMed

Tsujimura, Shizuyo; Adachi, Tomoko; Saito, Kazuyoshi; Tanaka, Yoshiya

2017-01-01

P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp + CD4 + cells in organ manifestations in refractory SLE. The proportion of P-gp + CD4 + cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4 + cells and CD69-expressing CD4 + cells in peripheral blood was higher in SLE than control. The proportion of P-gp + CD69 + CD4 + cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp + CD69 + CD4 + cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp + CD69 + CD4 + cells. Marked accumulation of P-gp + CD4 + cells in renal interstitial tissue and high proportion of peripheral P-gp + CD69 + CD4 + cells were noted in patients with proliferative LN. The results showed high proportion of P-gp + CD69 + CD4 + cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4 + T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.

Mind the gaps - the epidemiology of poor-quality anti-malarials in the malarious world - analysis of the WorldWide Antimalarial Resistance Network database

PubMed Central

2014-01-01

Background Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global database and linked Antimalarial Quality Surveyor, an online visualization tool. Analysis of the database is described here, the limitations of the studies and data reported, and their public health implications discussed. Methods The database collates customized summaries of 251 published anti-malarial quality reports in English, French and Spanish by time and location since 1946. It also includes information on assays to determine quality, sampling and medicine regulation. Results No publicly available reports for 60.6% (63) of the 104 malaria-endemic countries were found. Out of 9,348 anti-malarials sampled, 30.1% (2,813) failed chemical/packaging quality tests with 39.3% classified as falsified, 2.3% as substandard and 58.3% as poor quality without evidence available to categorize them as either substandard or falsified. Only 32.3% of the reports explicitly described their definitions of medicine quality and just 9.1% (855) of the samples collected in 4.6% (six) surveys were conducted using random sampling techniques. Packaging analysis was only described in 21.5% of publications and up to twenty wrong active ingredients were found in falsified anti-malarials. Conclusions There are severe neglected problems with anti-malarial quality but there are important caveats to accurately estimate the prevalence and distribution of poor quality anti-malarials. The lack of reports in many malaria-endemic areas, inadequate sampling techniques and inadequate chemical analytical methods and instrumental procedures emphasizes the need to interpret medicine quality results with caution. The available evidence demonstrates the need for more investment to improve both sampling and analytical methodology and to achieve consensus in defining different types of poor quality medicines. PMID:24712972

Achieving Operability via the Mission System Paradigm

NASA Technical Reports Server (NTRS)

Hammer, Fred J.; Kahr, Joseph R.

2006-01-01

In the past, flight and ground systems have been developed largely-independently, with the flight system taking the lead, and dominating the development process. Operability issues have been addressed poorly in planning, requirements, design, I&T, and system-contracting activities. In many cases, as documented in lessons-learned, this has resulted in significant avoidable increases in cost and risk. With complex missions and systems, operability is being recognized as an important end-to-end design issue. Never-the-less, lessons-learned and operability concepts remain, in many cases, poorly understood and sporadically applied. A key to effective application of operability concepts is adopting a 'mission system' paradigm. In this paradigm, flight and ground systems are treated, from an engineering and management perspective, as inter-related elements of a larger mission system. The mission system consists of flight hardware, flight software, telecom services, ground data system, testbeds, flight teams, science teams, flight operations processes, procedures, and facilities. The system is designed in functional layers, which span flight and ground. It is designed in response to project-level requirements, mission design and an operations concept, and is developed incrementally, with early and frequent integration of flight and ground components.

Perceptual and memorial contributions to developmental prosopagnosia.

PubMed

Ulrich, Philip I N; Wilkinson, David T; Ferguson, Heather J; Smith, Laura J; Bindemann, Markus; Johnston, Robert A; Schmalzl, Laura

2017-02-01

Developmental prosopagnosia (DP) is commonly associated with the failure to properly perceive individuating facial properties, notably those conveying configural or holistic content. While this may indicate that the primary impairment is perceptual, it is conceivable that some cases of DP are instead caused by a memory impairment, with any perceptual complaint merely allied rather than causal. To investigate this possibility, we administered a battery of face perception tasks to 11 individuals who reported that their face recognition difficulties disrupt daily activity and who also performed poorly on two formal tests of face recognition. Group statistics identified, relative to age- and gender-matched controls, difficulties in apprehending global-local relations and the holistic properties of faces, and in matching across viewpoints, but these were mild in nature and were not consistently evident at the level of individual participants. Six of the 11 individuals failed to show any evidence of perceptual impairment. In the remaining five individuals, no single perceptual deficit, or combination of deficits, was necessary or sufficient for poor recognition performance. These data suggest that some cases of DP are better explained by a memorial rather than perceptual deficit, and highlight the relevance of the apperceptive/associative distinction more commonly applied to the allied syndrome of acquired prosopagnosia.

Solution Coating of Pharmaceutical Nanothin Films and Multilayer Nanocomposites with Controlled Morphology and Polymorphism.

PubMed

Horstman, Elizabeth M; Kafle, Prapti; Zhang, Fengjiao; Zhang, Yifu; Kenis, Paul J A; Diao, Ying

2018-03-28

Nanosizing is rapidly emerging as an alternative approach to enhance solubility and thus the bioavailability of poorly aqueous soluble active pharmaceutical ingredients (APIs). Although numerous techniques have been developed to perform nanosizing of API crystals, precise control and modulation of their size in an energy and material efficient manner remains challenging. In this study, we present meniscus-guided solution coating as a new technique to produce pharmaceutical thin films of nanoscale thickness with controlled morphology. We demonstrate control of aspirin film thickness over more than 2 orders of magnitude, from 30 nm to 1.5 μm. By varying simple process parameters such as the coating speed and the solution concentration, the aspirin film morphology can also be modulated by accessing different coating regimes, namely the evaporation regime and the Landau-Levich regime. Using ellipticine-a poorly water-soluble anticancer drug-as another model compound, we discovered a new polymorph kinetically trapped during solution coating. Furthermore, the polymorphic outcome can be controlled by varying coating conditions. We further performed layer-by-layer coating of multilayer nanocomposites, with alternating thin films of ellipticine and a biocompatible polymer, which demonstrate the potential of additive manufacturing of multidrug-personalized dosage forms using this approach.

Improvement of Learning and Memory Induced by Cordyceps Polypeptide Treatment and the Underlying Mechanism

PubMed Central

2018-01-01

Our previous research revealed that Cordyceps militaris can improve the learning and memory, and although the main active ingredient should be its polypeptide complexes, the underlying mechanism of its activity remains poorly understood. In this study, we explored the mechanisms by which Cordyceps militaris improves learning and memory in a mouse model. Mice were given scopolamine hydrobromide intraperitoneally to establish a mouse model of learning and memory impairment. The effects of Cordyceps polypeptide in this model were tested using the Morris water maze test; serum superoxide dismutase activity; serum malondialdehyde levels; activities of acetyl cholinesterase, Na+-k+-ATPase, and nitric oxide synthase; and gamma aminobutyric acid and glutamate contents in brain tissue. Moreover, differentially expressed genes and the related cellular signaling pathways were screened using an mRNA expression profile chip. The results showed that the genes Pik3r5, Il-1β, and Slc18a2 were involved in the effects of Cordyceps polypeptide on the nervous system of these mice. Our findings suggest that Cordyceps polypeptide may improve learning and memory in the scopolamine-induced mouse model of learning and memory impairment by scavenging oxygen free radicals, preventing oxidative damage, and protecting the nervous system. PMID:29736181

Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin.

PubMed

Chen, Hsin-Yi; Shen, Che-Hung; Tsai, Yuh-Tyng; Lin, Feng-Chi; Huang, Yuan-Ping; Chen, Ruey-Hwa

2004-12-01

Brk (for breast tumor kinase) is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk was originally identified from a human metastatic breast tumor, and its overexpression is frequently observed in breast cancer and several other cancer types. However, the molecular mechanism by which this kinase participates in tumorigenesis remains poorly characterized. In the present study, we not only identified paxillin as the binding partner and substrate of Brk but also discovered a novel signaling pathway by which Brk mediates epidermal growth factor (EGF)-induced paxillin phosphorylation. We show that EGF stimulation activates the catalytic activity of Brk, which in turn phosphorylates paxillin at Y31 and Y118. These phosphorylation events promote the activation of small GTPase Rac1 via the function of CrkII. Through this pathway, Brk is capable of promoting cell motility and invasion and functions as a mediator of EGF-induced migration and invasion. In accordance with these functional roles, Brk translocates to membrane ruffles, where it colocalizes with paxillin during cell migration. Together, our findings identify novel signaling and biological roles of Brk and indicate the first potential link between Brk and metastatic malignancy.

