Construction and engineering of large biochemical pathways via DNA assembler

PubMed Central

Shao, Zengyi; Zhao, Huimin

2015-01-01

Summary DNA assembler enables rapid construction and engineering of biochemical pathways in a one-step fashion by exploitation of the in vivo homologous recombination mechanism in Saccharomyces cerevisiae. It has many applications in pathway engineering, metabolic engineering, combinatorial biology, and synthetic biology. Here we use two examples including the zeaxanthin biosynthetic pathway and the aureothin biosynthetic gene cluster to describe the key steps in the construction of pathways containing multiple genes using the DNA assembler approach. Methods for construct design, pathway assembly, pathway confirmation, and functional analysis are shown. The protocol for fine genetic modifications such as site-directed mutagenesis for engineering the aureothin gene cluster is also illustrated. PMID:23996442

Pathways for Emotions: Specializations in the Amygdalar, Mediodorsal Thalamic, and Posterior Orbitofrontal Network.

PubMed

Timbie, Clare; Barbas, Helen

2015-08-26

The primate amygdala projects to posterior orbitofrontal cortex (pOFC) directly and possibly indirectly through a pathway to the magnocellular mediodorsal thalamic nucleus (MDmc), which may convey signals about the significance of stimuli. However, because MDmc receives input from structures in addition to the amygdala and MDmc projects to areas in addition to pOFC, it is unknown whether amygdalar pathways in MDmc innervate pOFC-bound neurons. We addressed this issue using double- or triple-labeling approaches to identify pathways and key cellular and molecular features in rhesus monkeys. We found that amygdalar terminations innervated labeled neurons in MDmc that project to pOFC. Projection neurons in MDmc directed to pOFC included comparatively fewer "core" parvalbumin neurons that project focally to the middle cortical layers and more "matrix" calbindin neurons that project expansively to the upper cortical layers. In addition, a small and hitherto unknown pathway originated from MDmc calretinin neurons and projected to pOFC. Further, whereas projection neurons directed to MDmc and to pOFC were intermingled in the amygdala, none projected to both structures. Larger amygdalar neurons projected to MDmc and expressed the vesicular glutamate transporter 2 (VGLUT2), which is found in highly efficient "driver" pathways. In contrast, smaller amygdalar neurons directed to pOFC expressed VGLUT1 found in modulatory pathways. The indirect pathway from the amygdala to pOFC via MDmc may provide information about the emotional significance of events and, along with a parallel direct pathway, ensures transfer of signals to all layers of pOFC. The amygdala-the brain's center for emotions-is strongly linked with the orbital cortex, a region associated with social interactions. This study provides evidence that a robust pathway from the amygdala reaches neurons in the thalamus that link directly with the orbital cortex, forming a tight tripartite network. The dual pathways from the amygdala to the orbital cortex and to the thalamus are distinct by morphology, neurochemistry, and function. This tightly linked network suggests the presence of fool-proof avenues for emotions to influence high-order cortical areas associated with affective reasoning. Specific nodes of this tripartite network are disrupted in psychiatric diseases, divorcing areas that integrate emotions and thoughts for decisions and flexible behavior. Copyright © 2015 the authors 0270-6474/15/3511976-12$15.00/0.

Pathway fraction of bromate formation during O₃ and O₃/H₂O₂ processes in drinking water treatment.

PubMed

Qi, Shengqi; Mao, Yuqin; Lv, Miao; Sun, Lili; Wang, Xiaomao; Yang, Hongwei; Xie, Yuefeng F

2016-02-01

Ozone process has been widely used for drinking water treatment recently. In the oxidation process, bromate is formed by three pathways, i.e., the direct pathway, the direct-indirect pathway and the indirect-direct pathway. This study developed a method to calculate the percentage of these three pathways for bromate formation during O3 process and O3/H2O2 process. Two kinds of water, distilled water containing bromide (DW) and surface water from the Yellow River (SW) were selected as raw rater. The result showed that in natural water systems, the direct-indirect pathway was dominant for bromate formation during the oxidation process. When 3 mg L(-1) O3 was used as the only oxidant, nearly 26% of bromide ion was transferred into bromate in two kinds of water after 80 min. The dominant pathway in DW was the direct pathway (48.5%) and the direct-indirect pathway (46.5%), while that was the direct-indirect pathway (68.9%) in SW. When O3/H2O2 were used as oxidants, as the H2O2 dosage increased, the fractions of bromate formation by direct pathway and direct-indirect pathway decreased, while that by indirect-direct pathway increased. The conversion ratio from bromide to bromate first kept stable or increased, then decreased and reached its minimum when [H2O2]/[O3] ratio was 1.0 in DW and 1.5 in SW. Under this condition the indirect-direct pathway took the largest fraction of 70.7% in DW and 64.0% in SW, respectively. Copyright © 2015. Published by Elsevier Ltd.

A Multidisciplinary Self-Directed Learning Module Improves Knowledge of a Quality Improvement Instrument: The HEART Pathway.

PubMed

Hartman, Nicholas D; Harper, Erin N; Leppert, Lauren M; Browning, Brittany M; Askew, Kim; Manthey, David E; Mahler, Simon A

We created and tested an educational intervention to support implementation of an institution wide QI project (the HEART Pathway) designed to improve care for patients with acute chest pain. Although online learning modules have been shown effective in imparting knowledge regarding QI projects, it is unknown whether these modules are effective across specialties and healthcare professions. Participants, including nurses, advanced practice clinicians, house staff and attending physicians (N = 486), were enrolled into an online, self-directed learning course exploring the key concepts of the HEART Pathway. The module was completed by 97% of enrollees (469/486) and 90% passed on the first attempt (422/469). Out of 469 learners, 323 completed the pretest, learning module and posttest in the correct order. Mean test scores across learners improved significantly from 74% to 89% from the pretest to the posttest. Following the intervention, the HEART Pathway was used for 88% of patients presenting to our institution with acute chest pain. Our data demonstrate that this online, self-directed learning module can improve knowledge of the HEART Pathway across specialties-paving the way for more efficient and informed care for acute chest pain patients.

Quantitative assessment on the contribution of direct photolysis and radical oxidation in photochemical degradation of 4-chlorophenol and oxytetracycline.

PubMed

Liu, Yiqing; He, Xuexiang; Fu, Yongsheng; Dionysiou, Dionysios D

2016-07-01

In UV-254 nm/H2O2 advanced oxidation process (AOP), the potential degradation pathways for organic pollutants include (1) hydrolysis, (2) direct H2O2 oxidation, (3) UV direct photolysis, and (4) hydroxyl radical (HO(•)) reaction. In this study, the contribution of these pathways was quantitatively assessed in the photochemical destruction of 4-chlorophenol (4-CP), demonstrating pathways (3) and (4) to be predominantly responsible for the removal of 4-CP by UV/H2O2 in 50 mM phosphate buffer solution. Increasing reaction pH could significantly enhance the contribution of direct photolysis in UV/H2O2 process. The contribution of HO(•) oxidation was improved with increasing initial H2O2 concentration probably due to the increased formation of HO(•). Presence of sodium carbonate (Na2CO3) as in UV/H2O2/Na2CO3 system promoted the degradation of 4-CP, with carbonate radical (CO3 (•-)) reaction and direct photolysis identified to be the main contributing pathways. The trends in the contribution of each factor were further evaluated and validated on the degradation of the antibiotic compound oxytetracycline (OTC). This study provides valuable information on the relative importance of different reaction pathways on the photochemical degradation of organic contaminants such as 4-CP and OTC in the presence and absence of a CO3 (•-) precursor.

Conservation of Planar Polarity Pathway Function Across the Animal Kingdom.

PubMed

Hale, Rosalind; Strutt, David

2015-01-01

Planar polarity is a well-studied phenomenon resulting in the directional coordination of cells in the plane of a tissue. In invertebrates and vertebrates, planar polarity is established and maintained by the largely independent core and Fat/Dachsous/Four-jointed (Ft-Ds-Fj) pathways. Loss of function of these pathways can result in a wide range of developmental or cellular defects, including failure of gastrulation and problems with placement and function of cilia. This review discusses the conservation of these pathways across the animal kingdom. The lack of vital core pathway components in basal metazoans suggests that the core planar polarity pathway evolved shortly after, but not necessarily alongside, the emergence of multicellularity.

An Evaluation of Active Learning Causal Discovery Methods for Reverse-Engineering Local Causal Pathways of Gene Regulation

PubMed Central

Ma, Sisi; Kemmeren, Patrick; Aliferis, Constantin F.; Statnikov, Alexander

2016-01-01

Reverse-engineering of causal pathways that implicate diseases and vital cellular functions is a fundamental problem in biomedicine. Discovery of the local causal pathway of a target variable (that consists of its direct causes and direct effects) is essential for effective intervention and can facilitate accurate diagnosis and prognosis. Recent research has provided several active learning methods that can leverage passively observed high-throughput data to draft causal pathways and then refine the inferred relations with a limited number of experiments. The current study provides a comprehensive evaluation of the performance of active learning methods for local causal pathway discovery in real biological data. Specifically, 54 active learning methods/variants from 3 families of algorithms were applied for local causal pathways reconstruction of gene regulation for 5 transcription factors in S. cerevisiae. Four aspects of the methods’ performance were assessed, including adjacency discovery quality, edge orientation accuracy, complete pathway discovery quality, and experimental cost. The results of this study show that some methods provide significant performance benefits over others and therefore should be routinely used for local causal pathway discovery tasks. This study also demonstrates the feasibility of local causal pathway reconstruction in real biological systems with significant quality and low experimental cost. PMID:26939894

[Spatial imprinting influence on development of cognitive process in adult animals].

PubMed

Serkova, V V; Nikol'skaia, K A

2013-12-01

The influence of spatial imprinting on cognitive activity of adult mice F1 from DBA/2J C57BL/6J in a transformable multialternative maze has been studied. A control mice initially learned in a maze with "direct" and "bypass" pathway between feeders. They successfully formed a food-getting habit after 9-10 sessions using mainly direct pathway, so the final route decision was consistent with the principle of least action. Experimental mice previously placed into reduced maze with only "bypass" pathway between feeders for 1-2 trials (1-3 min), and turn up in the complete maze immediately after that. Experimental mice could not organize a food-getting behavior according a task conditions since attempted to include in final decision both "direct" and "bypass" pathways, united in a single ring-like construction. They demonstrated situational behavior running from one feeder to another one, despite of fact that therein had no feed. So it opposed the realization of least action principle, becoming a source of psycho-emotional stress. The results showed that spatial information perceiving in the first few minutes of exploring the experimental environment can manifest itself as the acquired preference and come in conflict with an instinctive one. Cognitive dissonance predetermined the direction of the cognitive process.

The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy.

PubMed

Akabane, Hugo; Sullivan, Ryan J

2016-02-01

Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.

Contributions of Rod and Cone Pathways to Retinal Direction Selectivity Through Development

PubMed Central

Rosa, Juliana M.; Morrie, Ryan D.; Baertsch, Hans C.

2016-01-01

Direction selectivity is a robust computation across a broad stimulus space that is mediated by activity of both rod and cone photoreceptors through the ON and OFF pathways. However, rods, S-cones, and M-cones activate the ON and OFF circuits via distinct pathways and the relative contribution of each to direction selectivity is unknown. Using a variety of stimulation paradigms, pharmacological agents, and knockout mice that lack rod transduction, we found that inputs from the ON pathway were critical for strong direction-selective (DS) tuning in the OFF pathway. For UV light stimulation, the ON pathway inputs to the OFF pathway originated with rod signaling, whereas for visible stimulation, the ON pathway inputs to the OFF pathway originated with both rod and M-cone signaling. Whole-cell voltage-clamp recordings revealed that blocking the ON pathway reduced directional tuning in the OFF pathway via a reduction in null-side inhibition, which is provided by OFF starburst amacrine cells (SACs). Consistent with this, our recordings from OFF SACs confirmed that signals originating in the ON pathway contribute to their excitation. Finally, we observed that, for UV stimulation, ON contributions to OFF DS tuning matured earlier than direct signaling via the OFF pathway. These data indicate that the retina uses multiple strategies for computing DS responses across different colors and stages of development. SIGNIFICANCE STATEMENT The retina uses parallel pathways to encode different features of the visual scene. In some cases, these distinct pathways converge on circuits that mediate a distinct computation. For example, rod and cone pathways enable direction-selective (DS) ganglion cells to encode motion over a wide range of light intensities. Here, we show that although direction selectivity is robust across light intensities, motion discrimination for OFF signals is dependent upon ON signaling. At eye opening, ON directional tuning is mature, whereas OFF DS tuning is significantly reduced due to a delayed maturation of S-cone to OFF cone bipolar signaling. These results provide evidence that the retina uses multiple strategies for computing DS responses across different stimulus conditions. PMID:27629718

Nucleolus-derived mediators in oncogenic stress response and activation of p53-dependent pathways.

PubMed

Stępiński, Dariusz

2016-08-01

Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. The output of nucleoli, organelles where translational machineries are formed, depends on a rate of particular stages of ribosome production and on accessibility of elements crucial for their effective functioning, including substrates, enzymes as well as energy resources. Different factors that induce cellular stress also often lead to nucleolar dysfunction which results in ribosome biogenesis impairment. Such nucleolar disorders, called nucleolar or ribosomal stress, usually affect cellular functioning which in fact is a result of p53-dependent pathway activation, elicited as a response to stress. These pathways direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. In the case of impaired nucleolar functioning, nucleolar and ribosomal proteins mediate activation of the p53 pathways. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Intentional impairment of any step of ribosome biosynthesis which would direct the cells to these destinations could be a strategy used in anticancer therapy. This review presents current knowledge on a nucleolus, mainly in relation to cancer biology, which is an important and extremely sensitive element of the mechanism participating in cellular stress reaction mediating activation of the p53 pathways in order to counteract stress effects, especially cancer development.

Consensus strategy in genes prioritization and combined bioinformatics analysis for preeclampsia pathogenesis.