High surface area synthesis, electrochemical activity, and stability of tungsten carbide supported Pt during oxygen reduction in proton exchange membrane fuel cells

NASA Astrophysics Data System (ADS)

Chhina, H.; Campbell, S.; Kesler, O.

The oxidation of carbon catalyst supports to carbon dioxide gas leads to degradation in catalyst performance over time in proton exchange membrane fuel cells (PEMFCs). The electrochemical stability of Pt supported on tungsten carbide has been evaluated on a carbon-based gas diffusion layer (GDL) at 80 °C and compared to that of HiSpec 4000™ Pt/Vulcan XC-72R in 0.5 M H 2SO 4. Due to other electrochemical processes occurring on the GDL, detailed studies were also performed on a gold mesh substrate. The oxygen reduction reaction (ORR) activity was measured both before and after accelerated oxidation cycles between +0.6 V and +1.8 V vs. RHE. Tafel plots show that the ORR activity remained high even after accelerated oxidation tests for Pt/tungsten carbide, while the ORR activity was extremely poor after accelerated oxidation tests for HiSpec 4000™. In order to make high surface area tungsten carbide, three synthesis routes were investigated. Magnetron sputtering of tungsten on carbon was found to be the most promising route, but needs further optimization.

Antiviral Activity of Porcine Interferon Regulatory Factor 1 against Swine Viruses in Cell Culture.

PubMed

Li, Yongtao; Chang, Hongtao; Yang, Xia; Zhao, Yongxiang; Chen, Lu; Wang, Xinwei; Liu, Hongying; Wang, Chuanqing; Zhao, Jun

2015-11-17

Interferon regulatory factor 1 (IRF1), as an important transcription factor, is abundantly induced upon virus infections and participates in host antiviral immune responses. However, the roles of porcine IRF1 (poIRF1) in host antiviral defense remain poorly understood. In this study, we determined that poIRF1 was upregulated upon infection with viruses and distributed in nucleus in porcine PK-15 cells. Subsequently, we tested the antiviral activities of poIRF1 against several swine viruses in cells. Overexpression of poIRF1 can efficiently suppress the replication of viruses, and knockdown of poIRF1 promotes moderately viral replication. Interestingly, overexpression of poIRF1 enhances dsRNA-induced IFN-β and IFN-stimulated response element (ISRE) promoter activation, whereas knockdown of poIRF1 cannot significantly affect the activation of IFN-β promoter induced by RNA viruses. This study suggests that poIRF1 plays a significant role in cellular antiviral response against swine viruses, but might be dispensable for IFN-β induction triggered by RNA viruses in PK-15 cells. Given these results, poIRF1 plays potential roles in cellular antiviral responses against swine viruses.

Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes.

PubMed

Dey, Aditi; Hao, Shuai; Wosiski-Kuhn, Marlena; Stranahan, Alexis M

2017-09-01

Type 2 diabetes is increasingly recognized as a risk factor for Alzheimer's disease, but the underlying mechanisms remain poorly understood. Hyperphosphorylation of the microtubule-associated protein tau has been reported in rodent models of diabetes, including db/db mice, which exhibit insulin resistance and chronically elevated glucocorticoids due to leptin receptor insufficiency. In this report, we investigated endocrine mechanisms for hippocampal tau phosphorylation in db/db and wild-type mice. By separately manipulating peripheral and intrahippocampal corticosterone levels, we determined that hippocampal corticosteroid exposure promotes tau phosphorylation and activates glycogen synthase kinase 3β (GSK3β). Subsequent experiments in hippocampal slice preparations revealed evidence for a nongenomic interaction between glucocorticoids and GSK3β. To examine whether GSK3β activation mediates tau phosphorylation and impairs memory in diabetes, db/db and wild-type mice received intrahippocampal infusions of TDZD-8, a non-ATP competitive thiadiazolidinone inhibitor of GSK3β. Intrahippocampal TDZD-8 blocked tau hyperphosphorylation and normalized hippocampus-dependent memory in db/db mice, suggesting that pathological synergy between diabetes and Alzheimer's disease may involve glucocorticoid-mediated activation of GSK3β. Copyright © 2017 Elsevier Inc. All rights reserved.

North Atlantic Storm Activity During the Younger Dryas

NASA Astrophysics Data System (ADS)

Toomey, M.

2015-12-01

The risks posed to cities along the Eastern Seaboard by a potential intensification of tropical cyclone activity over the coming decades remain poorly constrained, in part, due to a lack of available storm proxy records that extend beyond the relatively stable climates of the late Holocene. Previous work in the Bahamas shows that coarse-grained, high-energy event layers in carbonate bank margin sediments: (1) closely track recent historic hurricane events and (2) that the sensitivity of this proxy may be less affected by the deglacial changes in sea level that have limited our ability to reconstruct past hurricane activity using overwash records from back-barrier beach settings. Here we present a record of storm triggered turbidite deposition from a suite of well dated (e.g. Lynch-Stieglitz et al., 2011, Paleoceanography) jumbo piston cores taken offbank (300-500 mbsl) the Dry Tortugas, Florida, that spans abrupt transitions in North Atlantic sea surface temperature and thermohaline circulation during the Younger Dryas (12.9 - 11.5 kyr BP). This record, along with General Circulation Model output (TraCE: NCAR-CGD), indicates strong hurricane activity may have occurred along Southeastern US coasts through this interval despite considerably colder North Atlantic SSTs.

Human cytomegalovirus-induced NKG2C(hi) CD57(hi) natural killer cells are effectors dependent on humoral antiviral immunity.

PubMed

Wu, Zeguang; Sinzger, Christian; Frascaroli, Giada; Reichel, Johanna; Bayer, Carina; Wang, Li; Schirmbeck, Reinhold; Mertens, Thomas

2013-07-01

Recent studies indicate that expansion of NKG2C-positive natural killer (NK) cells is associated with human cytomegalovirus (HCMV); however, their activity in response to HCMV-infected cells remains unclear. We show that NKG2C(hi) CD57(hi) NK cells gated on CD3(neg) CD56(dim) cells can be phenotypically identified as HCMV-induced NK cells that can be activated by HCMV-infected cells. Using HCMV-infected autologous macrophages as targets, we were able to show that these NKG2C(hi) CD57(hi) NK cells are highly responsive to HCMV-infected macrophages only in the presence of HCMV-specific antibodies, whereas they are functionally poor effectors of natural cytotoxicity. We further demonstrate that NKG2C(hi) CD57(hi) NK cells are intrinsically responsive to signaling through CD16 cross-linking. Our findings show that the activity of pathogen-induced innate immune cells can be enhanced by adaptive humoral immunity. Understanding the activity of NKG2C(hi) CD57(hi) NK cells against HCMV-infected cells will be of relevance for the further development of adoptive immunotherapy.

Evaluation of fipronil and imidacloprid as bait active ingredients against fungus-growing termites (Blattodea: Termitidae: Macrotermitinae).

PubMed

Iqbal, N; Evans, T A

2018-02-01

Fungus-growing termites (Macrotermitinae) are important pests in tropical countries. They are difficult to control with existing baiting methods, as chitin synthesis inhibitors are not effectual as active ingredients. We tested two neurotoxins, fipronil and imidacloprid, as potential bait active ingredients against Macrotermes gilvus (Hagen) in Singapore. In laboratory bioassays, M. gilvus showed no preference for doses of 0-64 ppm fipronil, or for doses of 0-250 ppm imidacloprid, indicating no repellence. We tested each insecticide in toilet paper as a bait matrix in a field experiment. After 28 days, termites had eaten 5-13% of the fipronil treated toilet paper, abandoned bait and monitoring stations, contacted no new stations, and repaired poorly their experimentally damaged mounds. Termites ate no imidacloprid treated toilet paper, abandoned bait stations although contacted new stations, and repaired fully their damaged mounds. Termites ate 60-70% of the control toilet paper, remained in bait stations, and fully repaired damaged mounds. After 56 days, all five fipronil colonies were eliminated, whereas all of the imidacloprid and control colonies were healthy. The results suggest that fipronil could be an effective active ingredient in bait systems for fungus-growing termites in tropical countries.

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy.

PubMed

Ferguson, Bradley S; Harrison, Brooke C; Jeong, Mark Y; Reid, Brian G; Wempe, Michael F; Wagner, Florence F; Holson, Edward B; McKinsey, Timothy A

2013-06-11

Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogen-activated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophic growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase.

PubMed

Meiselbach, Heike; Sticht, Heinrich

2011-08-01

The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence remain poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck in which the SH3-SH2 domain linker is replaced by the corresponding sequence from the homologous kinase Lck. These simulations reveal that linker replacement not only affects the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or in fine-tuning the activation process itself.

Prevalence and risk factors of intestinal helminth infection among rural malay children.

PubMed

Huat, Lim Boon; Mitra, Amal K; Jamil, Noor Izani Noor; Dam, Pim Chau; Mohamed, Hamid Jan Jan; Muda, Wan Abdul Manan Wan

2012-01-01

Soil-transmitted intestinal helminth infection is prevalent in rural communities of Malaysia. Risk factors contributing to helminth infections are largely unknown in the country. To determine the prevalence and risk factors of intestinal helminth infections among children in Beris Lalang, a rural Muslim community of Malaysia. In this cross-sectional study, children aged 7-9 years were recruited during the mass Friday prayer at Beris Lalang mosque by trained imams (religious leaders). A standardized questionnaire was used to obtain information on socio-demographic profile, daily hygienic practices, and history of helminth infection. Out of 79 samples, 29 (37%) were positive for helminthic ova, of which 24 were ova of Trichuris trichiura. Poor education of the mother (primary education or less) (P=0.015), eating raw salad (P=0.03), and no physical activities (P=0.03) were found independent risk factors for the child's helminth infections in univariate analysis. A higher proportion of children with helminth infections complained of tiredness and fatigue compared to those without such infections (36% vs. 12%, P=0.019). In a multivariate analysis of predictors of helminth infection, poor education of the mother (P=0.02) and eating raw salad (P=0.04) remained statistically significant, after controlling for several other potential risk factors. T. trichiura was the most prevalent intestinal helminth infection in children in rural Malaysia. Risk factors of helminth infection included mother's poor education and eating raw salad and vegetables.

Global biogeography of human infectious diseases.

PubMed

Murray, Kris A; Preston, Nicholas; Allen, Toph; Zambrana-Torrelio, Carlos; Hosseini, Parviez R; Daszak, Peter

2015-10-13

The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non-vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set.

Watching television for more than two hours increases the likelihood of reporting poor sleep quality among Brazilian schoolteachers.

PubMed

de Souza, Sara Carolina Scremin; Campanini, Marcela Zambrim; de Andrade, Selma Maffei; González, Alberto Durán; de Melo, Juliana Moura; Mesas, Arthur Eumann

2017-10-01

Although time spent watching television and sleep problems have increased in the last few decades, it is unclear whether these conditions are associated in working adults after controlling for lifestyle, job characteristics and other individual aspects. The present study analyzed the association between time spent watching television and sleep quality among teachers from public schools in Londrina, Brazil. In this cross-sectional study, information from the Pittsburgh Sleep Quality Index (PSQI) and about time spent watching television was obtained during personal interviews. Logistic regression models adjusted by the main confounders (sociodemographic, occupational and lifestyle variables) were used in the analyses. Among the 959 studied teachers (68.2% women, median age: 42years), teachers who watched >120min/day had a higher likelihood of reporting poor sleep quality (PSQI>5) (odds ratio=1.41; 95% confidence interval=1.01; 1.98) compared with those who watched television for up to 60min/day, regardless of gender, age, work hours, leisure time physical activity and other lifestyle variables. This association did not remain significant after the adjustment for health conditions, i.e., obesity, anxiety, depression and chronic pain, which may act as confounding variables in the relationship between watching television and poor sleep quality. Watching television for >120min/day was independently associated with poorer sleep quality, which should be considered in the prevention and treatment of sleep disturbances among working population. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessing the mechanism of response in the retrosplenial cortex of good and poor navigators☆

PubMed Central

Auger, Stephen D.; Maguire, Eleanor A.

2013-01-01

The retrosplenial cortex (RSC) is consistently engaged by a range of tasks that examine episodic memory, imagining the future, spatial navigation, and scene processing. Despite this, an account of its exact contribution to these cognitive functions remains elusive. Here, using functional MRI (fMRI) and multi-voxel pattern analysis (MVPA) we found that the RSC coded for the specific number of permanent outdoor items that were in view, that is, items which are fixed and never change their location. Moreover, this effect was selective, and was not apparent for other item features such as size and visual salience. This detailed detection of the number of permanent items in view was echoed in the parahippocampal cortex (PHC), although the two brain structures diverged when participants were divided into good and poor navigators. There was no difference in the responsivity of the PHC between the two groups, while significantly better decoding of the number of permanent items in view was possible from patterns of activity in the RSC of good compared to poor navigators. Within good navigators, the RSC also facilitated significantly better prediction of item permanence than the PHC. Overall, these findings suggest that the RSC in particular is concerned with coding the presence of every permanent item that is in view. This mechanism may represent a key building block for spatial and scene representations that are central to episodic memories and imagining the future, and could also be a prerequisite for successful navigation. PMID:24012136

[Evaluation of professional development of Cambodian male nurses specializing in anesthesia and intensive care, trained through humanitarian care programs].

PubMed

Pinosa, C; Gagnayre, R

1998-01-01

To assess the working conditions of Cambodian male nurses specialised in anaesthesia and intensive care (NSAIs), degree of satisfaction, whether training was suited to the Cambodian needs and practical application of training. Prospective survey. Two training years including 30 NSAIs. External assessors evaluated working conditions, practice of anaesthesia, analysed logbooks and theatre reports, organised semi-directive interviews and examinations using clinical cases. Out of the 30 NSAIs, 28 had an appointment, mainly in anaesthesia (80% of their activity) and three-quarters of them felt that their skills were appreciated by their superiors. Seventeen had some form of responsibility in the management of a department. For the administration of an anaesthetic, 13 NSAIs of the second year had achieved an acceptable level of performance and resolved effectively 85% of the submitted cases. Twenty-two NSAIs reported difficulty in applying techniques learned during their training to real working conditions. The causes were poor equipment, poor organisation and poor relations with the hierarchy. The latter cause decreased the capacity to take appropriate decisions, which was the most common error made by the second year NSAIs. Finally, as their wages remained unchanged, 19 out of the 28 NSAIs were obliged to look for an additional source of income. This survey shows the medium-term effectiveness of an NSAI training programme basing on teaching and public health principles and organised in the humanitarian aid sector.

Proteomics analysis of maize (Zea mays L.) grain based on iTRAQ reveals molecular mechanisms of poor grain filling in inferior grains.

PubMed

Yu, Tao; Li, Geng; Liu, Peng; Dong, Shuting; Zhang, Jiwang; Zhao, Bin

2017-06-01

In maize, inferior grains (IG) located on the upper part of the ear have poor grain filling process compared to superior grains (SG) located on the middle and lower parts of the ear. This difference limits satisfactory yield and quality; however, the underlying molecular mechanisms remain unknown. Here, using the isobaric tag for relative and absolute quantification (iTRAQ) technology, the proteomes of IG and SG during early and middle grain filling stages were investigated. In total, 4720 proteins were identified in maize grain and 305 differentially accumulated proteins (DiAPs) were detected between IG and SG. These DiAPs were involved in diverse cellular and metabolic processes with preferred distribution in protein synthesis/destination and metabolism. Compared to SG, DiAPs related to cell growth/division and starch synthesis were lag-accumulated and down-regulated in IG, respectively, resulting in smaller sink sizes and lower sink activities in IG. Meanwhile, impediment of the glycolysis pathway in IG may lead to reduce energy supply and building materials for substance synthesis. Additionally, reactive oxygen species (ROS) homeostasis and the defense system were disturbed in IG, which might lead to reduce protection against various environmental stresses. The present study provides new information on the proteomic differences between IG and SG, and explains possible molecular mechanisms for poor grain filling in IG. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evaluation of task shifting in community-based DOTS program as an effective control strategy for tuberculosis.