PubMed

Tejera, Eduardo; Cruz-Monteagudo, Maykel; Burgos, Germán; Sánchez, María-Eugenia; Sánchez-Rodríguez, Aminael; Pérez-Castillo, Yunierkis; Borges, Fernanda; Cordeiro, Maria Natália Dias Soeiro; Paz-Y-Miño, César; Rebelo, Irene

2017-08-08

Preeclampsia is a multifactorial disease with unknown pathogenesis. Even when recent studies explored this disease using several bioinformatics tools, the main objective was not directed to pathogenesis. Additionally, consensus prioritization was proved to be highly efficient in the recognition of genes-disease association. However, not information is available about the consensus ability to early recognize genes directly involved in pathogenesis. Therefore our aim in this study is to apply several theoretical approaches to explore preeclampsia; specifically those genes directly involved in the pathogenesis. We firstly evaluated the consensus between 12 prioritization strategies to early recognize pathogenic genes related to preeclampsia. A communality analysis in the protein-protein interaction network of previously selected genes was done including further enrichment analysis. The enrichment analysis includes metabolic pathways as well as gene ontology. Microarray data was also collected and used in order to confirm our results or as a strategy to weight the previously enriched pathways. The consensus prioritized gene list was rationally filtered to 476 genes using several criteria. The communality analysis showed an enrichment of communities connected with VEGF-signaling pathway. This pathway is also enriched considering the microarray data. Our result point to VEGF, FLT1 and KDR as relevant pathogenic genes, as well as those connected with NO metabolism. Our results revealed that consensus strategy improve the detection and initial enrichment of pathogenic genes, at least in preeclampsia condition. Moreover the combination of the first percent of the prioritized genes with protein-protein interaction network followed by communality analysis reduces the gene space. This approach actually identifies well known genes related with pathogenesis. However, genes like HSP90, PAK2, CD247 and others included in the first 1% of the prioritized list need to be further explored in preeclampsia pathogenesis through experimental approaches.

Raft-mediated trafficking of apical resident proteins occurs in both direct and transcytotic pathways in polarized hepatic cells: role of distinct lipid microdomains.

PubMed

Slimane, Tounsia Aït; Trugnan, Germain; Van IJzendoorn, Sven C D; Hoekstra, Dick

2003-02-01

In polarized hepatic cells, pathways and molecular principles mediating the flow of resident apical bile canalicular proteins have not yet been resolved. Herein, we have investigated apical trafficking of a glycosylphosphatidylinositol-linked and two single transmembrane domain proteins on the one hand, and two polytopic proteins on the other in polarized HepG2 cells. We demonstrate that the former arrive at the bile canalicular membrane via the indirect transcytotic pathway, whereas the polytopic proteins reach the apical membrane directly, after Golgi exit. Most importantly, cholesterol-based lipid microdomains ("rafts") are operating in either pathway, and protein sorting into such domains occurs in the biosynthetic pathway, largely in the Golgi. Interestingly, rafts involved in the direct pathway are Lubrol WX insoluble but Triton X-100 soluble, whereas rafts in the indirect pathway are both Lubrol WX and Triton X-100 insoluble. Moreover, whereas cholesterol depletion alters raft-detergent insolubility in the indirect pathway without affecting apical sorting, protein missorting occurs in the direct pathway without affecting raft insolubility. The data implicate cholesterol as a traffic direction-determining parameter in the direct apical pathway. Furthermore, raft-cargo likely distinguishing single vs. multispanning membrane anchors, rather than rafts per se (co)determine the sorting pathway.

Raft-mediated Trafficking of Apical Resident Proteins Occurs in Both Direct and Transcytotic Pathways in Polarized Hepatic Cells: Role of Distinct Lipid Microdomains

PubMed Central

Slimane, Tounsia Aït; Trugnan, Germain; van IJzendoorn, Sven C.D.; Hoekstra, Dick

2003-01-01

In polarized hepatic cells, pathways and molecular principles mediating the flow of resident apical bile canalicular proteins have not yet been resolved. Herein, we have investigated apical trafficking of a glycosylphosphatidylinositol-linked and two single transmembrane domain proteins on the one hand, and two polytopic proteins on the other in polarized HepG2 cells. We demonstrate that the former arrive at the bile canalicular membrane via the indirect transcytotic pathway, whereas the polytopic proteins reach the apical membrane directly, after Golgi exit. Most importantly, cholesterol-based lipid microdomains (“rafts”) are operating in either pathway, and protein sorting into such domains occurs in the biosynthetic pathway, largely in the Golgi. Interestingly, rafts involved in the direct pathway are Lubrol WX insoluble but Triton X-100 soluble, whereas rafts in the indirect pathway are both Lubrol WX and Triton X-100 insoluble. Moreover, whereas cholesterol depletion alters raft-detergent insolubility in the indirect pathway without affecting apical sorting, protein missorting occurs in the direct pathway without affecting raft insolubility. The data implicate cholesterol as a traffic direction-determining parameter in the direct apical pathway. Furthermore, raft-cargo likely distinguishing single vs. multispanning membrane anchors, rather than rafts per se (co)determine the sorting pathway. PMID:12589058

Clinical Pathways and the Patient Perspective in the Pursuit of Value-Based Oncology Care.

PubMed

Ersek, Jennifer L; Nadler, Eric; Freeman-Daily, Janet; Mazharuddin, Samir; Kim, Edward S

2017-01-01

The art of practicing oncology has evolved substantially in the past 5 years. As more and more diagnostic tests, biomarker-directed therapies, and immunotherapies make their way to the oncology marketplace, oncologists will find it increasingly difficult to keep up with the many therapeutic options. Additionally, the cost of cancer care seems to be increasing. Clinical pathways are a systematic way to organize and display detailed, evidence-based treatment options and assist the practitioner with best practice. When selecting which treatment regimens to include on a clinical pathway, considerations must include the efficacy and safety, as well as costs, of the therapy. Pathway treatment regimens must be continually assessed and modified to ensure that the most up-to-date, high-quality options are incorporated. Value-based models, such as the ASCO Value Framework, can assist providers in presenting economic evaluations of clinical pathway treatment options to patients, thus allowing the patient to decide the overall value of each treatment regimen. Although oncologists and pathway developers can decide which treatment regimens to include on a clinical pathway based on the efficacy of the treatment, assessment of the value of that treatment regimen ultimately lies with the patient. Patient definitions of value will be an important component to enhancing current value-based oncology care models and incorporating new, high-quality, value-based therapeutics into oncology clinical pathways.

BMP Signaling in Astrocytes Downregulates EGFR to Modulate Survival and Maturation

PubMed Central

Scholze, Anja R.; Foo, Lynette C.; Mulinyawe, Sara; Barres, Ben A.

2014-01-01

Astrocytes constitute a major cell population in the brain with a myriad of essential functions, yet we know remarkably little about the signaling pathways and mechanisms that direct astrocyte maturation. To explore the signals regulating astrocyte development, we prospectively purified and cultured immature postnatal rodent astrocytes. We identified fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) as robust trophic factors for immature astrocytes. We showed that astrocytes respond directly to BMPs via phosphorylation of the smad1/5/8 pathway. In vitro, BMP signaling promoted immature astrocytes to adopt multiple characteristics of mature astrocytes, including a more process-bearing morphology, aquaporin-4 (AQP4) and S100β immunoreactivity, limited proliferation, and strong downregulation of epidermal growth factor receptor (EGFR). In vivo, activation of the smad1/5/8 pathway in astrocytes was seen during early postnatal development, but inhibition of astrocyte proliferation was not observed. These insights can aid in the further dissection of the mechanisms and pathways controlling astrocyte biology and development. PMID:25330173

The Hippo Pathway: Immunity and Cancer.

PubMed

Taha, Zaid; J Janse van Rensburg, Helena; Yang, Xiaolong

2018-03-28

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

Possible Exposure Pathways During Emergencies

EPA Pesticide Factsheets

There are three basic ways a person may be exposed to a hazardous substance: inhalation, ingestion, or direct contact. Points of contact include groundwater or surface water; soil, sediment, or dust; air; or food.

Childhood maltreatment and violence: mediation through psychiatric morbidity.

PubMed

González, Rafael A; Kallis, Constantinos; Ullrich, Simone; Barnicot, Kirsten; Keers, Robert; Coid, Jeremy W

2016-02-01

Childhood maltreatment is associated with multiple adverse outcomes in adulthood including poor mental health and violence. We investigated direct and indirect pathways from childhood maltreatment to adult violence perpetration and the explanatory role of psychiatric morbidity. Analyses were based on a population survey of 2,928 young men 21-34 years in Great Britain in 2011, with boost surveys of black and minority ethnic groups and lower social grades. Respondents completed questionnaires measuring psychiatric diagnoses using standardized screening instruments, including antisocial personality disorder (ASPD), drug and alcohol dependence and psychosis. Maltreatment exposures included childhood physical abuse, neglect, witnessing domestic violence and being bullied. Adult violence outcomes included: any violence, violence toward strangers and intimate partners (IPV), victim injury and minor violence. Witnessing domestic violence showed the strongest risk for adult violence (AOR 2.70, 95% CI 2.00, 3.65) through a direct pathway, with psychotic symptoms and ASPD as partial mediators. Childhood physical abuse was associated with IPV (AOR 2.33, 95% CI 1.25, 4.35), mediated by ASPD and alcohol dependence. Neglect was associated with violence toward strangers (AOR 1.73, 95% CI 1.03, 2.91), mediated by ASPD. Prevention of violence in adulthood following childhood physical abuse and neglect requires treatment interventions for associated alcohol dependence, psychosis, and ASPD. However, witnessing family violence in childhood had strongest and direct effects on the pathway to adult violence, with important implications for primary prevention. In this context, prevention strategies should prioritize and focus on early childhood exposure to violence in the family home. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pathway Thermodynamics Highlights Kinetic Obstacles in Central Metabolism

PubMed Central

Flamholz, Avi; Reznik, Ed; Liebermeister, Wolfram; Milo, Ron

2014-01-01

In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG′). Accordingly, if an enzyme catalyzes a reaction with a ΔrG′ of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG′ approaches equilibrium (ΔrG′ = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the thermodynamic and kinetic quality of different pathway chemistries that produce the same molecules. PMID:24586134

Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.

PubMed

Schor, Raissa; Cox, Russell

2018-03-01

Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydrocurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.

Crosstalk between the Notch signaling pathway and non-coding RNAs in gastrointestinal cancers

PubMed Central

Pan, Yangyang; Mao, Yuyan; Jin, Rong; Jiang, Lei

2018-01-01

The Notch signaling pathway is one of the main signaling pathways that mediates direct contact between cells, and is essential for normal development. It regulates various cellular processes, including cell proliferation, apoptosis, migration, invasion, angiogenesis and metastasis. It additionally serves an important function in tumor progression. Non-coding RNAs mainly include small microRNAs, long non-coding RNAs and circular RNAs. At present, a large body of literature supports the biological significance of non-coding RNAs in tumor progression. It is also becoming increasingly evident that cross-talk exists between Notch signaling and non-coding RNAs. The present review summarizes the current knowledge of Notch-mediated gastrointestinal cancer cell processes, and the effect of the crosstalk between the three major types of non-coding RNAs and the Notch signaling pathway on the fate of gastrointestinal cancer cells. PMID:29285185

Pathways to Adult Sexual Revictimization: Direct and Indirect Behavioral Risk Factors across the Lifespan

ERIC Educational Resources Information Center

Fargo, Jamison D.

2009-01-01

The purpose of this study is to investigate direct and indirect social and behavioral risk factors for adult sexual revictimization. Participants include 147 adult, predominantly African American (88%) women, 59% of whom had a documented history of child sexual abuse. Participants are interviewed in adulthood about adolescent and adult sexual…

Chemistry at molecular junctions: Rotation and dissociation of O2 on the Ag(110) surface induced by a scanning tunneling microscope.

PubMed

Roy, Sharani; Mujica, Vladimiro; Ratner, Mark A

2013-08-21

The scanning tunneling microscope (STM) is a fascinating tool used to perform chemical processes at the single-molecule level, including bond formation, bond breaking, and even chemical reactions. Hahn and Ho [J. Chem. Phys. 123, 214702 (2005)] performed controlled rotations and dissociations of single O2 molecules chemisorbed on the Ag(110) surface at precise bias voltages using STM. These threshold voltages were dependent on the direction of the bias voltage and the initial orientation of the chemisorbed molecule. They also observed an interesting voltage-direction-dependent and orientation-dependent pathway selectivity suggestive of mode-selective chemistry at molecular junctions, such that in one case the molecule underwent direct dissociation, whereas in the other case it underwent rotation-mediated dissociation. We present a detailed, first-principles-based theoretical study to investigate the mechanism of the tunneling-induced O2 dynamics, including the origin of the observed threshold voltages, the pathway dependence, and the rate of O2 dissociation. Results show a direct correspondence between the observed threshold voltage for a process and the activation energy for that process. The pathway selectivity arises from a competition between the voltage-modified barrier heights for rotation and dissociation, and the coupling strength of the tunneling electrons to the rotational and vibrational modes of the adsorbed molecule. Finally, we explore the "dipole" and "resonance" mechanisms of inelastic electron tunneling to elucidate the energy transfer between the tunneling electrons and chemisorbed O2.

Concurrent activation of striatal direct and indirect pathways during action initiation.

PubMed

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Pham, Michael D; Vogel, Steven S; Lovinger, David M; Costa, Rui M

2013-02-14

The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.

The patient-breast cancer care pathway: how could it be optimized?

PubMed

Baffert, Sandrine; Hoang, Huong Ly; Brédart, Anne; Asselain, Bernard; Alran, Séverine; Berseneff, Hélène; Huchon, Cyrille; Trichot, Caroline; Combes, Aline; Alves, Karine; Koskas, Martin; Nguyen, Thuy; Roulot, Aurélie; Rouzier, Roman; Héquet, Delphine

2015-05-12

A care pathway is defined as patient-focused global care that addresses temporal (effective and coordinated management throughout the illness) and spatial issues (treatment is provided near the health territory in or around the patient's home). Heterogeneity of the care pathways in breast cancer (BC) is presumed but not well evaluated. The OPTISOINS01 study aims to assess every aspect of the care pathway for early BC patients using a temporal and spatial scope. An observational, prospective, multicenter study in a regional health territory (Ile-de-France, France) in different types of structures: university or local hospitals and comprehensive cancer centers. We will include and follow during 1 year 1,000 patients. The study consists of 3 work-packages: - Cost of pathway The aim of this WP is to calculate the overall costs of the early BC pathway at 1 year from different perspectives (society, health insurance and patient) using a cost-of-illness analysis. Using a bottom-up method, we will assess direct costs, including medical direct costs and nonmedical direct costs (transportation, home modifications, home care services, and social services), and indirect costs (loss of production). - Patient satisfaction and work reintegration Three questionnaires will assess the patients' satisfaction and possible return to work: the occupational questionnaire for employed women; the questionnaire on the need for supportive care, SCNS-SF34 ('breast cancer' module, SCNS-BR8); and the OUTPASSAT-35 questionnaire. - Quality, coordination and access to innovation Quality will be evaluated based on visits and treatment within a set period, whether the setting offers a multidisciplinary consultative framework, the management by nurse coordinators, the use of a personalized care plan, the provision of information via documents about treatments and the provision of supportive care. The coordination between structures and caregivers will be evaluated at several levels. Day surgery, home hospitalization and one-stop breast clinic visits will be recorded to assess the patient's access to innovation. The assessment of care pathways encourages the implementation of new payment models. Our approach could help health care professionals and policymakers to establish other cost-of-illness studies and plan the allocation of resources on a patient basis rather than a visit basis.

Synergy and Interactions Among Biological Pathways Leading to Preterm Premature Rupture of Membranes

PubMed Central

Lannon, Sophia M. R.; Vanderhoeven, Jeroen P.; Eschenbach, David A.; Gravett, Michael G.; Waldorf, Kristina M. Adams

2014-01-01

Preterm premature rupture of membranes (PPROM) occurs in 1% to 2% of births. Impact of PPROM is greatest in low- and middle-income countries where prematurity-related deaths are most common. Recent investigations identify cytokine and matrix metalloproteinase activation, oxidative stress, and apoptosis as primary pathways to PPROM. These biological processes are initiated by heterogeneous etiologies including infection/inflammation, placental bleeding, uterine overdistention, and genetic polymorphisms. We hypothesize that pathways to PPROM overlap and act synergistically to weaken membranes. We focus our discussion on membrane composition and strength, pathways linking risk factors to membrane weakening, and future research directions to reduce the global burden of PPROM. PMID:24840939

The suppression of apoptosis by α-herpesvirus

PubMed Central

You, Yu; Cheng, An-Chun; Wang, Ming-Shu; Jia, Ren-Yong; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Zhu, Dekang; Chen, Shun; Liu, Ma-Feng; Zhao, Xin-Xin; Chen, Xiao-Yue

2017-01-01

Apoptosis, an important innate immune mechanism that eliminates pathogen-infected cells, is primarily triggered by two signalling pathways: the death receptor pathway and the mitochondria-mediated pathway. However, many viruses have evolved various strategies to suppress apoptosis by encoding anti-apoptotic factors or regulating apoptotic signalling pathways, which promote viral propagation and evasion of the host defence. During its life cycle, α-herpesvirus utilizes an elegant multifarious anti-apoptotic strategy to suppress programmed cell death. This progress article primarily focuses on the current understanding of the apoptosis-inhibition mechanisms of α-herpesvirus anti-apoptotic genes and their expression products and discusses future directions, including how the anti-apoptotic function of herpesvirus could be targeted therapeutically. PMID:28406478

PathwayAccess: CellDesigner plugins for pathway databases.

PubMed

Van Hemert, John L; Dickerson, Julie A

2010-09-15

CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy.

PubMed

Bacyinski, Andrew; Xu, Maosheng; Wang, Wei; Hu, Jiani

2017-01-01

The paravascular pathway, also known as the "glymphatic" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted.

Assessing natural direct and indirect effects through multiple pathways.

PubMed

Lange, Theis; Rasmussen, Mette; Thygesen, Lau Caspar

2014-02-15

Within the fields of epidemiology, interventions research and social sciences researchers are often faced with the challenge of decomposing the effect of an exposure into different causal pathways working through defined mediator variables. The goal of such analyses is often to understand the mechanisms of the system or to suggest possible interventions. The case of a single mediator, thus implying only 2 causal pathways (direct and indirect) from exposure to outcome, has been extensively studied. By using the framework of counterfactual variables, researchers have established theoretical properties and developed powerful tools. However, in practical problems, it is not uncommon to have several distinct causal pathways from exposure to outcome operating through different mediators. In this article, we suggest a widely applicable approach to quantifying and ranking different causal pathways. The approach is an extension of the natural effect models proposed by Lange et al. (Am J Epidemiol. 2012;176(3):190-195). By allowing the analysis of distinct multiple pathways, the suggested approach adds to the capabilities of modern mediation techniques. Furthermore, the approach can be implemented using standard software, and we have included with this article implementation examples using R (R Foundation for Statistical Computing, Vienna, Austria) and Stata software (StataCorp LP, College Station, Texas).

The Hippo Pathway: Immunity and Cancer

PubMed Central

J. Janse van Rensburg, Helena

2018-01-01

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work. PMID:29597279

Production of Odd-Carbon Dicarboxylic Acids in Escherichia coli Using an Engineered Biotin-Fatty Acid Biosynthetic Pathway.

PubMed

Haushalter, Robert W; Phelan, Ryan M; Hoh, Kristina M; Su, Cindy; Wang, George; Baidoo, Edward E K; Keasling, Jay D

2017-04-05

Dicarboxylic acids are commodity chemicals used in the production of plastics, polyesters, nylons, fragrances, and medications. Bio-based routes to dicarboxylic acids are gaining attention due to environmental concerns about petroleum-based production of these compounds. Some industrial applications require dicarboxylic acids with specific carbon chain lengths, including odd-carbon species. Biosynthetic pathways involving cytochrome P450-catalyzed oxidation of fatty acids in yeast and bacteria have been reported, but these systems produce almost exclusively even-carbon species. Here we report a novel pathway to odd-carbon dicarboxylic acids directly from glucose in Escherichia coli by employing an engineered pathway combining enzymes from biotin and fatty acid synthesis. Optimization of the pathway will lead to industrial strains for the production of valuable odd-carbon diacids.

Why are Religiousness and Spirituality Associated with Externalizing Psychopathology? A Literature Review.

PubMed

Holmes, Christopher; Kim-Spoon, Jungmeen

2016-03-01

This review explores the relation of religiousness and spirituality with externalizing psychopathology in adolescence given the heightened externalizing psychopathology during this developmental period. Utilizing a developmental psychopathology framework, previous literature is reviewed focusing on the diversity of pathways from religiousness and spirituality to externalizing psychopathology at multiple levels of analysis. Moreover, the pathways considered include both intraindividual factors (e.g., self-control, monitoring, delay discounting and time orientation, and neurobiological regulatory systems) and ecological factors (e.g., intergenerational transmission, parent-child relationships, and community relationships). These pathways are explored in light of theoretical viewpoints including social control theory, divine interaction theory, and the religious ecology model. Limitations of extant work are examined, including measurement and design issues, exploration of potential negative effects of religiousness and spirituality, and bias toward Western religions. Finally, future directions of research and clinical implications are discussed.

Why Are Religiousness and Spirituality Associated with Externalizing Psychopathology? A Literature Review

PubMed Central

Holmes, Christopher; Kim-Spoon, Jungmeen

2015-01-01

This review explores the relation of religiousness and spirituality with externalizing psychopathology in adolescence given the heightened externalizing psychopathology during this developmental period. Utilizing a developmental psychopathology framework, previous literature is reviewed focusing on the diversity of pathways from religiousness and spirituality to externalizing psychopathology at multiple levels of analysis. Moreover, the pathways considered include both intraindividual factors (e.g., self-control, monitoring, delay discounting and time orientation, and neurobiological regulatory systems) and ecological factors (e.g., intergenerational transmission, parent-child relationships, and community relationships). These pathways are explored in light of theoretical viewpoints including social control theory, divine interaction theory, and the religious ecology model. Limitations of extant work are examined, including measurement and design issues, exploration of potential negative effects of religiousness and spirituality, and bias towards Western religions. Finally, future directions of research and clinical implications are discussed. PMID:26662624

Roles of microRNA on cancer cell metabolism

PubMed Central

2012-01-01

Advanced studies of microRNAs (miRNAs) have revealed their manifold biological functions, including control of cell proliferation, cell cycle and cell death. However, it seems that their roles as key regulators of metabolism have drawn more and more attention in the recent years. Cancer cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. MiRNAs regulate cell metabolic processes through complicated mechanisms, including directly targeting key enzymes or transporters of metabolic processes and regulating transcription factors, oncogenes / tumor suppressors as well as multiple oncogenic signaling pathways. MiRNAs like miR-375, miR-143, miR-14 and miR-29b participate in controlling cancer cell metabolism by regulating the expression of genes whose protein products either directly regulate metabolic machinery or indirectly modulate the expression of metabolic enzymes, serving as master regulators, which will hopefully lead to a new therapeutic strategy for malignant cancer. This review focuses on miRNA regulations of cancer cell metabolism,including glucose uptake, glycolysis, tricarboxylic acid cycle and insulin production, lipid metabolism and amino acid biogenesis, as well as several oncogenic signaling pathways. Furthermore, the challenges of miRNA-based strategies for cancer diagnosis, prognosis and therapeutics have been discussed. PMID:23164426

Direct vs. indirect pathway for nitrobenzene reduction reaction on a Ni catalyst surface: a density functional study.

PubMed

Mahata, Arup; Rai, Rohit K; Choudhuri, Indrani; Singh, Sanjay K; Pathak, Biswarup

2014-12-21

Density functional theory (DFT) calculations are performed to understand and address the previous experimental results that showed the reduction of nitrobenzene to aniline prefers direct over indirect reaction pathways irrespective of the catalyst surface. Nitrobenzene to aniline conversion occurs via the hydroxyl amine intermediate (direct pathway) or via the azoxybenzene intermediate (indirect pathway). Through our computational study we calculated the spin polarized and dispersion corrected reaction energies and activation barriers corresponding to various reaction pathways for the reduction of nitrobenzene to aniline over a Ni catalyst surface. The adsorption behaviour of the substrate, nitrobenzene, on the catalyst surface was also considered and the energetically most preferable structural orientation was elucidated. Our study indicates that the parallel adsorption behaviour of the molecules over a catalyst surface is preferable over vertical adsorption behaviour. Based on the reaction energies and activation barrier of the various elementary steps involved in direct or indirect reaction pathways, we find that the direct reduction pathway of nitrobenzene over the Ni(111) catalyst surface is more favourable than the indirect reaction pathway.

Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation

PubMed Central

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Pham, Michael D.

2014-01-01

Summary The basal ganglia are subcortical nuclei that control voluntary actions, and are affected by a number of debilitating neurological disorders1–4. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum5,6 - the so-called direct and indirect pathways - have opposing effects on movement: while activity of direct-pathway SPNs purportedly facilitates movement, activity of indirect-pathway SPNs inhibits movement1,2. This model has been difficult to test due to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. We developed a novel in-vivo method that allowed us to specifically measure direct- and indirect-pathway SPN activity using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCAMP3 in the dorsal striatum of D1-Cre (direct-pathway specific6,7) and A2A-Cre (indirect-pathway specific8,9) mice10. Using fiber optics and time-correlated single photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements, and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function, and may have implications for understanding the origin of motor symptoms in basal ganglia disorders. PMID:23354054

Spatially Compact Neural Clusters in the Dorsal Striatum Encode Locomotion Relevant Information.

PubMed

Barbera, Giovanni; Liang, Bo; Zhang, Lifeng; Gerfen, Charles R; Culurciello, Eugenio; Chen, Rong; Li, Yun; Lin, Da-Ting

2016-10-05

An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior. VIDEO ABSTRACT. Published by Elsevier Inc.

Local strategies to prevent and treat osteoporosis.

PubMed

Torstrick, F Brennan; Guldberg, Robert E

2014-03-01

Despite advances in systemic osteoporosis therapeutic outcomes, management of fragility fractures and implant fixation in osteoporotic bone remain difficult clinical challenges. Low initial bone density and a prolonged healing response can lead to fracture nonunion and aseptic implant loosening. Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways. Local strategies under investigation include direct drug release from injectable materials or implant surface coatings. Common locally delivered drugs include bisphosphonates, parathyroid hormone, and bone morphogenetic proteins, yet additional compounds targeting novel pathways in bone biology are also being actively explored. Mechanical stimulation via low intensity pulsed ultrasound, alone or in combination with drug therapy, may also prove effective to promote local bone healing and implant fixation within osteoporotic bone.

Investigation of Ruthenium Dissolution in Advanced Membrane Electrode Assemblies for Direct Methanol Based Fuel Cells Stacks

NASA Technical Reports Server (NTRS)

Valdez, T. I.; Firdosy, S.; Koel, B. E.; Narayanan, S. R.

2005-01-01

This viewgraph presentation gives a detailed review of the Direct Methanol Based Fuel Cell (DMFC) stack and investigates the Ruthenium that was found at the exit of the stack. The topics include: 1) Motivation; 2) Pathways for Cell Degradation; 3) Cell Duration Testing; 4) Duration Testing, MEA Analysis; and 5) Stack Degradation Analysis.

The Frustrated and Helpless Healer: Pathways Approaches to Posttraumatic Stress Disorders.

PubMed

Moss, Donald

2017-01-01

Posttraumatic stress disorder is a psychophysiological disorder, characterized by the following: chronic sympathetic nervous activation; persisting perceptual/sensory vigilance for threats; recurrent distressing memories of the event, including intrusive memories, flashbacks lived as if in the present moment, and nightmares; and a persisting negative emotional state including fear and shame. The psychophysiological basis for this disorder calls for psychophysiologically based interventions. This article presents the case narrative of a 29-year-old national guardsman, exposed to combat trauma and later to civilian trauma in public safety work. His treatment followed the Pathways model, comprised of multimodal interventions, beginning with self-directed behavioral changes, then the acquisition of skills (including self-hypnosis), and finally professional treatment including clinical hypnosis and EMDR.

The Path from Childhood Behavioural Disorders to Felony Offending: Investigating the Role of Adolescent Drinking, Peer Marginalization, and School Failure

PubMed Central

Savolainen, Jukka; Mason, W. Alex; Bolen, Jonathan D.; Chmelka, Mary B.; Hurtig, Tuula; Ebeling, Hanna; Nordström, Tanja; Taanila, Anja

2016-01-01

Background Although a pathway from childhood behavioural disorders to criminal offending is well-established, the aetiological processes remain poorly understood. Also, it is not clear if attention deficit hyperactivity disorder (ADHD) is predictive of crime in the absence of comorbid disruptive behaviour disorder (DBD). Hypothesis We examined two research questions: (1) Does ADHD have a unique effect on the risk of criminal offending, independently of DBD? (2) Is the effect of childhood behavioural disorders on criminal offending direct or mediated by adolescent processes related to school experience, substance misuse, and peers? Method Structural equation modelling, with latent variables, was applied to longitudinally collected data on 4,644 males from the 1986 Northern Finland Birth Cohort Study. Results Both ADHD and DBD separately predicted felony conviction risk. Most of these effects were mediated by adolescent alcohol use and low academic performance. The effect of DBD was stronger and included a direct pathway to criminal offending. Conclusion Findings were more consistent with the life course mediation hypothesis of pathways into crime, in that the effects of each disorder category were mediated by heavy drinking and educational failure. Preventing these adolescent risk outcomes may be an effective approach to closing pathways to criminal behaviour among behaviourally disordered children. However, as there was some evidence of a direct pathway from DBD, effective treatments targeting this disorder are also expected to reduce criminal offending. PMID:25250918

The path from childhood behavioural disorders to felony offending: Investigating the role of adolescent drinking, peer marginalisation and school failure.