PubMed

Gabriel, André P; Mercado, Charles P

2011-01-01

Tuberculosis (TB) remains to be the most prevalent and debilitating pulmonary (PTB) infection in the world today, affecting about one-third of the world's population. TB is an endemic disease in many developing countries, and efforts at eliminating the disease remain futile. While the course of the disease is indolent with years of latency, the reactivation of the disease can pose serious pulmonary and systemic infections that compromise multiple organ functions which lead to respiratory failure or end-organ damage. Despite attempts to control and eradicate the mycobacterium, the prevalence of the disease remains high due to increasing population rate, persistence of poverty and poor health care, treatment failure, increasing multidrug resistance as a consequence of treatment failure and poor compliance, and existence of comorbid conditions that compromise immune response. Limited government resources to screen and monitor disease progression of TB in third world countries hamper the eradication of the disease. In response, we have evaluated the efficiency and effectivity of a Community-Based Directly Observed Treatment, Short-Course (CB-DOTS), which is an equally effective alternative strategy to health center DOTS.

[Impairment and disability in patients with a severe ischemic cerebral infarction at admission to the rehabilitation center and six months after stroke].

PubMed

Prevo, A J; Dijkman, M M; Le Fèvre, F A

1998-03-21

Evaluation of impairment and disability in stroke patients with a severe cortical infarction at admission as well as six months after the stroke. Prospective and descriptive study. Rehabilitation Centre Heliomare, Wijk aan Zee, the Netherlands. Between 1 January 1987 en 31 May 1992 stroke patients were admitted to the rehabilitation centre with a severe, first ever, cortical infarction without any comorbidity. The patients were dependent in activities of daily living and wheel-chair-bound. Motor and neuropsychological impairment and disability were evaluated at admission to the rehabilitation centre as well as six months after the stroke. Return to home and length of stay were evaluated. 43 patients were included. Recovery of arm and hand function was very poor (there was complete paresis at admission in 33 patients (77%) and six months after the CVA in 25 patients (58%)); recovery of the affected leg was reasonable (complete paresis in 10 (23%) and 0 patients, respectively). Cognitive deficits diminished in severity, but remained noticeable in three-quarters of the patients. Independent walking was achieved by 30 patients (70%), independence in personal activities of daily living by 32 patients (74%) and returning home by 36 patients (84%). The mean hospital stay was 26 weeks (SD: 9.26; range: 11-30). Prognosis of personal independence and returning home after a severe cortical infarction was rather good despite poor recovery of motor and cognitive impairment.

Metacarpophalangeal joint stiffness. Still a challenge for the hand surgeon?

PubMed

Jiménez, I; Muratore-Moreno, G; Marcos-García, A; Medina, J

2016-01-01

The aim of this study is to analyse the outcomes of the surgical treatment of metacarpophalangeal stiffness by dorsal teno-arthrolysis in our centre, and present a review the literature. This is a retrospective study of 21 cases of metacarpophalangeal stiffness treated surgically. Dorsal teno-arthrolysis was carried out on all patients. A rehabilitation programme was started ten days after surgery. An evaluation was performed on the aetiology, variation in pre- and post-operative active mobility, complications, DASH questionnaire, and a subjective satisfaction questionnaire. The mean age of the patients was 36.5 years and the mean follow-up was 6.5 years. Of the 21 cases, the most common cause was a metacarpal fracture (52.4%), followed by complex trauma of the forearm (19%). Improvement in active mobility was 30.5°, despite obtaining an intra-operative mobility 0-90° in 80% of cases. Mean DASH questionnaire score was 36.9 points. The outcome was described as excellent in 10% of our patients, good in 30%, poor in 40%, and bad in the remaining 20%. There was a complex regional pain syndrome in 9.5% of cases, and intrinsic muscle injury in 14.3%. Because of its difficult management and poor outcomes, surgical treatment of metacarpophalangeal stiffness in extension is highly complex, with dorsal teno-arthrolysis being a reproducible technique according to our results, and the results reported in the literature. Copyright © 2016 SECOT. Published by Elsevier Espana. All rights reserved.

Psychosocial work conditions, unemployment and self-reported psychological health: a population-based study.

PubMed

Lindström, Martin

2005-10-01

To investigate the association between psychosocial conditions at work, unemployment and self-reported psychological health. A cross-sectional postal questionnaire for the 2000 public health survey in Scania was administered to both working and unemployed people aged 18-64 years. Logistic regression models were used to investigate the association between psychosocial factors at work/unemployment and self-reported psychological health (General Health Questionnaire 12). Psychosocial conditions at work were classified according to the Karasek-Theorell demand-control/decision latitudes into relaxed, active, passive and job strain. The multivariate analyses included age, country of origin, education, economic stress and social participation. A total of 5180 people returned their questionnaire, giving a participation rate of 59%. Fifteen per cent of men and 20% of women reported poor psychological health. Those with high demands and high control (active category), those with high demands and low control (job strain category) and the unemployed had significantly higher odds ratios of poor psychological health compared to those with low demands and high control (relaxed category). Those with low demands and low control (passive category) did not differ significantly from the relaxed category. The associations remained in the multivariate analyses. The study found that certain psychosocial work factors are associated with higher levels of self-reported psychological ill-health and illustrates the great importance of psychosocial conditions in determining psychological health at the population level. As found elsewhere, being unemployed was an even stronger predictor of psychological ill-health.

Local deposition of mercury in topsoils around coal-fired power plants: is it always true?

PubMed

Rodriguez Martin, José Antonio; Nanos, Nikos; Grigoratos, Theodoros; Carbonell, Gregoria; Samara, Constantini

2014-09-01

Mercury (Hg) is a toxic element that is emitted to the atmosphere through human activities, mainly fossil fuel combustion. Hg accumulations in soil are associated with atmospheric deposition, while coal-burning power plants remain the most important source of anthropogenic mercury emissions. In this study, we analyzed the Hg concentration in the topsoil of the Kozani-Ptolemais basin where four coal-fired power plants (4,065 MW) run to provide 50 % of electricity in Greece. The study aimed to investigate the extent of soil contamination by Hg using geostatistical techniques to evaluate the presumed Hg enrichment around the four power plants. Hg variability in agricultural soils was evaluated using 276 soil samples from 92 locations covering an area of 1,000 km(2). We were surprised to find a low Hg content in soil (range 1-59 μg kg(-1)) and 50 % of samples with a concentration lower than 6 μg kg(-1). The influence of mercury emissions from the four coal-fired power plants on soil was poor or virtually nil. We associate this effect with low Hg contents in the coal (1.5-24.5 μg kg(-1)) used in the combustion of these power plants (one of the most Hg-poor in the world). Despite anthropic activity in the area, we conclude that Hg content in the agricultural soils of the Kozani-Ptolemais basin is present in low concentrations.

A brief structured education programme enhances self-care practices and improves glycaemic control in Malaysians with poorly controlled diabetes.

PubMed

Tan, M Y; Magarey, J M; Chee, S S; Lee, L F; Tan, M H

2011-10-01

We assessed the effectiveness of a brief structured diabetes education programme based on the concept of self-efficacy on self-care and glycaemic control using single-blind study design. One hundred and sixty-four participants with poorly controlled diabetes from two settings were randomized using computer-generated list into control (n = 82) and intervention (n = 82) groups, of which 151 completed the study. Monthly interventions over 12 weeks addressed the self-care practices of diet, physical activity, medication adherence and self-monitoring of blood glucose (SMBG). These self-care practices were assessed at Weeks 0 and 12 using pre- and post-questionnaires in both groups together with glycated haemoglobin A1c (HbA1c) and diabetes knowledge. In the intention-to-treat analysis (n = 164), the intervention group improved their SMBG (P = <0.001), physical activity (P = 0.001), HbA1c (P = 0.03), diabetes knowledge (P = <0.001) and medication adherence. At Week 12, HbA1c difference adjusted for SMBG frequency, medication adherence and weight change remained significant (P = 0.03) compared with control group. For within group comparisons, diabetes knowledge (P = <0.001), HbA1c level (P = <0.001), SMBG (P = <0.001) and medication adherence (P = 0.008) improved from baseline in the intervention group. In the control group, only diabetes knowledge improved (P = <0.001). These findings can contribute to the development of self-management diabetes education in Malaysia.

Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex.

PubMed

Yaffe, Robert B; Shaikhouni, Ammar; Arai, Jennifer; Inati, Sara K; Zaghloul, Kareem A

2017-04-26

Converging evidence suggests that reinstatement of neural activity underlies our ability to successfully retrieve memories. However, the temporal dynamics of reinstatement in the human cortex remain poorly understood. One possibility is that neural activity during memory retrieval, like replay of spiking neurons in the hippocampus, occurs at a faster timescale than during encoding. We tested this hypothesis in 34 participants who performed a verbal episodic memory task while we recorded high gamma (62-100 Hz) activity from subdural electrodes implanted for seizure monitoring. We show that reinstatement of distributed patterns of high gamma activity occurs faster than during encoding. Using a time-warping algorithm, we quantify the timescale of the reinstatement and identify brain regions that show significant timescale differences between encoding and retrieval. Our data suggest that temporally compressed reinstatement of cortical activity is a feature of cued memory retrieval. SIGNIFICANCE STATEMENT We show that cued memory retrieval reinstates neural activity on a faster timescale than was present during encoding. Our data therefore provide a link between reinstatement of neural activity in the cortex and spontaneous replay of cortical and hippocampal spiking activity, which also exhibits temporal compression, and suggest that temporal compression may be a universal feature of memory retrieval. Copyright © 2017 the authors 0270-6474/17/374472-09$15.00/0.

Physical activity: does environment make a difference for tension, stress, emotional outlook, and perceptions of health status?

PubMed

Puett, Robin; Teas, Jane; España-Romero, Vanesa; Artero, Enrique Garcia; Lee, Duck-chul; Baruth, Meghan; Sui, Xuemei; Montresor-López, Jessica; Blair, Steven N

2014-11-01

The importance of physical activity for health is well-established. Questions remain whether outdoor exercise additionally benefits overall mental and physical well-being. Using cross-sectional data from the Aerobics Center Longitudinal Study, we examined relationships of physical activity environment (PAE) with reported tension, stress, emotional outlook, and health. 11,649 participants were included. 18% exercised indoors, 54% outdoors, and 28% in both. Participants who exercised partially or entirely outdoors exercised more. In fully adjusted models, for women combined PAE was protective for worse emotional outlook (OR: 0.72; 95% CI: 0.52-0.98). Combined PAE was also protective for reported poor health (OR for women: 0.63; 95% CI: 0.44-0.91; OR for men: 0.75; 95% CI: 0.61-0.92). Amount of physical activity modified PAE relationships with outcomes. Combined and outdoor PAE were more consistently protective for worse outcomes among high activity participants. Regardless of PAE, better outcomes were observed in active versus inactive participants. The current study suggests addition of outdoor PAE may be linked with better stress management, outlook and health perceptions for more active populations, whereas indoor PAE may be more important for low active populations. Further research should examine the order of causation and whether type of outdoor PAE (eg, urban, natural) is important.

Physical activity and psychological distress amongst Vietnamese living in the Mekong Delta.

PubMed

Rees, Susan; Silove, Derrick; Chey, Tien; Steel, Zachary; Bauman, Adrian; Phan, Thuy

2012-10-01

Regular physical activity may be an important contributor to psychological well-being. This link has not been explored in ethnically distinct, low- and middle-income countries (LMIC), especially in countries affected by war. This study aimed to examine the relationship between physical activity and levels of psychological distress in an epidemiological cross-representative sample of Vietnamese living in the Mekong Delta region of Vietnam. The sample was drawn from an urban (Cn Th City) and a rural (H u Giang) region, using a multi-stage probabilistic cluster sampling frame. The measures applied included the Composite International Diagnostic Interview (CIDI 2.0) yielding 12-month prevalence rates of common mental disorders, including anxiety, mood and substance use disorders; the Phan Vietnamese Psychiatric Scale (PVPS), a culturally specific self-report measure; and the Harvard Trauma Questionnaire. The Global Physical Activity Questionnaire (GPAQ version 1) was used to measure activity. Analyses were conducted using SAS software v.9.1.3. The population was assigned to three (high, moderate and low) physical activity levels. Analyses included chi-square tests and univariable and multivariable logistic models. Physical activity was greater in males, the middle-aged group (30-54 years), those who were married, the rural population, less educated individuals and those who were employed. High physical activity was significantly associated with low levels of psychological distress (indexed by a combination of CIDI and PVPS cases identified) when controlling for socio-demographic factors and number of medical conditions). Membership of the lowest of the three physical activity groups was associated with a psychological distress odds ratio of 2.19 (95% CI 1.28-3.75). The results remained consistent when analyses were undertaken separately for males and females. Low levels of physical activity appear to be associated with greater psychological distress in the Mekong Delta of Vietnam. The association remained after adjusting for the influence of socio-demographic characteristics, exposure to past trauma, urban-rural residency and the presence of self-reported physical disorders. These data provide a foundation for exploring the role of physical activity as an adjunct to conventional interventions for common mental disorders in resource-poor LMIC countries.

Drosophila Neuropeptide F Signaling Independently Regulates Feeding and Sleep-Wake Behavior.

PubMed

Chung, Brian Y; Ro, Jennifer; Hutter, Sabine A; Miller, Kylie M; Guduguntla, Lakshmi S; Kondo, Shu; Pletcher, Scott D

2017-06-20

Proper regulation of sleep-wake behavior and feeding is essential for organismal health and survival. While previous studies have isolated discrete neural loci and substrates important for either sleep or feeding, how the brain is organized to coordinate both processes with respect to one another remains poorly understood. Here, we provide evidence that the Drosophila Neuropeptide F (NPF) network forms a critical component of both adult sleep and feeding regulation. Activation of NPF signaling in the brain promotes wakefulness and adult feeding, likely through its cognate receptor NPFR. Flies carrying a loss-of-function NPF allele do not suppress sleep following prolonged starvation conditions, suggesting that NPF acts as a hunger signal to keep the animal awake. NPF-expressing cells, specifically those expressing the circadian photoreceptor cryptochrome, are largely responsible for changes to sleep behavior caused by NPF neuron activation, but not feeding, demonstrating that different NPF neurons separately drive wakefulness and hunger. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Attributes of γδ intraepithelial lymphocytes as suggested by their transcriptional profile

PubMed Central

Fahrer, Aude M.; Konigshofer, Yves; Kerr, Elizabeth M.; Ghandour, Ghassan; Mack, David H.; Davis, Mark M.; Chien, Yueh-hsiu

2001-01-01

γδ T lymphocytes in the intestinal intraepithelial layer (γδ IELs) are thought to contribute to immune competence, but their actual function remains poorly understood. Here we used DNA microarrays to study the gene expression profile of γδ IELs in a Yersinia infection system to better define their roles. To validate this approach, mesenteric lymph node CD8+ αβ T cells were similarly analyzed. The transcription profiles show that, whereas lymph node CD8+ αβ T cells must be activated to become cytotoxic effectors, γδ IELs are constitutively activated and appear to use different signaling cascades. Our data suggest that γδ IELs may respond efficiently to a broad range of pathological situations irrespective of their diverse T cell antigen receptor repertoire. γδ IELs may modulate local immune responses and participate in intestinal lipid metabolism, cholesterol homeostasis, and physiology. This study provides a strong basis for further investigations of the roles of these cells as well as mucosal immune defense in general. PMID:11526237

[Animal nutrition for veterinarians--actual cases: tulip bulbs with leaves (Tulipa gesneriana)--an unusual and high risk plant for ruminant feeding].