PubMed

Savolainen, Jukka; Mason, W Alex; Bolen, Jonathan D; Chmelka, Mary B; Hurtig, Tuula; Ebeling, Hanna; Nordström, Tanja; Taanila, Anja

2015-12-01

Although a pathway from childhood behavioural disorders to criminal offending is well established, the aetiological processes remain poorly understood. Also, it is not clear if attention deficit hyperactivity disorder (ADHD) is predictive of crime in the absence of comorbid disruptive behaviour disorder (DBD). We examined two research questions: (1) Does ADHD have a unique effect on the risk of criminal offending, independently of DBD? (2) Is the effect of childhood behavioural disorders on criminal offending direct or mediated by adolescent processes related to school experience, substance misuse and peers? Structural equation modelling, with latent variables, was applied to longitudinally collected data on 4644 men from the 1986 Northern Finland Birth Cohort Study. Both ADHD and DBD separately predicted felony conviction risk. Most of these effects were mediated by adolescent alcohol use and low academic performance. The effect of DBD was stronger and included a direct pathway to criminal offending. Findings were more consistent with the life course mediation hypothesis of pathways into crime than the behavioural continuity path, in that the effects of each disorder category were mediated by heavy drinking and educational failure. Preventing these adolescent risk outcomes may be an effective approach to closing pathways to criminal behaviour amongst behaviourally disordered children. However, as there was some evidence of a direct pathway from DBD, effective treatments targeting this disorder are also expected to reduce criminal offending. Copyright © 2014 John Wiley & Sons, Ltd.

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

PubMed Central

2014-01-01

Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism. PMID:25152696

Apoptosis in mammalian oocytes: a review.

PubMed

Tiwari, Meenakshi; Prasad, Shilpa; Tripathi, Anima; Pandey, Ashutosh N; Ali, Irfan; Singh, Arvind K; Shrivastav, Tulsidas G; Chaube, Shail K

2015-08-01

Apoptosis causes elimination of more than 99% of germ cells from cohort of ovary through follicular atresia. Less than 1% of germ cells, which are culminated in oocytes further undergo apoptosis during last phases of oogenesis and depletes ovarian reserve in most of the mammalian species including human. There are several players that induce apoptosis directly or indirectly in oocytes at various stages of meiotic cell cycle. Premature removal of encircling granulosa cells from immature oocytes, reduced levels of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate, increased levels of calcium (Ca(2+)) and oxidants, sustained reduced level of maturation promoting factor, depletion of survival factors, nutrients and cell cycle proteins, reduced meiotic competency, increased levels of proapoptotic as well as apoptotic factors lead to oocyte apoptosis. The BH3-only proteins also act as key regulators of apoptosis in oocyte within the ovary. Both intrinsic (mitochondria-mediated) as well as extrinsic (cell surface death receptor-mediated) pathways are involved in oocyte apoptosis. BID, a BH3-only protein act as a bridge between both apoptotic pathways and its cleavage activates cell death machinery of both the pathways inside the follicular microenvironment. Oocyte apoptosis leads to the depletion of ovarian reserve that directly affects reproductive outcome of various mammals including human. In this review article, we highlight some of the important players and describe the pathways involved during oocyte apoptosis in mammals.

Negative emotionality moderates associations among attachment, toddler sleep, and later problem behaviors.

PubMed

Troxel, Wendy M; Trentacosta, Christopher J; Forbes, Erika E; Campbell, Susan B

2013-02-01

Secure parent-child relationships are implicated in children's self-regulation, including the ability to self-soothe at bedtime. Sleep, in turn, may serve as a pathway linking attachment security with subsequent emotional and behavioral problems in children. We used path analysis to examine the direct relationship between attachment security and maternal reports of sleep problems during toddlerhood and the degree to which sleep serves as a pathway linking attachment with subsequent teacher-reported emotional and behavioral problems. We also examined infant negative emotionality as a vulnerability factor that may potentiate attachment-sleep-adjustment outcomes. Data were drawn from 776 mother-infant dyads participating in the National Institute of Child and Human Development Study of Early Child Care. After statistically adjusting for mother and child characteristics, including child sleep and emotional and behavioral problems at 24 months, we found no evidence for a statistically significant direct path between attachment security and sleep problems at 36 months; however, there was a direct relationship between sleep problems at 36 months and internalizing problems at 54 months. Path models that examined the moderating influence of infant negative emotionality demonstrated significant direct relationships between attachment security and toddler sleep problems and between sleep problems and subsequent emotional and behavioral problems, but only among children characterized by high negative emotionality at 6 months. In addition, among this subset, there was a significant indirect path between attachment and internalizing problems through sleep problems. These longitudinal findings implicate sleep as one critical pathway linking attachment security with adjustment difficulties, particularly among temperamentally vulnerable children. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Negative Emotionality Moderates Associations among Attachment, Toddler Sleep, and Later Problem Behaviors

PubMed Central

Troxel, Wendy M.; Trentacosta, Christopher J.; Forbes, Erika E.; Campbell, Susan B.

2013-01-01

Secure parent-child relationships are implicated in children’s self-regulation, including the ability to self-soothe at bedtime. Sleep, in turn, may serve as a pathway linking attachment security with subsequent emotional and behavioral problems in children. We used path analysis to examine the direct relationship between attachment security and maternal-reports of sleep problems during toddlerhood, and the degree to which sleep serves as a pathway linking attachment with subsequent teacher-reported emotional and behavioral problems. We also examined infant negative emotionality as a vulnerability factor that may potentiate attachment-sleep-adjustment outcomes. Data were drawn from 776 mother-infant dyads participating in the NICHD Study of Early Child Care (SECC). In the full sample, after statistically adjusting for mother and child characteristics, including child sleep and emotional and behavioral problems at 24 months, we did not find evidence for a statistically significant direct path between attachment security and sleep problems at 36 months; however, there was a direct relationship between sleep problems at 36 months and internalizing problems at 54 months. Path models that examined the moderating influence of infant negative emotionality demonstrated significant direct relationships between attachment security and toddler sleep problems, and sleep problems and subsequent emotional and behavioral problems, but only among children characterized by high negative emotionality at 6 months of age. In addition, among this subset, there was a significant indirect path between attachment and internalizing problems through sleep problems. These longitudinal findings implicate sleep as one critical pathway linking attachment security with adjustment difficulties, particularly among temperamentally vulnerable children. PMID:23421840

Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets.

PubMed

Wang, Zhang; Arat, Seda; Magid-Slav, Michal; Brown, James R

2018-01-10

With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors. Here we performed a statistical meta-analysis of human gene expression in response to both latent and active pulmonary tuberculosis infections from nine published datasets. We found 1655 genes that were significantly differentially expressed during active tuberculosis infection. In contrast, no gene was significant for latent tuberculosis. Pathway enrichment analysis identified 90 significant canonical human pathways, including several pathways more commonly related to non-infectious diseases such as the LRRK2 pathway in Parkinson's disease, and PD-1/PD-L1 signaling pathway important for new immuno-oncology therapies. The analysis of human genome-wide association studies datasets revealed tuberculosis-associated genetic variants proximal to several genes in major histocompatibility complex for antigen presentation. We propose several new targets and drug-repurposing opportunities including intravenous immunoglobulin, ion-channel blockers and cancer immuno-therapeutics for development as combination therapeutics with anti-mycobacterial agents. Our meta-analysis provides novel insights into host genes and pathways important for tuberculosis and brings forth potential drug repurposing opportunities for host-directed therapies.

Production of Odd-Carbon Dicarboxylic Acids in Escherichia coli Using an Engineered Biotin–Fatty Acid Biosynthetic Pathway

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

Haushalter, Robert W.; Phelan, Ryan M.; Hoh, Kristina M.

Dicarboxylic acids are commodity chemicals used in the production of plastics, polyesters, nylons, fragrances, and medications. Bio-based routes to dicarboxylic acids are gaining attention due to environmental concerns about petroleum-based production of these compounds. Some industrial applications require dicarboxylic acids with specific carbon chain lengths, including odd-carbon species. Biosynthetic pathways involving cytochrome P450-catalyzed oxidation of fatty acids in yeast and bacteria have been reported, but these systems produce almost exclusively even-carbon species. Here in this paper we report a novel pathway to odd-carbon dicarboxylic acids directly from glucose in Escherichia coli by employing an engineered pathway combining enzymes from biotinmore » and fatty acid synthesis. Optimization of the pathway will lead to industrial strains for the production of valuable odd-carbon diacids.« less

Social position, social ties and adult's oral health: 13 year cohort study.

PubMed

Vettore, Mario Vianna; Faerstein, Eduardo; Baker, Sarah Ruth

2016-01-01

This study explored different pathways by which social position and social ties influence adult's oral health over a 13-year period. A cohort investigation (Pro-Saúde Study) was conducted of non-faculty civil servants at a university in Rio de Janeiro, Brazil (N=1613). Baseline data collected in 1999 included age, social position, social ties, and access to dental care. Psychological factors and smoking were assessed in 2001, whereas tooth loss and self-rated oral health (SROH) were collected in 2012. A hypothesised model exploring different direct and indirect pathways was developed and tested using structural equation modelling. The model was a good fit to the data and accounted for 40% and 27% of the variance in tooth loss and SROH, respectively. A greater social position was linked to more social ties (β=0.31), health insurance (β=0.48), low psychological distress (β=0.07), less smoking (β=-0.21), more regular dental visiting (β=0.30), less tooth loss (β=-0.44) and better SROH (β=-0.25) over time. Social position (β=0.0005) and social ties (β=-0.0015) were linked indirectly with psychological distress, smoking and tooth loss. Social position was linked indirectly with social ties, psychological distress and SROH (β=-0.0071). Poor social position and weak social ties were important predictors for tooth loss and poor SROH in adults over the 13-year period. Direct and indirect pathways via psychological factors and smoking on the aforementioned relationships were identified, suggesting different areas of intervention to promote adults' oral health. Adult's oral health is influenced by social conditions through direct and indirect pathways, including via psychological factors and smoking. Copyright © 2015. Published by Elsevier Ltd.

Flow directionality, mountain barriers and functional traits determine diatom metacommunity structuring of high mountain streams.

PubMed

Dong, Xiaoyu; Li, Bin; He, Fengzhi; Gu, Yuan; Sun, Meiqin; Zhang, Haomiao; Tan, Lu; Xiao, Wen; Liu, Shuoran; Cai, Qinghua

2016-04-19

Stream metacommunities are structured by a combination of local (environmental filtering) and regional (dispersal) processes. The unique characters of high mountain streams could potentially determine metacommunity structuring, which is currently poorly understood. Aiming at understanding how these characters influenced metacommunity structuring, we explored the relative importance of local environmental conditions and various dispersal processes, including through geographical (overland), topographical (across mountain barriers) and network (along flow direction) pathways in shaping benthic diatom communities. From a trait perspective, diatoms were categorized into high-profile, low-profile and motile guild to examine the roles of functional traits. Our results indicated that both environmental filtering and dispersal processes influenced metacommunity structuring, with dispersal contributing more than environmental processes. Among the three pathways, stream corridors were primary pathway. Deconstructive analysis suggested different responses to environmental and spatial factors for each of three ecological guilds. However, regardless of traits, dispersal among streams was limited by mountain barriers, while dispersal along stream was promoted by rushing flow in high mountain stream. Our results highlighted that directional processes had prevailing effects on metacommunity structuring in high mountain streams. Flow directionality, mountain barriers and ecological guilds contributed to a better understanding of the roles that mountains played in structuring metacommunity.

DNA repair targeted therapy: the past or future of cancer treatment?

PubMed Central

Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Hinshaw, Hilary D.; Jalal, Shadia I.; Sears, Catherine R.; Pawelczak, Katherine S.; Turchi, John J.

2016-01-01

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy. PMID:26896565

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

PubMed Central

Chisholm, Andrew D.; Hutter, Harald; Jin, Yishi; Wadsworth, William G.

2016-01-01

The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regeneration-specific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment. PMID:28114100

The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy

PubMed Central

Bacyinski, Andrew; Xu, Maosheng; Wang, Wei; Hu, Jiani

2017-01-01

The paravascular pathway, also known as the “glymphatic” pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted. PMID:29163074

Simultaneous Identification of Multiple Driver Pathways in Cancer

PubMed Central

Leiserson, Mark D. M.; Blokh, Dima

2013-01-01

Distinguishing the somatic mutations responsible for cancer (driver mutations) from random, passenger mutations is a key challenge in cancer genomics. Driver mutations generally target cellular signaling and regulatory pathways consisting of multiple genes. This heterogeneity complicates the identification of driver mutations by their recurrence across samples, as different combinations of mutations in driver pathways are observed in different samples. We introduce the Multi-Dendrix algorithm for the simultaneous identification of multiple driver pathways de novo in somatic mutation data from a cohort of cancer samples. The algorithm relies on two combinatorial properties of mutations in a driver pathway: high coverage and mutual exclusivity. We derive an integer linear program that finds set of mutations exhibiting these properties. We apply Multi-Dendrix to somatic mutations from glioblastoma, breast cancer, and lung cancer samples. Multi-Dendrix identifies sets of mutations in genes that overlap with known pathways – including Rb, p53, PI(3)K, and cell cycle pathways – and also novel sets of mutually exclusive mutations, including mutations in several transcription factors or other genes involved in transcriptional regulation. These sets are discovered directly from mutation data with no prior knowledge of pathways or gene interactions. We show that Multi-Dendrix outperforms other algorithms for identifying combinations of mutations and is also orders of magnitude faster on genome-scale data. Software available at: http://compbio.cs.brown.edu/software. PMID:23717195

Amygdaloid projections to the ventral striatum in mice: direct and indirect chemosensory inputs to the brain reward system.

PubMed

Novejarque, Amparo; Gutiérrez-Castellanos, Nicolás; Lanuza, Enrique; Martínez-García, Fernando

2011-01-01

Rodents constitute good models for studying the neural basis of sociosexual behavior. Recent findings in mice have revealed the molecular identity of the some pheromonal molecules triggering intersexual attraction. However, the neural pathways mediating this basic sociosexual behavior remain elusive. Since previous work indicates that the dopaminergic tegmento-striatal pathway is not involved in pheromone reward, the present report explores alternative pathways linking the vomeronasal system with the tegmento-striatal system (the limbic basal ganglia) by means of tract-tracing experiments studying direct and indirect projections from the chemosensory amygdala to the ventral striato-pallidum. Amygdaloid projections to the nucleus accumbens, olfactory tubercle, and adjoining structures are studied by analyzing the retrograde transport in the amygdala from dextran amine and fluorogold injections in the ventral striatum, as well as the anterograde labeling found in the ventral striato-pallidum after dextran amine injections in the amygdala. This combination of anterograde and retrograde tracing experiments reveals direct projections from the vomeronasal cortex to the ventral striato-pallidum, as well as indirect projections through different nuclei of the basolateral amygdala. Direct projections innervate mainly the olfactory tubercle and the islands of Calleja, whereas indirect projections are more widespread and reach the same structures and the shell and core of nucleus accumbens. These pathways are likely to mediate innate responses to pheromones (direct projections) and conditioned responses to associated chemosensory and non-chemosensory stimuli (indirect projections). Comparative studies indicate that similar connections are present in all the studied amniote vertebrates and might constitute the basic circuitry for emotional responses to conspecifics in most vertebrates, including humans.