PubMed

Wolf, P; Blanke, H J; Wohlsein, P; Kamphues, J; Stöber, M

2003-07-01

14 cattle (mainly younger ones) of a total of 50 extensively kept Galloways died within 6 weeks in late winter 2001/02. According to the owner's report, grass growth had been rather poor; therefore, the herd was fed additionally hay as well as large amounts of tulip onions. In the microbiological examination a highly reduced hygienic quality of the roughage could be detected. In the rumen contents of two dissected young cattle parts of tulip onions were found. According to pertinent literature, tulip onions (in particular their external layers) contain variant-specific amounts of anti-nutritive substances; main active agents are tulipin (a glycoprotein), tuliposid A and B, and lectins. They may cause intensive mucosal irritation, accompanied by reduced feed digestion and body-weight gains, drooling, vomiting and diarrhea. This case report underlines risks caused by feeding of plants originally not destined as forage, if their active ingredients and effects are unknown or remain unconsidered.

Novel Procedure for Extraction of a Latent Grape Polyphenoloxidase Using Temperature-Induced Phase Separation in Triton X-114 1

PubMed Central

Sánchez-Ferrer, Alvaro; Bru, Roque; Garcia-Carmona, Francisco

1989-01-01

Polyphenoloxidase from grape berries is extracted only by nonionic detergents with a hydrophilic-lipophilic balance between 12.4 and 13.5. The enzyme was partially purified in latent form, free of phenolics and chlorophylls, by using temperature phase partitioning in a solution of Triton X-114. This method permits the purification of the enzyme with the same fold purification as the commonly used method, but with a yield three times higher and a 90% reduction in time needed. The latent enzyme can be activated by different treatments, including trypsin and cationic and anionic detergents. Cetyltrimethylamonium bromide was found to be the most effective detergent activator, followed by sodium dodecyl sulfate. Polyphenoloxidase in grape berries, in spite of being an integral membrane protein, had an anomalous interaction with Triton X-114, remaining in the detergent-poor phase after phase separation. This could be explained by its having a short hydrophobic tail that anchors it to the membrane. Images Figure 1 Figure 3 PMID:16667205

Evidence of active methanogen communities in shallow sediments of the sonora margin cold seeps.

PubMed

Vigneron, Adrien; L'Haridon, Stéphane; Godfroy, Anne; Roussel, Erwan G; Cragg, Barry A; Parkes, R John; Toffin, Laurent

2015-05-15

In the Sonora Margin cold seep ecosystems (Gulf of California), sediments underlying microbial mats harbor high biogenic methane concentrations, fueling various microbial communities, such as abundant lineages of anaerobic methanotrophs (ANME). However, the biodiversity, distribution, and metabolism of the microorganisms producing this methane remain poorly understood. In this study, measurements of methanogenesis using radiolabeled dimethylamine, bicarbonate, and acetate showed that biogenic methane production in these sediments was mainly dominated by methylotrophic methanogenesis, while the proportion of autotrophic methanogenesis increased with depth. Congruently, methane production and methanogenic Archaea were detected in culture enrichments amended with trimethylamine and bicarbonate. Analyses of denaturing gradient gel electrophoresis (DGGE) fingerprinting and reverse-transcribed PCR-amplified 16S rRNA sequences retrieved from these enrichments revealed the presence of active methylotrophic Methanococcoides burtonii relatives and several new autotrophic Methanogenium lineages, confirming the cooccurrence of Methanosarcinales and Methanomicrobiales methanogens with abundant ANME populations in the sediments of the Sonora Margin cold seeps. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Slug inhibits the proliferation and tumor formation of human cervical cancer cells by up-regulating the p21/p27 proteins and down-regulating the activity of the Wnt/β-catenin signaling pathway via the trans-suppression Akt1/p-Akt1 expression

PubMed Central

Cui, Nan; Yang, Wen-Ting; Zheng, Peng-Sheng

2016-01-01

Slug (Snai2) has been demonstrated to act as an oncogene or tumor suppressor in different human cancers, but the function of Slug in cervical cancer remains poorly understood. In this study, we demonstrated that Slug could suppress the proliferation of cervical cancer cells in vitro and tumor formation in vivo. Further experiments found that Slug could trans-suppress the expression of Akt1/p-Akt1 by binding to E-box motifs in the promoter of the Akt1 gene and then inhibit the cell proliferation and tumor formation of cervical cancer cells by up-regulating p21/p27 and/or down-regulating the activity of the Wnt/β-catenin signaling pathway. Therefore, Slug acts as a tumor suppressor during cervical carcinogenesis. PMID:27036045

Involvement of phosphatidate phosphatase in the biosynthesis of triacylglycerols in Chlamydomonas reinhardtii * #

PubMed Central

Deng, Xiao-dong; Cai, Jia-jia; Fei, Xiao-wen

2013-01-01

Lipid biosynthesis is essential for eukaryotic cells, but the mechanisms of the process in microalgae remain poorly understood. Phosphatidic acid phosphohydrolase or 3-sn-phosphatidate phosphohydrolase (PAP) catalyzes the dephosphorylation of phosphatidic acid to form diacylglycerols and inorganic orthophosphates. This reaction is integral in the synthesis of triacylglycerols. In this study, the mRNA level of the PAP isoform CrPAP2 in a species of Chlamydomonas was found to increase in nitrogen-free conditions. Silencing of the CrPAP2 gene using RNA interference resulted in the decline of lipid content by 2.4%–17.4%. By contrast, over-expression of the CrPAP2 gene resulted in an increase in lipid content by 7.5%–21.8%. These observations indicate that regulation of the CrPAP2 gene can control the lipid content of the algal cells. In vitro CrPAP2 enzyme activity assay indicated that the cloned CrPAP2 gene exhibited biological activities. PMID:24302712

Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

PubMed Central

Brereton, Melissa F.; Iberl, Michaela; Shimomura, Kenju; Zhang, Quan; Adriaenssens, Alice E.; Proks, Peter; Spiliotis, Ioannis I.; Dace, William; Mattis, Katia K.; Ramracheya, Reshma; Gribble, Fiona M.; Reimann, Frank; Clark, Anne; Rorsman, Patrik; Ashcroft, Frances M.

2014-01-01

Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized. PMID:25145789

Fibronectin regulates Wnt7a signaling and satellite cell expansion

PubMed Central

Bentzinger, C. Florian; Wang, Yu Xin; von Maltzahn, Julia; Soleimani, Vahab D.; Yin, Hang; Rudnicki, Michael A.

2012-01-01

SUMMARY The influence of the extracellular matrix (ECM) within the stem cell niche remains poorly understood. We found that Syndecan-4 (Sdc4) and Frizzled-7 (Fzd7) form a co-receptor complex in satellite cells and that binding of the ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells. Newly activated satellite cells dynamically remodel their niche by transient high-level expression of FN. Knockdown of FN in prospectively isolated satellite cells severely impaired their ability to repopulate the satellite cell niche. Conversely, in vivo over-expression of FN with Wnt7a dramatically stimulated the expansion of satellite stem cells in regenerating muscle. Therefore, activating satellite cells remodel their niche through autologous expression of FN that provides feedback to stimulate Wnt7a signaling through the Fzd7/Sdc4 co-receptor complex. Thus, FN and Wnt7a together regulate the homeostatic levels of satellite stem cells and satellite myogenic cells during regenerative myogenesis. PMID:23290138

Report on maloine, a new alkaloid discovered from G. maloi: Structural characterization and biological activity

NASA Astrophysics Data System (ADS)

Çela, Dorisa; Nepravishta, Ridvan; Lazari, Diamanto; Gaziano, Roberta; Moroni, Gabriella; Pica, Francesca; Paci, Maurizio; Abazi, Sokol

2017-02-01

Gymnospermium maloi Kit Tan, & Shuka is a new endemic species of the genus Gymnospermium Spach which has been described recently from the southern part of Albania. The members of this genus are poorly studied for what it concern the secondary metabolites in general and the class of alkaloids in particular. In fact from Gymnospermium genus, there are only few alkaloids characterized, (namely albertramine, albertidine, and albertine) isolated from G. albertii. Until now the chemical composition and the structure elucidation of other possible secondary metabolites, especially alkaloids, remain largely unknown. Here we report, for the first time, the structure of a new alkaloid isolated from G. maloi, designated by us as maloine, and obtained by the use of 2D homonuclear and heteronuclear NMR spectroscopy, FTIR, UV, Fluorescence and HPLC/MS spectra. The biological activity of the crude extract of Gymnospermium maloi and of its alkaloid maloine, was evaluated in vitro on human chronic myeloid leukemia cell line K562 and results herewith reported.

Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors.