Amygdaloid Projections to the Ventral Striatum in Mice: Direct and Indirect Chemosensory Inputs to the Brain Reward System

PubMed Central

Novejarque, Amparo; Gutiérrez-Castellanos, Nicolás; Lanuza, Enrique; Martínez-García, Fernando

2011-01-01

Rodents constitute good models for studying the neural basis of sociosexual behavior. Recent findings in mice have revealed the molecular identity of the some pheromonal molecules triggering intersexual attraction. However, the neural pathways mediating this basic sociosexual behavior remain elusive. Since previous work indicates that the dopaminergic tegmento-striatal pathway is not involved in pheromone reward, the present report explores alternative pathways linking the vomeronasal system with the tegmento-striatal system (the limbic basal ganglia) by means of tract-tracing experiments studying direct and indirect projections from the chemosensory amygdala to the ventral striato-pallidum. Amygdaloid projections to the nucleus accumbens, olfactory tubercle, and adjoining structures are studied by analyzing the retrograde transport in the amygdala from dextran amine and fluorogold injections in the ventral striatum, as well as the anterograde labeling found in the ventral striato-pallidum after dextran amine injections in the amygdala. This combination of anterograde and retrograde tracing experiments reveals direct projections from the vomeronasal cortex to the ventral striato-pallidum, as well as indirect projections through different nuclei of the basolateral amygdala. Direct projections innervate mainly the olfactory tubercle and the islands of Calleja, whereas indirect projections are more widespread and reach the same structures and the shell and core of nucleus accumbens. These pathways are likely to mediate innate responses to pheromones (direct projections) and conditioned responses to associated chemosensory and non-chemosensory stimuli (indirect projections). Comparative studies indicate that similar connections are present in all the studied amniote vertebrates and might constitute the basic circuitry for emotional responses to conspecifics in most vertebrates, including humans. PMID:22007159

Improvement in resource utilization after development of a clinical pathway for patients with pressure ulcers.

PubMed

Dzwierzynski, W W; Spitz, K; Hartz, A; Guse, C; Larson, D L

1998-11-01

Clinical pathways are interdisciplinary patient care plans intended to reduce variance and improve quality of care while lowering health care cost. This study was undertaken to determine whether the development of a clinical pathway for care of patients with pressure ulcers can indeed decrease health care costs while preserving quality of care. A clinical pathway for surgical reconstruction of pressure ulcers was developed by standardizing the current practices of our plastic surgeon group. The pathway provided direction in optimal scheduling of physician interventions along with nursing, physical and occupational therapies, and spinal cord rehabilitation interventions. It covered all potential elements of patient care, including laboratory, radiology, dietary services, intravenous fluids, and use of specialty beds. It defined patient outcomes and outlined discharge planning. Pathways were distributed throughout all services caring for patients with pressure ulcers. Patient charts and billing data were reviewed for the 16-month periods before and after initiation of the pathway. No other significant changes in treatment occurred during this time frame. Ninety-seven patient charts were examined (54 before pathway and 43 after pathway implementation). Parameters evaluated included length of stay and total charges (including bed use, medications, laboratory tests, and radiology). Patient readmission rate was also examined. A significant reduction in patient length of stay and total charges was achieved after implementation of the clinical pathway. Reduction was seen not only for patients treated with flaps by plastic surgery but also for patients with pressure ulcers who were not specifically targeted such as those from other services. The readmission rate decreased slightly, although not significantly, after the pathway inception. Total cost saving was almost $11,000 per patient (23 percent). In conclusion, implementation of a clinical pathway, because it standardizes care and reduces variations and duplication of care, can reduce health care cost without impairing quality of care in the treatment of decubitus ulcer patients.

Direct conversion of bio-ethanol to isobutene on nanosized Zn(x)Zr(y)O(z) mixed oxides with balanced acid-base sites.

PubMed

Sun, Junming; Zhu, Kake; Gao, Feng; Wang, Chongmin; Liu, Jun; Peden, Charles H F; Wang, Yong

2011-07-27

We report the design and synthesis of nanosized Zn(x)Zr(y)O(z) mixed oxides for direct and high-yield conversion of bio-ethanol to isobutene (~83%). ZnO is addded to ZrO(2) to selectively passivate zirconia's strong Lewis acidic sites and weaken Brönsted acidic sites, while simultaneously introducing basicity. As a result, the undesired reactions of bio-ethanol dehydration and acetone polymerization/coking are suppressed. Instead, a surface basic site-catalyzed ethanol dehydrogenation to acetaldehyde, acetaldehyde to acetone conversion via a complex pathway including aldol-condensation/dehydrogenation, and a Brönsted acidic site-catalyzed acetone-to-isobutene reaction pathway dominates on the nanosized Zn(x)Zr(y)O(z) mixed oxide catalyst, leading to a highly selective process for direct conversion of bio-ethanol to isobutene.

Mechanisms of ROS modulated cell survival during carcinogenesis.

PubMed

Clerkin, J S; Naughton, R; Quiney, C; Cotter, T G

2008-07-18

There is increasing evidence within the literature that the decreased susceptibility of tumour cells to stimuli that induce apoptosis can be linked to their inherently increased redox potential. The review primarily focuses on the PI3-kinase/Akt pathway, and the multiple points along this signalling pathway that may be redox regulated. The PI3-kinase/Akt pathway can influence a cells' sensitivity to death inducing signals, through direct manipulation of apoptosis regulating molecules or by regulating the activity of key transcription factors. Proteins involved in the control of apoptosis that are directly regulated by the PI3-kinase/Akt pathway include caspase-9, Bad and the transcription factor GSK-3beta. Lately, it is becoming increasingly obvious that phosphatases are a major counter balance to the PI3-kinase/Akt pathway. Phosphatases such as PP2A and PP1alpha can dephosphorylate signalling molecules within the PI3-kinase/Akt pathway, blocking their activity. It is the balance between the kinase activity and the phosphatase activity that determines the presence and strength of the PI3-kinase/Akt signal. This is why any protein modifications that hinder dephosphorylation can increase the tumours survival advantage. One such modification is the oxidation of the sulphydryl group in key cysteine residues present within the active site of the phosphatases. This highlights the link between the increased redox stress in tumours with the PI3-kinase/Akt pathway. This review will discuss the various sources of reactive oxygen species within a tumour and the effect of these radicals on the PI3-kinase/Akt pathway.

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

PubMed Central

Wang, Wenting; Li, Chenchen; Chen, Qian; Hawrot, James; Yao, Annie Y.; Gao, Xian; Lu, Congyi; Zang, Ying; Lyman, Katherine; Wang, Dongqing; Guo, Baolin; Wu, Shengxi; Gerfen, Charles R.; Fu, Zhanyan

2017-01-01

The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice. PMID:28414301

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.

PubMed

Muhar, Matthias; Ebert, Anja; Neumann, Tobias; Umkehrer, Christian; Jude, Julian; Wieshofer, Corinna; Rescheneder, Philipp; Lipp, Jesse J; Herzog, Veronika A; Reichholf, Brian; Cisneros, David A; Hoffmann, Thomas; Schlapansky, Moritz F; Bhat, Pooja; von Haeseler, Arndt; Köcher, Thomas; Obenauf, Anna C; Popow, Johannes; Ameres, Stefan L; Zuber, Johannes

2018-05-18

Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Polarised Clathrin-Mediated Endocytosis of EGFR During Chemotactic Invasion

PubMed Central

Mutch, Laura Jane; Howden, Jake Davey; Jenner, Emma Poppy Louise; Poulter, Natalie Sarah; Rappoport, Joshua Zachary

2014-01-01

Directed cell migration is critical for numerous physiological processes including development and wound healing. However chemotaxis is also exploited during cancer progression. Recent reports have suggested links between vesicle trafficking pathways and directed cell migration. Very little is known about the potential roles of endocytosis pathways during metastasis. Therefore we performed a series of studies employing a previously characterised model for chemotactic invasion of cancer cells to assess specific hypotheses potentially linking endocytosis to directed cell migration. Our results demonstrate that clathrin-mediated endocytosis is indispensable for epidermal growth factor (EGF) directed chemotactic invasion of MDA-MB-231 cells. Conversely, caveolar endocytosis is not required in this mode of migration. We further found that chemoattractant receptor (EGFR) trafficking occurs by clathrin-mediated endocytosis and is polarised towards the front of migrating cells. However, we found no role for clathrin-mediated endocytosis in focal adhesion disassembly in this migration model. Thus, this study has characterised the role of endocytosis during chemotactic invasion and has identified functions mechanistically linking clathrin-mediated endocytosis to directed cell motility. PMID:24921075

Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.

PubMed

Cavill, Rachel; Kamburov, Atanas; Ellis, James K; Athersuch, Toby J; Blagrove, Marcus S C; Herwig, Ralf; Ebbels, Timothy M D; Keun, Hector C

2011-03-01

Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.

Joint Attention without Gaze Following: Human Infants and Their Parents Coordinate Visual Attention to Objects through Eye-Hand Coordination

PubMed Central

Yu, Chen; Smith, Linda B.

2013-01-01

The coordination of visual attention among social partners is central to many components of human behavior and human development. Previous research has focused on one pathway to the coordination of looking behavior by social partners, gaze following. The extant evidence shows that even very young infants follow the direction of another's gaze but they do so only in highly constrained spatial contexts because gaze direction is not a spatially precise cue as to the visual target and not easily used in spatially complex social interactions. Our findings, derived from the moment-to-moment tracking of eye gaze of one-year-olds and their parents as they actively played with toys, provide evidence for an alternative pathway, through the coordination of hands and eyes in goal-directed action. In goal-directed actions, the hands and eyes of the actor are tightly coordinated both temporally and spatially, and thus, in contexts including manual engagement with objects, hand movements and eye movements provide redundant information about where the eyes are looking. Our findings show that one-year-olds rarely look to the parent's face and eyes in these contexts but rather infants and parents coordinate looking behavior without gaze following by attending to objects held by the self or the social partner. This pathway, through eye-hand coupling, leads to coordinated joint switches in visual attention and to an overall high rate of looking at the same object at the same time, and may be the dominant pathway through which physically active toddlers align their looking behavior with a social partner. PMID:24236151

The chemistry and anticarcinogenic mechanisms of glycoalkaloids produced by eggplants, potatoes, and tomatoes

USDA-ARS?s Scientific Manuscript database

Inhibition of cancer can occur via apoptosis, a genetically directed process of cell self-destruction that involves numerous biomarkers and signaling pathways. Glycoalkaloids are nitrogen-containing secondary plant metabolites found in numerous Solanaceous plants including eggplants, potatoes, and ...

Mean-field modeling of the basal ganglia-thalamocortical system. II Dynamics of parkinsonian oscillations.

PubMed

van Albada, S J; Gray, R T; Drysdale, P M; Robinson, P A

2009-04-21

Neuronal correlates of Parkinson's disease (PD) include a shift to lower frequencies in the electroencephalogram (EEG) and enhanced synchronized oscillations at 3-7 and 7-30 Hz in the basal ganglia, thalamus, and cortex. This study describes the dynamics of a recent physiologically based mean-field model of the basal ganglia-thalamocortical system, and shows how it accounts for many key electrophysiological correlates of PD. Its detailed functional connectivity comprises partially segregated direct and indirect pathways through two populations of striatal neurons, a hyperdirect pathway involving a corticosubthalamic projection, thalamostriatal feedback, and local inhibition in striatum and external pallidum (GPe). In a companion paper, realistic steady-state firing rates were obtained for the healthy state, and after dopamine loss modeled by weaker direct and stronger indirect pathways, reduced intrapallidal inhibition, lower firing thresholds of the GPe and subthalamic nucleus (STN), a stronger projection from striatum to GPe, and weaker cortical interactions. Here it is shown that oscillations around 5 and 20 Hz can arise with a strong indirect pathway, which also causes increased synchronization throughout the basal ganglia. Furthermore, increased theta power with progressive nigrostriatal degeneration is correlated with reduced alpha power and peak frequency, in agreement with empirical results. Unlike the hyperdirect pathway, the indirect pathway sustains oscillations with phase relationships that coincide with those found experimentally. Alterations in the responses of basal ganglia to transient stimuli accord with experimental observations. Reduced cortical gains due to both nigrostriatal and mesocortical dopamine loss lead to slower changes in cortical activity and may be related to bradykinesia. Finally, increased EEG power found in some studies may be partly explained by a lower effective GPe firing threshold, reduced GPe-GPe inhibition, and/or weaker intracortical connections in parkinsonian patients. Strict separation of the direct and indirect pathways is not necessary to obtain these results.

Heavy Alcohol Use in Early Adulthood as a Function of Childhood ADHD: Developmentally-Specific Mediation by Social Impairment and Delinquency

PubMed Central

Molina, Brooke S.G.; Walther, Christine A. P.; Cheong, JeeWon; Pedersen, Sarah; Gnagy, Elizabeth M.; Pelham, William E.

2014-01-01

Frequent heavy drinking in early adulthood, particularly prior to age 21, is associated with multiple health and legal consequences including continued problems with drinking later into adulthood. Children with Attention-Deficit/Hyperactivity Disorder (ADHD) are at risk of alcohol use disorder in adulthood, but little is known about their frequency of underage drinking as young adults or about mediational pathways that might contribute to this risky outcome. The current study used data from the Pittsburgh ADHD Longitudinal Study (PALS) to test social impairment and delinquency pathways from childhood ADHD to heavy drinking in early adulthood for individuals with (n=148) and without (n=117) childhood ADHD. Although ADHD did not predict heavy drinking, indirect mediating effects in opposing directions were found. A delinquency pathway from childhood ADHD to increased heavy drinking included adolescent and subsequently adult delinquent behavior. A social impairment pathway from childhood ADHD to decreased heavy drinking included adolescent, but not adult, social impairment. These findings help to explain the heterogeneity of results for alcohol use among individuals with ADHD and suggest that common ADHD-related impairments may operate differently from each other and distinctly across developmental periods. PMID:24611838

Signaling Pathways in Cardiac Myocyte Apoptosis

PubMed Central

Xia, Peng; Liu, Yuening

2016-01-01

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

The Role of Non-Targeted Effects as Mediators in the Biological Effects of Proton Irradiation

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Dicello, John F.

2006-01-01

In recent years, the hypothesis that non-DNA targets are primary initiators and mediators of the biological effects of ionizing radiation, such as proton beams and heavy ions, has gained much interest. These phenomena have been denoted as non-targeted or bystander effects to distinguish them from the more traditionally studied model that focuses on direct damage to DNA causing chromosomal rearrangements and mutations as causative of most biological endpoints such as cell killing, tissue damage, and cancer. We review cellular and extra-cellular structures and signal transduction pathways that have been implemented in these recent studies. Non-targeted effects of interest include oxidative damage to the cytoplasm and mitochondria, disruption of the extra-cellular matrix, and modification of cytokine signaling including TGF-beta, and gap junction communication. We present an introduction to these targets and pathways, and contrast there role with DNA damage pathways.

Projecting state-level air pollutant emissions using an integrated assessment model: GCAM-USA.

EPA Science Inventory

Integrated Assessment Models (IAMs) characterize the interactions among human and earth systems. IAMs typically have been applied to investigate future energy, land use, and emission pathways at global to continental scales. Recent directions in IAM development include enhanced t...

EG-1 interacts with c-Src and activates its signaling pathway.

PubMed

Lu, Ming; Zhang, Liping; Sartippour, Maryam R; Norris, Andrew J; Brooks, Mai N

2006-10-01

EG-1 is significantly elevated in breast, colorectal, and prostate cancers. Overexpression of EG-1 stimulates cellular proliferation, and targeted inhibition blocks mouse xenograft tumor growth. To further clarify the function of EG-1, we investigated its role in c-Src activation. We observed that EG-1 overexpression results in activation of c-Src, but found no evidence that EG-1 is a direct Src substrate. EG-1 also binds to other members of the Src family. Furthermore, EG-1 shows interaction with multiple other SH3- and WW-containing molecules involved in various signaling pathways. These observations suggest that EG-1 may be involved in signaling pathways including c-Src activation.

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

PubMed Central

Arima, Yasunobu; Ohki, Takuto; Nishikawa, Naoki; Higuchi, Kotaro; Ota, Mitsutoshi; Tanaka, Yuki; Nio-Kobayashi, Junko; Elfeky, Mohamed; Sakai, Ryota; Mori, Yuki; Kawamoto, Tadafumi; Stofkova, Andrea; Sakashita, Yukihiro; Morimoto, Yuji; Kuwatani, Masaki; Iwanaga, Toshihiko; Yoshioka, Yoshichika; Sakamoto, Naoya; Yoshimura, Akihiko; Takiguchi, Mitsuyoshi; Sakoda, Saburo; Prinz, Marco; Kamimura, Daisuke; Murakami, Masaaki

2017-01-01

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis. DOI: http://dx.doi.org/10.7554/eLife.25517.001 PMID:28809157

A Comparative study for striatal-direct and -indirect pathway neurons to DA depletion-induced lesion in a PD rat model.

PubMed

Zheng, Xuefeng; Wu, Jiajia; Zhu, Yaofeng; Chen, Si; Chen, Zhi; Chen, Tao; Huang, Ziyun; Wei, Jiayou; Li, Yanmei; Lei, Wanlong

2018-04-16

Striatal-direct and -indirect Pathway Neurons showed different vulnerability in basal ganglia disorders. Therefore, present study aimed to examine and compare characteristic changes of densities, protein and mRNA levels of soma, dendrites, and spines between striatal-direct and -indirect pathway neurons after DA depletion by using immunohistochemistry, Western blotting, real-time PCR and immunoelectron microscopy techniques. Experimental results showed that: 1) 6OHDA-induced DA depletion decreased the soma density of striatal-direct pathway neurons (SP+), but no significant changes for striatal-indirect pathway neurons (ENK+). 2) DA depletion resulted in a decline of dendrite density for both striatal-direct (D1+) and -indirect (D2+) pathway neurons, and D2+ dendritic density declined more obviously. At the ultrastructure level, the densities of D1+ and D2+ dendritic spines reduced in the 6OHDA groups compared with their control groups, but the density of D2+ dendritic spines reduced more significant than that of D1. 3) Striatal DA depletion down-regulated protein and mRNA expression levels of SP and D1, on the contrary, ENK and D2 protein and mRNA levels of indirect pathway neurons were up-regulated significantly. Present results suggested that indirect pathway neurons be more sensitive to 6OHDA-induced DA depletion. Copyright © 2018 Elsevier Ltd. All rights reserved.

Spectrally Resolved Fiber Photometry for Multi-component Analysis of Brain Circuits.

PubMed

Meng, Chengbo; Zhou, Jingheng; Papaneri, Amy; Peddada, Teja; Xu, Karen; Cui, Guohong

2018-04-25

To achieve simultaneous measurement of multiple cellular events in molecularly defined groups of neurons in vivo, we designed a spectrometer-based fiber photometry system that allows for spectral unmixing of multiple fluorescence signals recorded from deep brain structures in behaving animals. Using green and red Ca 2+ indicators differentially expressed in striatal direct- and indirect-pathway neurons, we were able to simultaneously monitor the neural activity in these two pathways in freely moving animals. We found that the activities were highly synchronized between the direct and indirect pathways within one hemisphere and were desynchronized between the two hemispheres. We further analyzed the relationship between the movement patterns and the magnitude of activation in direct- and indirect-pathway neurons and found that the striatal direct and indirect pathways coordinately control the dynamics and fate of movement. Published by Elsevier Inc.

Fight or Flight - Regulation of Emergency Hematopoiesis by Pyroptosis and Necroptosis

PubMed Central

Croker, Ben A.; Silke, John; Gerlic, Motti

2015-01-01

Purpose of review A feature of the innate immune response that is conserved across kingdoms is the induction of cell death. In this review, we discuss the direct and indirect effects of increased inflammatory cell death, including pyroptosis, a caspase-1-dependent cell death, and necroptosis, a RIPK3/MLKL-dependent, caspase-independent cell death, on emergency hematopoiesis. Recent findings Activation of non-apoptotic cell death pathways during infection can trigger release of cytokines and/or damage-associated molecular patterns (DAMPs) such as IL-1α, IL-1β, IL-18, IL-33, HMGB1 and mtDNA to promote emergency hematopoiesis. During systemic infection, pyroptosis and necroptosis can directly kill hematopoietic stem and progenitor cells, which results in impaired hematopoiesis, cytopenia and immunosuppression. Although originally described as discrete entities, there now appears to be more intimate connections between the non-apoptotic and death receptor signaling pathways. Summary The choice to undergo pyroptotic and necroptotic cell death constitutes a rapid response system serving to eliminate infected cells, including hematopoietic stem and progenitor cells. This system has the potential to be detrimental to emergency hematopoiesis during severe infection. We discuss the potential of pharmacological intervention for the pyroptosis and necroptosis pathways that may be beneficial during periods of infection and emergency hematopoiesis. PMID:26049749

Glycolytic strategy as a tradeoff between energy yield and protein cost

PubMed Central

Flamholz, Avi; Noor, Elad; Bar-Even, Arren; Liebermeister, Wolfram; Milo, Ron

2013-01-01

Contrary to the textbook portrayal of glycolysis as a single pathway conserved across all domains of life, not all sugar-consuming organisms use the canonical Embden–Meyerhoff–Parnass (EMP) glycolytic pathway. Prokaryotic glucose metabolism is particularly diverse, including several alternative glycolytic pathways, the most common of which is the Entner–Doudoroff (ED) pathway. The prevalence of the ED pathway is puzzling as it produces only one ATP per glucose—half as much as the EMP pathway. We argue that the diversity of prokaryotic glucose metabolism may reflect a tradeoff between a pathway’s energy (ATP) yield and the amount of enzymatic protein required to catalyze pathway flux. We introduce methods for analyzing pathways in terms of thermodynamics and kinetics and show that the ED pathway is expected to require several-fold less enzymatic protein to achieve the same glucose conversion rate as the EMP pathway. Through genomic analysis, we further show that prokaryotes use different glycolytic pathways depending on their energy supply. Specifically, energy-deprived anaerobes overwhelmingly rely upon the higher ATP yield of the EMP pathway, whereas the ED pathway is common among facultative anaerobes and even more common among aerobes. In addition to demonstrating how protein costs can explain the use of alternative metabolic strategies, this study illustrates a direct connection between an organism’s environment and the thermodynamic and biochemical properties of the metabolic pathways it employs. PMID:23630264

Referral pathways for patients with TIA avoiding hospital admission: a scoping review

PubMed Central

Evans, Bridie Angela; Ali, Khalid; Bulger, Jenna; Ford, Gary A; Jones, Matthew; Moore, Chris; Porter, Alison; Pryce, Alan David; Quinn, Tom; Seagrove, Anne C; Whitman, Shirley; Rees, Nigel

2017-01-01

Objective To identify the features and effects of a pathway for emergency assessment and referral of patients with suspected transient ischaemic attack (TIA) in order to avoid admission to hospital. Design Scoping review. Data sources PubMed, CINAHL Web of Science, Scopus. Study selection Reports of primary research on referral of patients with suspected TIA directly to specialist outpatient services. Data extraction We screened studies for eligibility and extracted data from relevant studies. Data were analysed to describe setting, assessment and referral processes, treatment, implementation and outcomes. Results 8 international studies were identified, mostly cohort designs. 4 pathways were used by family doctors and 3 pathways by emergency department physicians. No pathways used by paramedics were found. Referrals were made to specialist clinic either directly or via a 24-hour helpline. Practitioners identified TIA symptoms and risk of further events using a checklist including the ABCD2 tool or clinical assessment. Antiplatelet medication was often given, usually aspirin unless contraindicated. Some patients underwent tests before referral and discharge. 5 studies reported reduced incident of stroke at 90 days, from 6–10% predicted rate to 1.3–2.1% actual rate. Between 44% and 83% of suspected TIA cases in these studies were referred through the pathways. Conclusions Research literature has focused on assessment and referral by family doctors and ED physicians to reduce hospitalisation of patients with TIA. No pathways for paramedical use were reported. We will use results of this scoping review to inform development of a paramedical referral pathway to be tested in a feasibility trial. Trial registration number ISRCTN85516498. Stage: pre-results. PMID:28196949

Referral pathways for patients with TIA avoiding hospital admission: a scoping review.

PubMed

Evans, Bridie Angela; Ali, Khalid; Bulger, Jenna; Ford, Gary A; Jones, Matthew; Moore, Chris; Porter, Alison; Pryce, Alan David; Quinn, Tom; Seagrove, Anne C; Snooks, Helen; Whitman, Shirley; Rees, Nigel

2017-02-14

To identify the features and effects of a pathway for emergency assessment and referral of patients with suspected transient ischaemic attack (TIA) in order to avoid admission to hospital. Scoping review. PubMed, CINAHL Web of Science, Scopus. Reports of primary research on referral of patients with suspected TIA directly to specialist outpatient services. We screened studies for eligibility and extracted data from relevant studies. Data were analysed to describe setting, assessment and referral processes, treatment, implementation and outcomes. 8 international studies were identified, mostly cohort designs. 4 pathways were used by family doctors and 3 pathways by emergency department physicians. No pathways used by paramedics were found. Referrals were made to specialist clinic either directly or via a 24-hour helpline. Practitioners identified TIA symptoms and risk of further events using a checklist including the ABCD2 tool or clinical assessment. Antiplatelet medication was often given, usually aspirin unless contraindicated. Some patients underwent tests before referral and discharge. 5 studies reported reduced incident of stroke at 90 days, from 6-10% predicted rate to 1.3-2.1% actual rate. Between 44% and 83% of suspected TIA cases in these studies were referred through the pathways. Research literature has focused on assessment and referral by family doctors and ED physicians to reduce hospitalisation of patients with TIA. No pathways for paramedical use were reported. We will use results of this scoping review to inform development of a paramedical referral pathway to be tested in a feasibility trial. ISRCTN85516498. Stage: pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Ethylene resistance in flowering ornamental plants – improvements and future perspectives

PubMed Central

Olsen, Andreas; Lütken, Henrik; Hegelund, Josefine Nymark; Müller, Renate

2015-01-01

Various strategies of plant breeding have been attempted in order to improve the ethylene resistance of flowering ornamental plants. These approaches span from conventional techniques such as simple cross-pollination to new breeding techniques which modify the plants genetically such as precise genome-editing. The main strategies target the ethylene pathway directly; others focus on changing the ethylene pathway indirectly via pathways that are known to be antagonistic to the ethylene pathway, e.g. increasing cytokinin levels. Many of the known elements of the ethylene pathway have been addressed experimentally with the aim of modulating the overall response of the plant to ethylene. Elements of the ethylene pathway that appear particularly promising in this respect include ethylene receptors as ETR1, and transcription factors such as EIN3. Both direct and indirect approaches seem to be successful, nevertheless, although genetic transformation using recombinant DNA has the ability to save much time in the breeding process, they are not readily used by breeders yet. This is primarily due to legislative issues, economic issues, difficulties of implementing this technology in some ornamental plants, as well as how these techniques are publically perceived, particularly in Europe. Recently, newer and more precise genome-editing techniques have become available and they are already being implemented in some crops. New breeding techniques may help change the current situation and pave the way toward a legal and public acceptance if products of these technologies are indistinguishable from plants obtained by conventional techniques. PMID:26504580

Regulating ehrlich and demethiolation pathways for alcohols production by the expression of ubiquitin-protein ligase gene HUWE1.

PubMed

Zhang, Quan; Jia, Kai-Zhi; Xia, Shi-Tao; Xu, Yang-Hua; Liu, Rui-Sang; Li, Hong-Mei; Tang, Ya-Jie

2016-02-10

Ehrlich and demethiolation pathways as two competing branches converted amino acid into alcohols. Controlling both pathways offers considerable potential for industrial applications including alcohols overproduction, flavor-quality control and developing new flavors. While how to regulate ehrlich and demethiolation pathways is still not applicable. Taking the conversion of methionine into methionol and methanethiol for example, we constructed two suppression subtractive cDNA libraries of Clonostachys rosea by using suppression subtractive hybridization (SSH) technology for screening regulators controlling the conversion. E3 ubiquitin-protein ligase gene HUWE1 screened from forward SSH library was validated to be related with the biosynthesis of end products. Overexpressing HUWE1 in C. rosea and S. cerevisiae significantly increased the biosynthesis of methanethiol and its derivatives in demethiolation pathway, while suppressed the biosynthesis of methional and methionol in ehrlich pathway. These results attained the directional regulation of both pathways by overexpressing HUWE1. Thus, HUWE1 has potential to be a key target for controlling and enhancing alcohols production by metabolic engineering.

Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

PubMed Central

Blankfield, Adele

2013-01-01

The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms. Tryptophan and nicotinamide deficiencies fall within the protein energy malnutrition (PEM) spectrum. They can arise if the kynurenine pathway is stressed by primary or secondary inflammatory conditions and the consequent imbalance of available catabolic/anabolic substrates may adversely influence convalescent phase efficiency. The replacement of depleted or reduced NAD+ levels and other cofactors can perhaps improve the clinical management of these disorders. Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae. Aspects of some of the putative precipitating factors have been previously outlined.2,3 An analysis of the areas of metabolic dysfunction will focus on future directions for research and management. PMID:23922501

Strategic larval decision-making in a bivoltine butterfly.

PubMed

Friberg, Magne; Dahlerus, Josefin; Wiklund, Christer

2012-07-01

In temperate areas, insect larvae must decide between entering winter diapause or developing directly and reproducing in the same season. Long daylength and high temperature promote direct development, which is generally associated with a higher growth rate. In this work, we investigated whether the larval pathway decision precedes the adjustment of growth rate (state-independent), or whether the pathway decision is conditional on the individual's growth rate (state-dependent), in the butterfly Pieris napi. This species typically makes the pathway decision in the penultimate instar. We measured growth rate throughout larval development under two daylengths: slightly shorter and slightly longer than the critical daylength. Results indicate that the pathway decision can be both state-independent and state-dependent; under the shorter daylength condition, most larvae entered diapause, and direct development was chosen exclusively by a small subset of larvae showing the highest growth rates already in the early instars; under the longer daylength condition, most larvae developed directly, and the diapause pathway was chosen exclusively by a small subset of slow-growing individuals. Among the remainder, the choice of pathway was independent of the early growth rate; larvae entering diapause under the short daylength grew as fast as or faster than the direct developers under the longer daylength in the early instars, whereas the direct developers grew faster than the diapausers only in the ultimate instar. Hence, the pathway decision was state-dependent in a subset with a very high or very low growth rate, whereas the decision was state-independent in the majority of the larvae, which made the growth rate adjustment downstream from the pathway decision.

Pathway-Specific Striatal Substrates for Habitual Behavior.

PubMed

O'Hare, Justin K; Ade, Kristen K; Sukharnikova, Tatyana; Van Hooser, Stephen D; Palmeri, Mark L; Yin, Henry H; Calakos, Nicole

2016-02-03

The dorsolateral striatum (DLS) is implicated in habit formation. However, the DLS circuit mechanisms underlying habit remain unclear. A key role for DLS is to transform sensorimotor cortical input into firing of output neurons that project to the mutually antagonistic direct and indirect basal ganglia pathways. Here we examine whether habit alters this input-output function. By imaging cortically evoked firing in large populations of pathway-defined striatal projection neurons (SPNs), we identify features that strongly correlate with habitual behavior on a subject-by-subject basis. Habitual behavior correlated with strengthened DLS output to both pathways as well as a tendency for action-promoting direct pathway SPNs to fire before indirect pathway SPNs. In contrast, habit suppression correlated solely with a weakened direct pathway output. Surprisingly, all effects were broadly distributed in space. Together, these findings indicate that the striatum imposes broad, pathway-specific modulations of incoming activity to render learned motor behaviors habitual. Copyright © 2016 Elsevier Inc. All rights reserved.

A novel pathway of direct methane production and emission by eukaryotes including plants, animals and fungi: An overview

NASA Astrophysics Data System (ADS)

Liu, Jiangong; Chen, Huai; Zhu, Qiuan; Shen, Yan; Wang, Xue; Wang, Meng; Peng, Changhui

2015-08-01

Methane (CH4) is a powerful greenhouse gas with a global warming potential 28 times that of carbon dioxide (CO2). CH4 is responsible for approximately 20% of the Earth's warming since pre-industrial times. Knowledge of the sources of CH4 is crucial due to the recent substantial interannual variability of growth rates and uncertainties regarding individual sources. The prevailing paradigm is that methanogenesis carried out by methanogenic archaea occurs primarily under strictly anaerobic conditions. However, in the past decade, studies have confirmed direct CH4 release from three important kingdoms of eukaryotes-Plantae, Animalia and Fungi-even in the presence of oxygen. This novel CH4 production pathway has been aptly termed ;aerobic CH4 production; to distinguish it from the well-known anaerobic CH4 production pathway, which involves catalytic activity by methanogenic archaeal enzymes. In this review, we collated recent experimental evidence from the published literature and documented this novel pathway of direct CH4 production and emission by eukaryotes. The mechanisms involved in this pathway may be related to protective strategies of eukaryotes in response to changing environmental stresses, with CH4 a by-product or end-product during or at the end of the process(es) that originates from organic methyl-type compounds. Based on the existing, albeit uncertain estimates, plants seem to contribute less to the global CH4 budget (3-24%) compared to previous estimates (10-37%). We still lack estimates of CH4 emissions by animals and fungi. Overall, there is an urgent need to identify the precursors for this novel CH4 source and improve our understanding of the mechanisms of direct CH4 production and the impacts of environmental stresses. An estimate of this new CH4 source, which was not considered as a CH4 source by the Intergovernmental Panel on Climate Change (IPCC) (2013), could be useful for better quantitation of the global CH4 budget.

Striatal Mechanisms Underlying Movement, Reinforcement, and Punishment

PubMed Central

Kravitz, Alexxai V.; Kreitzer, Anatol C.

2013-01-01

Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion. PMID:22689792

Lewis Acid Induced Toggle from Ir(II) to Ir(IV) Pathways in Photocatalytic Reactions: Synthesis of Thiomorpholines and Thiazepanes from Aldehydes and SLAP Reagents

PubMed Central

2016-01-01

Redox neutral photocatalytic transformations often require careful pairing of the substrates and photoredox catalysts in order to achieve a catalytic cycle. This can limit the range of viable transformations, as we recently observed in attempting to extend the scope of the photocatalytic synthesis of N-heterocycles using silicon amine protocol (SLAP) reagents to include starting materials that require higher oxidation potentials. We now report that the inclusion of Lewis acids in photocatalytic reactions of organosilanes allows access to a distinct reaction pathway featuring an Ir(III)*/Ir(IV) couple instead of the previously employed Ir(III)*/Ir(II) pathway, enabling the transformation of aromatic and aliphatic aldehydes to thiomorpholines and thiazepanes. The role of the Lewis acid in accepting an electron—either directly or via coordination to an imine—can be extended to other classes of photocatalysts and transformations, including oxidative cyclizations. The combination of light induced reactions and Lewis acids therefore promises access to new pathways and transformations that are not viable using the photocatalysts alone. PMID:28149955

The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer.

PubMed

Henick, Brian S; Herbst, Roy S; Goldberg, Sarah B

2014-12-01

Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies. This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations. PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates.

Pathways to catastrophic health expenditure for acute coronary syndrome in Kerala: ‘Good health at low cost’?

PubMed Central

2012-01-01

Background Universal health coverage through the removal of financial and other barriers to access, particularly for people who are poor, is a global priority. This viewpoint describes the many pathways to catastrophic health expenditure (CHE) for patients with Acute Coronary Syndrome (ACS) based on two case studies and the thematic analysis of field notes regarding 210 patients and their households from a study based in Kerala, India. Discussion There is evidence of the severe financial impact of non-communicable diseases (NCDs), which is in contradiction to the widely acclaimed Kerala model: Good health at low cost. However, it is important to look beyond the out-of-pocket expenditure (OOPE) and CHE to the possible pathways and identify the triggers that make families vulnerable to CHE. The identified pathways include a primary and secondary loop. The primary pathway describes the direct path by which families experience CHE. These include: 1) factors related to the pre-event period that increase the likelihood of experiencing CHE, such as being from the lower socio-economic strata (SES), past financial losses or loans that leave families with no financial shock absorber at the time of illness; 2) factors related to the acute event, diagnosis, treatment and hospitalization and expenditures incurred for the same and; 3) factors related to the post-event period such as loss of gainful employment and means of financing both the acute period and the long-term management particularly through distress financing. The secondary pathway arises from the primary and includes: 1) the impact of distress financing and; 2) the long- and short- term consequences of CHE. These factors ultimately result in a vicious cycle of debt and poverty through non-compliance and repeat acute events. Summary This paper outlines the direct and indirect pathways by which patients with ACS and their families are trapped in a vicious cycle of debt and poverty. It also contradicts the prevailing impression that only low-income families are susceptible to CHE, distress financing and their aftermaths and underscores the need for a deeper understanding at the micro-level, if Kerala and India as a whole are to undertake the difficult exercise of achieving universal health coverage to successfully tackle its growing NCD burden. PMID:22537240

Free energy landscape and molecular pathways of gas hydrate nucleation.

PubMed

Bi, Yuanfei; Porras, Anna; Li, Tianshu

2016-12-07

Despite the significance of gas hydrates in diverse areas, a quantitative knowledge of hydrate formation at a molecular level is missing. The impediment to acquiring this understanding is primarily attributed to the stochastic nature and ultra-fine scales of nucleation events, posing a great challenge for both experiment and simulation to explore hydrate nucleation. Here we employ advanced molecular simulation methods, including forward flux sampling (FFS), p B histogram analysis, and backward flux sampling, to overcome the limit of direct molecular simulation for exploring both the free energy landscape and molecular pathways of hydrate nucleation. First we test the half-cage order parameter (H-COP) which we developed for driving FFS, through conducting the p B histogram analysis. Our results indeed show that H-COP describes well the reaction coordinates of hydrate nucleation. Through the verified order parameter, we then directly compute the free energy landscape for hydrate nucleation by combining both forward and backward flux sampling. The calculated stationary distribution density, which is obtained independently of nucleation theory, is found to fit well against the classical nucleation theory (CNT). Subsequent analysis of the obtained large ensemble of hydrate nucleation trajectories show that although on average, hydrate formation is facilitated by a two-step like mechanism involving a gradual transition from an amorphous to a crystalline structure, there also exist nucleation pathways where hydrate crystallizes directly, without going through the amorphous stage. The CNT-like free energy profile and the structural diversity suggest the existence of multiple active transition pathways for hydrate nucleation, and possibly also imply the near degeneracy in their free energy profiles among different pathways. Our results thus bring a new perspective to the long standing question of how hydrates crystallize.

Free energy landscape and molecular pathways of gas hydrate nucleation

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

Bi, Yuanfei; Porras, Anna; Li, Tianshu, E-mail: tsli@gwu.edu

Despite the significance of gas hydrates in diverse areas, a quantitative knowledge of hydrate formation at a molecular level is missing. The impediment to acquiring this understanding is primarily attributed to the stochastic nature and ultra-fine scales of nucleation events, posing a great challenge for both experiment and simulation to explore hydrate nucleation. Here we employ advanced molecular simulation methods, including forward flux sampling (FFS), p{sub B} histogram analysis, and backward flux sampling, to overcome the limit of direct molecular simulation for exploring both the free energy landscape and molecular pathways of hydrate nucleation. First we test the half-cage ordermore » parameter (H-COP) which we developed for driving FFS, through conducting the p{sub B} histogram analysis. Our results indeed show that H-COP describes well the reaction coordinates of hydrate nucleation. Through the verified order parameter, we then directly compute the free energy landscape for hydrate nucleation by combining both forward and backward flux sampling. The calculated stationary distribution density, which is obtained independently of nucleation theory, is found to fit well against the classical nucleation theory (CNT). Subsequent analysis of the obtained large ensemble of hydrate nucleation trajectories show that although on average, hydrate formation is facilitated by a two-step like mechanism involving a gradual transition from an amorphous to a crystalline structure, there also exist nucleation pathways where hydrate crystallizes directly, without going through the amorphous stage. The CNT-like free energy profile and the structural diversity suggest the existence of multiple active transition pathways for hydrate nucleation, and possibly also imply the near degeneracy in their free energy profiles among different pathways. Our results thus bring a new perspective to the long standing question of how hydrates crystallize.« less

Kainate Receptors Inhibit Glutamate Release Via Mobilization of Endocannabinoids in Striatal Direct Pathway Spiny Projection Neurons.

PubMed

Marshall, John J; Xu, Jian; Contractor, Anis

2018-04-18

Kainate receptors are members of the glutamate receptor family that function by both generating ionotropic currents through an integral ion channel pore and coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum, yet their roles in regulating striatal synapses are not known. Using mice of both sexes, we demonstrate that GluK2-containing kainate receptors expressed in direct pathway spiny projection neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum. This inhibition requires postsynaptic kainate-receptor-mediated mobilization of a retrograde endocannabinoid (eCB) signal and activation of presynaptic CB1 receptors. This pathway can be activated during repetitive 25 Hz trains of synaptic stimulation, causing short-term depression of corticostriatal synapses. This is the first study to demonstrate a role for kainate receptors in regulating eCB-mediated plasticity at the corticostriatal synapse and demonstrates an important role for these receptors in regulating basal ganglia circuits. SIGNIFICANCE STATEMENT The GRIK2 gene, encoding the GluK2 subunit of the kainate receptor, has been linked to several neuropsychiatric and neurodevelopmental disorders including obsessive compulsive disorder (OCD). Perseverative behaviors associated with OCD are known to result from pathophysiological changes in the striatum and kainate receptor knock-out mice have striatal-dependent phenotypes. However, the role of kainate receptors in striatal synapses is not known. We demonstrate that GluK2-containing kainate receptors regulate corticostriatal synapses by mobilizing endocannabinoids from direct pathway spiny projection neurons. Synaptic activation of GluK2 receptors during trains of synaptic input causes short-term synaptic depression, demonstrating a novel role for these receptors in regulating striatal circuits. Copyright © 2018 the authors 0270-6474/18/383901-10$15.00/0.

The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases

PubMed Central

Nisini, Roberto; Poerio, Noemi; Mariotti, Sabrina; De Santis, Federica; Fraziano, Maurizio

2018-01-01

Liposomes are closed bilayer structures spontaneously formed by hydrated phospholipids that are widely used as efficient delivery systems for drugs or antigens, due to their capability to encapsulate bioactive hydrophilic, amphipathic, and lipophilic molecules into inner water phase or within lipid leaflets. The efficacy of liposomes as drug or antigen carriers has been improved in the last years to ameliorate pharmacokinetics and capacity to release their cargo in selected target organs or cells. Moreover, different formulations and variations in liposome composition have been often proposed to include immunostimulatory molecules, ligands for specific receptors, or stimuli responsive compounds. Intriguingly, independent research has unveiled the capacity of several phospholipids to play critical roles as intracellular messengers in modulating both innate and adaptive immune responses through various mechanisms, including (i) activation of different antimicrobial enzymatic pathways, (ii) driving the fusion–fission events between endosomes with direct consequences to phagosome maturation and/or to antigen presentation pathway, and (iii) modulation of the inflammatory response. These features can be exploited by including selected bioactive phospholipids in the bilayer scaffold of liposomes. This would represent an important step forward since drug or antigen carrying liposomes could be engineered to simultaneously activate different signal transduction pathways and target specific cells or tissues to induce antigen-specific T and/or B cell response. This lipid-based host-directed strategy can provide a focused antimicrobial innate and adaptive immune response against specific pathogens and offer a novel prophylactic or therapeutic option against chronic, recurrent, or drug-resistant infections. PMID:29459867

A Pathway-based Approach to Predicting Interactions between Chemical and Non-chemical Stressors: Applications to Global Climate Change

EPA Science Inventory

A variety of environmental variables influenced by global climate change (GCC) can directly or indirectly affect the health of organisms. These variables may include temperature, salinity, pH, and penetration of ultraviolet radiation (UVR) in aquatic environments, and water shor...