PubMed

Pattyn, Alexandre; Vallstedt, Anna; Dias, José M; Samad, Omar Abdel; Krumlauf, Robb; Rijli, Filippo M; Brunet, Jean-Francois; Ericson, Johan

2003-03-15

Neural progenitor cells often produce distinct types of neurons in a specific order, but the determinants that control the sequential generation of distinct neuronal subclasses in the vertebrate CNS remain poorly defined. We examined the sequential generation of visceral motor neurons and serotonergic neurons from a common pool of neural progenitors located in the ventral hindbrain. We found that the temporal specification of these neurons varies along the anterior-posterior axis of the hindbrain, and that the timing of their generation critically depends on the integrated activities of Nkx- and Hox-class homeodomain proteins. A primary function of these proteins is to coordinate the spatial and temporal activation of the homeodomain protein Phox2b, which in turn acts as a binary switch in the selection of motor neuron or serotonergic neuronal fate. These findings assign new roles for Nkx, Hox, and Phox2 proteins in the control of temporal neuronal fate determination, and link spatial and temporal patterning of CNS neuronal fates.

Early bioelectric activities mediate redox-modulated regeneration

PubMed Central

Ferreira, Fernando; Luxardi, Guillaume; Reid, Brian

2016-01-01

Reactive oxygen species (ROS) and electric currents modulate regeneration; however, the interplay between biochemical and biophysical signals during regeneration remains poorly understood. We investigate the interactions between redox and bioelectric activities during tail regeneration in Xenopus laevis tadpoles. We show that inhibition of NADPH oxidase-mediated production of ROS, or scavenging or blocking their diffusion into cells, impairs regeneration and consistently regulates the dynamics of membrane potential, transepithelial potential (TEP) and electric current densities (JI) during regeneration. Depletion of ROS mimics the altered TEP and JI observed in the non-regenerative refractory period. Short-term application of hydrogen peroxide (H2O2) rescues (from depleted ROS) and induces (from the refractory period) regeneration, TEP increase and JI reversal. H2O2 is therefore necessary for and sufficient to induce regeneration and to regulate TEP and JI. Epistasis assays show that voltage-gated Na+ channels act downstream of H2O2 to modulate regeneration. Altogether, these results suggest a novel mechanism for regeneration via redox-bioelectric orchestration. PMID:27827821

The E3 ubiquitin ligase RNF146 promotes colorectal cancer by activating the Wnt/β-catenin pathway via ubiquitination of Axin1.

PubMed

Shen, Jiangli; Yu, Zhaohui; Li, Na

2018-06-20

The E3 ubiquitin ligase ring finger protein 146 (RNF146) has been implicated in tumor development. However, the role and clinical significance of RNF146 in colorectal cancer (CRC) remain unknown. In this study, we reported for the first time that RNF146 was upregulated in CRC tissues as well as in cell lines. Further, RNF146 expression was independent prognostic factor for poor outcome of CRC patients. RNF146 knockdown in cell lines inhibited cell growth, promoted cell apoptosis in vitro and suppressed colorectal tumor growth in vivo. Mechanistic investigations revealed that RNF146 exerted oncogenic role through ubiquitination of Axin1 to activate β-catenin signalling. In addition, RNF146 expression was positively correlated with β-catenin expression in CRC tissues. Collectively, our data suggest that RNF146 might function as a oncogene in human CRC, and represent a promising prognostic factor and a valuable therapeutic target for CRC. Copyright © 2018. Published by Elsevier Inc.

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.

PubMed

Seiler, Sarah E; Koves, Timothy R; Gooding, Jessica R; Wong, Kari E; Stevens, Robert D; Ilkayeva, Olga R; Wittmann, April H; DeBalsi, Karen L; Davies, Michael N; Lindeboom, Lucas; Schrauwen, Patrick; Schrauwen-Hinderling, Vera B; Muoio, Deborah M

2015-07-07

Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance. Copyright © 2015 Elsevier Inc. All rights reserved.

Establishment and function of tissue-resident innate lymphoid cells in the skin.

PubMed

Yang, Jie; Zhao, Luming; Xu, Ming; Xiong, Na

2017-07-01

Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.

Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response

PubMed Central

Truttmann, Matthias C.; Zheng, Xu; Hanke, Leo; Damon, Jadyn R.; Grootveld, Monique; Krakowiak, Joanna; Pincus, David; Ploegh, Hidde L.

2017-01-01

Protein AMPylation is a conserved posttranslational modification with emerging roles in endoplasmic reticulum homeostasis. However, the range of substrates and cell biological consequences of AMPylation remain poorly defined. We expressed human and Caenorhabditis elegans AMPylation enzymes—huntingtin yeast-interacting protein E (HYPE) and filamentation-induced by cyclic AMP (FIC)-1, respectively—in Saccharomyces cerevisiae, a eukaryote that lacks endogenous protein AMPylation. Expression of HYPE and FIC-1 in yeast induced a strong cytoplasmic Hsf1-mediated heat shock response, accompanied by attenuation of protein translation, massive protein aggregation, growth arrest, and lethality. Overexpression of Ssa2, a cytosolic heat shock protein (Hsp)70, was sufficient to partially rescue growth. In human cell lines, overexpression of active HYPE similarly induced protein aggregation and the HSF1-dependent heat shock response. Excessive AMPylation also abolished HSP70-dependent influenza virus replication. Our findings suggest a mode of Hsp70 inactivation by AMPylation and point toward a role for protein AMPylation in the regulation of cellular protein homeostasis beyond the endoplasmic reticulum. PMID:28031489

Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP

PubMed Central

Scaglione, K. Matthew; Zavodszky, Eszter; Todi, Sokol V.; Patury, Srikanth; Xu, Ping; Rodríguez-Lebrón, Edgardo; Fischer, Svetlana; Konen, John; Djarmati, Ana; Peng, Junmin; Gestwicki, Jason E.; Paulson, Henry L.

2011-01-01

Summary The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, the initiator E2, Ube2w, and the specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating and terminating the CHIP ubiquitination cycle. Monoubiquitination of CHIP by Ube2w stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the length of chains attached to CHIP substrates. Upon completion of substrate ubiquitination ataxin-3 deubiquitinates CHIP, effectively terminating the reaction. Our results suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point of regulation in ubiquitin-dependent protein quality control. In addition, the results shed light on disease pathogenesis in SCA3, a neurodegenerative disorder caused by polyglutamine expansion in ataxin-3. PMID:21855799

Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain.

PubMed

Liu, Yuan; Gordesky-Gold, Beth; Leney-Greene, Michael; Weinbren, Nathan L; Tudor, Matthew; Cherry, Sara

2018-06-09

The emerging arthropod-borne flavivirus Zika virus (ZIKV) is associated with neurological complications. Innate immunity is essential for the control of virus infection, but the innate immune mechanisms that impact viral infection of neurons remain poorly defined. Using the genetically tractable Drosophila system, we show that ZIKV infection of the adult fly brain leads to NF-kB-dependent inflammatory signaling, which serves to limit infection. ZIKV-dependent NF-kB activation induces the expression of Drosophila stimulator of interferon genes (dSTING) in the brain. dSTING protects against ZIKV by inducing autophagy in the brain. Loss of autophagy leads to increased ZIKV infection of the brain and death of the infected fly, while pharmacological activation of autophagy is protective. These data suggest an essential role for an inflammation-dependent STING pathway in the control of neuronal infection and a conserved role for STING in antimicrobial autophagy, which may represent an ancestral function for this essential innate immune sensor. Copyright © 2018. Published by Elsevier Inc.

Anatomy of Old Faithful From Subsurface Seismic Imaging of the Yellowstone Upper Geyser Basin

NASA Astrophysics Data System (ADS)

Wu, Sin-Mei; Ward, Kevin M.; Farrell, Jamie; Lin, Fan-Chi; Karplus, Marianne; Smith, Robert B.

2017-10-01

The Upper Geyser Basin in Yellowstone National Park contains one of the highest concentrations of hydrothermal features on Earth including the iconic Old Faithful geyser. Although this system has been the focus of many geological, geochemical, and geophysical studies for decades, the shallow (<200 m) subsurface structure remains poorly characterized. To investigate the detailed subsurface geologic structure including the hydrothermal plumbing of the Upper Geyser Basin, we deployed an array of densely spaced three-component nodal seismographs in November of 2015. In this study, we extract Rayleigh wave seismic signals between 1 and 10 Hz utilizing nondiffusive seismic waves excited by nearby active hydrothermal features with the following results: (1) imaging the shallow subsurface structure by utilizing stationary hydrothermal activity as a seismic source, (2) characterizing how local geologic conditions control the formation and location of the Old Faithful hydrothermal system, and (3) resolving a relatively shallow (10-60 m) and large reservoir located 100 m southwest of Old Faithful geyser.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism.

PubMed

Aleksandrova, Lily R; Phillips, Anthony G; Wang, Yu Tian

2017-06-01

The molecular mechanisms underlying major depressive disorder remain poorly understood, and current antidepressant treatments have many shortcomings. The recent discovery that a single intravenous infusion of ketamine at a subanesthetic dose had robust, rapid and sustained antidepressant effects in individuals with treatment-resistant depression inspired tremendous interest in investigating the molecular mechanisms mediating ketamine's clinical efficacy as well as increased efforts to identify new targets for antidepressant action. We review the clinical utility of ketamine and recent insights into its mechanism of action as an antidepressant, including the roles of N -methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor upregulation, activation of downstream synaptogenic signalling pathways and the production of an active ketamine metabolite, hydroxynorketamine. Emerging knowledge of the molecular mechanisms underlying both ketamine's positive therapeutic and detrimental side effects will aid the development of a new generation of much-needed superior antidepressant agents.

Hypothalamic Circuits for Predation and Evasion.

PubMed

Li, Yi; Zeng, Jiawei; Zhang, Juen; Yue, Chenyu; Zhong, Weixin; Liu, Zhixiang; Feng, Qiru; Luo, Minmin

2018-02-21

The interactions between predator and prey represent some of the most dramatic events in nature and constitute a matter of life and death for both sides. The hypothalamus has been implicated in driving predation and evasion; however, the exact hypothalamic neural circuits underlying these behaviors remain poorly defined. Here, we demonstrate that inhibitory and excitatory projections from the mouse lateral hypothalamus (LH) to the periaqueductal gray (PAG) in the midbrain drive, respectively, predation and evasion. LH GABA neurons were activated during predation. Optogenetically stimulating PAG-projecting LH GABA neurons drove strong predatory attack, and inhibiting these cells reversibly blocked predation. In contrast, LH glutamate neurons were activated during evasion. Stimulating PAG-projecting LH glutamate neurons drove evasion and inhibiting them impeded predictive evasion. Therefore, the seemingly opposite behaviors of predation and evasion are tightly regulated by two dissociable modular command systems within a single neural projection from the LH to the PAG. VIDEO ABSTRACT. Copyright © 2018 Elsevier Inc. All rights reserved.

Anatomy of a fumarolic system inferred from a multiphysics approach.

PubMed

Gresse, Marceau; Vandemeulebrouck, Jean; Byrdina, Svetlana; Chiodini, Giovanni; Roux, Philippe; Rinaldi, Antonio Pio; Wathelet, Marc; Ricci, Tullio; Letort, Jean; Petrillo, Zaccaria; Tuccimei, Paola; Lucchetti, Carlo; Sciarra, Alessandra

2018-05-15

Fumaroles are a common manifestation of volcanic activity that are associated with large emissions of gases into the atmosphere. These gases originate from the magma, and they can provide indirect and unique insights into magmatic processes. Therefore, they are extensively used to monitor and forecast eruptive activity. During their ascent, the magmatic gases interact with the rock and hydrothermal fluids, which modify their geochemical compositions. These interactions can complicate our understanding of the real volcanic dynamics and remain poorly considered. Here, we present the first complete imagery of a fumarolic plumbing system using three-dimensional electrical resistivity tomography and new acoustic noise localization. We delineate a gas reservoir that feeds the fumaroles through distinct channels. Based on this geometry, a thermodynamic model reveals that near-surface mixing between gas and condensed steam explains the distinct geochemical compositions of fumaroles that originate from the same source. Such modeling of fluid interactions will allow for the simulation of dynamic processes of magmatic degassing, which is crucial to the monitoring of volcanic unrest.

Autonomous Onboard Science Data Analysis for Comet Missions

NASA Technical Reports Server (NTRS)

Thompson, David R.; Tran, Daniel Q.; McLaren, David; Chien, Steve A.; Bergman, Larry; Castano, Rebecca; Doyle, Richard; Estlin, Tara; Lenda, Matthew

2012-01-01

Coming years will bring several comet rendezvous missions. The Rosetta spacecraft arrives at Comet 67P/Churyumov-Gerasimenko in 2014. Subsequent rendezvous might include a mission such as the proposed Comet Hopper with multiple surface landings, as well as Comet Nucleus Sample Return (CNSR) and Coma Rendezvous and Sample Return (CRSR). These encounters will begin to shed light on a population that, despite several previous flybys, remains mysterious and poorly understood. Scientists still have little direct knowledge of interactions between the nucleus and coma, their variation across different comets or their evolution over time. Activity may change on short timescales so it is challenging to characterize with scripted data acquisition. Here we investigate automatic onboard image analysis that could act faster than round-trip light time to capture unexpected outbursts and plume activity. We describe one edge-based method for detect comet nuclei and plumes, and test the approach on an existing catalog of comet images. Finally, we quantify benefits to specific measurement objectives by simulating a basic plume monitoring campaign.

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology.

PubMed

Serralheiro, Pedro; Soares, Andreia; Costa Almeida, Carlos M; Verde, Ignacio

2017-11-26

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

Occupational and Environmental Health Risks Associated with Informal Sector Activities-Selected Case Studies from West Africa.

PubMed

Basu, Niladri; Ayelo, Paul Ahoumènou; Djogbénou, Luc S; Kedoté, Marius; Lawin, Herve; Tohon, Honesty; Oloruntoba, Elizabeth O; Adebisi, Nurudeen A; Cazabon, Danielle; Fobil, Julius; Robins, Thomas; Fayomi, Benjamin

2016-08-01

Most in the Economic Community of West African States region are employed in the informal sector. While the informal sector plays a significant role in the region's economy, policymakers and the scientific community have long neglected it. To better understand informal-sector work conditions, the goal here is to bring together researchers to exchange findings and catalyze dialogue. The article showcases research studies on several economic systems, namely agriculture, resource extraction, transportation, and trade/commerce. Site-specific cases are provided concerning occupational health risks within artisanal and small-scale gold mining, aggregate mining, gasoline trade, farming and pesticide applications, and electronic waste recycling. These cases emphasize the vastness of the informal sector and that the majority of work activities across the region remain poorly documented, and thus no data or knowledge is available to help improve conditions and formulate policies and programs to promote and ensure decent work conditions. © The Author(s) 2016.

Regulation of mRNA translation during mitosis

PubMed Central

Tanenbaum, Marvin E; Stern-Ginossar, Noam; Weissman, Jonathan S; Vale, Ronald D

2015-01-01

Passage through mitosis is driven by precisely-timed changes in transcriptional regulation and protein degradation. However, the importance of translational regulation during mitosis remains poorly understood. Here, using ribosome profiling, we find both a global translational repression and identified ∼200 mRNAs that undergo specific translational regulation at mitotic entry. In contrast, few changes in mRNA abundance are observed, indicating that regulation of translation is the primary mechanism of modulating protein expression during mitosis. Interestingly, 91% of the mRNAs that undergo gene-specific regulation in mitosis are translationally repressed, rather than activated. One of the most pronounced translationally-repressed genes is Emi1, an inhibitor of the anaphase promoting complex (APC) which is degraded during mitosis. We show that full APC activation requires translational repression of Emi1 in addition to its degradation. These results identify gene-specific translational repression as a means of controlling the mitotic proteome, which may complement post-translational mechanisms for inactivating protein function. DOI: http://dx.doi.org/10.7554/eLife.07957.001 PMID:26305499

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

PubMed Central

Chen, Peiwen; Zuo, Hao; Xiong, Hu; Kolar, Matthew J.; Chu, Qian; Saghatelian, Alan; Siegwart, Daniel J.; Wan, Yihong

2017-01-01

Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor–macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor–macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment. PMID:28049847