Understanding Motivation for Study: Human Capital or Human Capability?

ERIC Educational Resources Information Center

Fredman, Nick

2014-01-01

Much research into the reasons students undertake tertiary study is at least implicitly based on rational choice theory: students calculate costs in order to maximize direct individual gain. The policy emphasis on pathways has somewhat broader bases including social inclusion as well as economic productivity, but narrowly focuses on institutional…

NEW APPLICATIONS OF LC-MS AND LC-MS2 TOWARD UNDERSTANDING THE ENVIRONMENTAL FATE OF ORGANOMETALLICS

EPA Science Inventory

Over the last 40 years, many organometallic compounds have been synthesized and used in a variety of consumer, agricultural, and industrial products. Including wastewater effluents, leaching, and direct land and water applications, there are many pathways that can disperse organo...

STAT3 selectively interacts with Smad3 to antagonize TGF-β signaling

PubMed Central

Wang, Gaohang; Yu, Yi; Sun, Chuang; Liu, Ting; Liang, Tingbo; Zhan, Lixing; Lin, Xia; Feng, Xin-Hua

2015-01-01

Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates TGF-β-induced responses through a direct Smad3-STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3-Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3-Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. PMID:26616859

Predicting transformation products from the direct photolysis of organic compounds in aquatic systems

EPA Science Inventory

Direct photolysis is an important degradation pathway for organic compounds bearing sunlight-absorbing chromophores in aquatic systems. An ever-growing body of process science underlying direct photolysis transformation pathways provides the basis for the development of predictiv...

A new neural framework for visuospatial processing.

PubMed

Kravitz, Dwight J; Saleem, Kadharbatcha S; Baker, Chris I; Mishkin, Mortimer

2011-04-01

The division of cortical visual processing into distinct dorsal and ventral streams is a key framework that has guided visual neuroscience. The characterization of the ventral stream as a 'What' pathway is relatively uncontroversial, but the nature of dorsal stream processing is less clear. Originally proposed as mediating spatial perception ('Where'), more recent accounts suggest it primarily serves non-conscious visually guided action ('How'). Here, we identify three pathways emerging from the dorsal stream that consist of projections to the prefrontal and premotor cortices, and a major projection to the medial temporal lobe that courses both directly and indirectly through the posterior cingulate and retrosplenial cortices. These three pathways support both conscious and non-conscious visuospatial processing, including spatial working memory, visually guided action and navigation, respectively.

VEGF-independent angiogenic pathways induced by PDGF-C

PubMed Central

Kumar, Anil; Zhang, Fan; Lee, Chunsik; Li, Yang; Tang, Zhongshu; Arjunan, Pachiappan

2010-01-01

VEGF is believed to be a master regulator in both developmental and pathological angiogenesis. The role of PDGF-C in angiogenesis, however, is only at the beginning of being revealed. We and others have shown that PDGF-C is a critical player in pathological angiogenesis because of its pleiotropic effects on multiple cellular targets. The angiogenic pathways induced by PDGF-C are, to a large extent, VEGF-independent. These pathways may include, but not limited to, the direct effect of PDGF-C on vascular cells, the effect of PDGF-C on tissue stroma fibroblasts, and its effect on macrophages. Taken together, the pleiotropic, versatile and VEGF-independent angiogenic nature of PDGF-C has placed it among the most important target genes for antiangiogenic therapy. PMID:20871734

Visualization of Oxytocin Release that Mediates Paired Pulse Facilitation in Hypothalamic Pathways to Brainstem Autonomic Neurons

PubMed Central

Piñol, Ramón A.; Jameson, Heather; Popratiloff, Anastas; Lee, Norman H.; Mendelowitz, David

2014-01-01

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection. PMID:25379676

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

PubMed Central

Jo, Dong-Gyu; Park, Daeui; Chung, Hae Young

2014-01-01

During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied. PMID:24958636

Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

NASA Technical Reports Server (NTRS)

Carra, Claudio; Wang, Minli; Huff, Janice L.; Hada, Megumi; ONeill, Peter; Cucinotta, Francis A.

2010-01-01

Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor.

PubMed

Sasai, Ken; Romer, Justyna T; Kimura, Hiromichi; Eberhart, Derek E; Rice, Dennis S; Curran, Tom

2007-04-15

The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.

The economic implications of a multimodal analgesic regimen for patients undergoing major orthopedic surgery: a comparative study of direct costs.

PubMed

Duncan, Christopher M; Hall Long, Kirsten; Warner, David O; Hebl, James R

2009-01-01

Total knee and total hip arthoplasty (THA) are 2 of the most common surgical procedures performed in the United States and represent the greatest single Medicare procedural expenditure. This study was designed to evaluate the economic impact of implementing a multimodal analgesic regimen (Total Joint Regional Anesthesia [TJRA] Clinical Pathway) on the estimated direct medical costs of patients undergoing lower extremity joint replacement surgery. An economic cost comparison was performed on Mayo Clinic patients (n = 100) undergoing traditional total knee or total hip arthroplasty using the TJRA Clinical Pathway. Study patients were matched 1:1 with historical controls undergoing similar procedures using traditional anesthetic (non-TJRA) techniques. Matching criteria included age, sex, surgeon, type of procedure, and American Society of Anesthesiologists (ASA) physical status (PS) classification. Hospital-based direct costs were collected for each patient and analyzed in standardized inflation-adjusted constant dollars using cost-to-charge ratios, wage indexes, and physician services valued using Medicare reimbursement rates. The estimated mean direct hospital costs were compared between groups, and a subgroup analysis was performed based on ASA PS classification. The estimated mean direct hospital costs were significantly reduced among TJRA patients when compared with controls (cost difference, 1999 dollars; 95% confidence interval, 584-3231 dollars; P = 0.0004). A significant reduction in hospital-based (Medicare Part A) costs accounted for the majority of the total cost savings. Use of a comprehensive, multimodal analgesic regimen (TJRA Clinical Pathway) in patients undergoing lower extremity joint replacement surgery provides a significant reduction in the estimated total direct medical costs. The reduction in mean cost is primarily associated with lower hospital-based (Medicare Part A) costs, with the greatest overall cost difference appearing among patients with significant comorbidities (ASA PS III-IV patients).

Direct inhibition of excision/synthesis DNA repair activities by cadmium: analysis on dedicated biochips.

PubMed

Candéias, S; Pons, B; Viau, M; Caillat, S; Sauvaigo, S

2010-12-10

The well established toxicity of cadmium and cadmium compounds results from their additive effects on several key cellular processes, including DNA repair. Mammalian cells have evolved several biochemical pathways to repair DNA lesions and maintain genomic integrity. By interfering with the homeostasis of redox metals and antioxidant systems, cadmium promotes the development of an intracellular environment that results in oxidative DNA damage which can be mutagenic if unrepaired. Small base lesions are recognised by specialized glycosylases and excised from the DNA molecule. The resulting abasic sites are incised, and the correct sequences restored by DNA polymerases using the opposite strands as template. Bulky lesions are recognised by a different set of proteins and excised from DNA as part of an oligonucleotide. As in base repair, the resulting gaps are filled by DNA polymerases using the opposite strands as template. Thus, these two repair pathways consist in excision of the lesion followed by DNA synthesis. In this study, we analysed in vitro the direct effects of cadmium exposure on the functionality of base and nucleotide DNA repair pathways. To this end, we used recently described dedicated microarrays that allow the parallel monitoring in cell extracts of the repair activities directed against several model base and/or nucleotide lesions. Both base and nucleotide excision/repair pathways are inhibited by CdCl₂, with different sensitivities. The inhibitory effects of cadmium affect mainly the recognition and excision stages of these processes. Furthermore, our data indicate that the repair activities directed against different damaged bases also exhibit distinct sensitivities, and the direct comparison of cadmium effects on the excision of uracile in different sequences even allows us to propose a hierarchy of cadmium sensibility within the glycosylases removing U from DNA. These results indicate that, in our experimental conditions, cadmium is a very potent DNA repair poison. Copyright © 2010 Elsevier B.V. All rights reserved.

Estimating human exposure to PFOS isomers and PFCA homologues: the relative importance of direct and indirect (precursor) exposure.

PubMed

Gebbink, Wouter A; Berger, Urs; Cousins, Ian T

2015-01-01

Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer-specific human pharmacokinetic processes of PFOS, its precursors and intermediates. Copyright © 2014. Published by Elsevier Ltd.

Targeting Notch signalling pathway of cancer stem cells.

PubMed

Venkatesh, Vandana; Nataraj, Raghu; Thangaraj, Gopenath S; Karthikeyan, Murugesan; Gnanasekaran, Ashok; Kaginelli, Shanmukhappa B; Kuppanna, Gobianand; Kallappa, Chandrashekrappa Gowdru; Basalingappa, Kanthesh M

2018-01-01

Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. CSCs have been increasingly identified in blood cancer, prostate, ovarian, lung, melanoma, pancreatic, colon, brain and many more malignancies. CSCs have slow growth rate and are resistant to chemotherapy and radiotherapy that lead to the failure of traditional current therapy. Eradicating the CSCs and recurrence, is promising aspect for the cure of cancer. The CSCs like any other stem cells activate the signal transduction pathways that involve the development and tissue homeostasis, which include Notch signaling pathway. The new treatment targets these pathway that control stem-cell replication, survival and differentiation that are under development. Notch inhibitors either single or in combination with chemotherapy drugs have been developed to treat cancer and its recurrence. This approach of targeting signaling pathway of CSCs represents a promising future direction for the therapeutic strategy to cure cancer.

Divergence of macrophage phagocytic and antimicrobial programs in leprosy.

PubMed

Montoya, Dennis; Cruz, Daniel; Teles, Rosane M B; Lee, Delphine J; Ochoa, Maria Teresa; Krutzik, Stephan R; Chun, Rene; Schenk, Mirjam; Zhang, Xiaoran; Ferguson, Benjamin G; Burdick, Anne E; Sarno, Euzenir N; Rea, Thomas H; Hewison, Martin; Adams, John S; Cheng, Genhong; Modlin, Robert L

2009-10-22

Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. We investigated the regulation of these key functions in human blood-derived macrophages. Interleukin-10 (IL-10) induced the phagocytic pathway, including the C-type lectin CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxidized low-density lipoprotein. IL-15 induced the vitamin D-dependent antimicrobial pathway and CD209, yet the cells were less phagocytic. The differential regulation of macrophage functional programs was confirmed by analysis of leprosy lesions: the macrophage phagocytosis pathway was prominent in the clinically progressive, multibacillary form of the disease, whereas the vitamin D-dependent antimicrobial pathway predominated in the self-limited form and in patients undergoing reversal reactions from the multibacillary to the self-limited form. These data indicate that macrophage programs for phagocytosis and antimicrobial responses are distinct and differentially regulated in innate immunity to bacterial infections.

Local Anesthetic-Induced Neurotoxicity

PubMed Central

Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

2016-01-01

This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

Local Anesthetic-Induced Neurotoxicity.

PubMed

Verlinde, Mark; Hollmann, Markus W; Stevens, Markus F; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

2016-03-04

This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor.

Pathobiology of tobacco smoking and neurovascular disorders: untied strings and alternative products.

PubMed

Naik, Pooja; Cucullo, Luca

2015-10-31

Tobacco smoke (TS) is the leading cause of preventable deaths worldwide. In addition to a host of well characterized diseases including chronic obstructive pulmonary disease, oral and peripheral cancers and cardiovascular complications, epidemiological evidence suggests that chronic smokers are at equal risk to develop neurological and neurovascular complications such as multiple sclerosis, Alzheimer's disease, stroke, vascular dementia and small vessel ischemic disease (SVID). Unfortunately, few direct neurotoxicology studies of tobacco smoking and its pathogenic pathways have been produced so far. A major link between TS and CNS disorders is the blood-brain barrier (BBB). In this review article, we summarize the current understanding of the toxicological impact of TS on BBB physiology and function and major compensatory mechanisms such as nrf2- ARE signaling and anti-inflammatory pathways activated by TS. In the same context, we discuss the controversial role of antioxidant supplementation as a prophylactic and/or therapeutic approach in delaying or decreasing the disease complications in smokers. Further, we cover a number of toxicological studies associated with "reduced exposure" cigarette products including electronic cigarettes. Finally, we provide insights on possible avenues for future research including mechanistic studies using direct inhalation rodent models.

Climate change and mental health: a causal pathways framework.

PubMed

Berry, Helen Louise; Bowen, Kathryn; Kjellstrom, Tord

2010-04-01

Climate change will bring more frequent, long lasting and severe adverse weather events and these changes will affect mental health. We propose an explanatory framework to enhance consideration of how these effects may operate and to encourage debate about this important aspect of the health impacts of climate change. Literature review. Climate change may affect mental health directly by exposing people to trauma. It may also affect mental health indirectly, by affecting (1) physical health (for example, extreme heat exposure causes heat exhaustion in vulnerable people, and associated mental health consequences) and (2) community wellbeing. Within community, wellbeing is a sub-process in which climate change erodes physical environments which, in turn, damage social environments. Vulnerable people and places, especially in low-income countries, will be particularly badly affected. Different aspects of climate change may affect mental health through direct and indirect pathways, leading to serious mental health problems, possibly including increased suicide mortality. We propose that it is helpful to integrate these pathways in an explanatory framework, which may assist in developing public health policy, practice and research.

Code System to Calculate Tornado-Induced Flow Material Transport.

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

ANDRAE, R. W.

1999-11-18

Version: 00 TORAC models tornado-induced flows, pressures, and material transport within structures. Its use is directed toward nuclear fuel cycle facilities and their primary release pathway, the ventilation system. However, it is applicable to other structures and can model other airflow pathways within a facility. In a nuclear facility, this network system could include process cells, canyons, laboratory offices, corridors, and offgas systems. TORAC predicts flow through a network system that also includes ventilation system components such as filters, dampers, ducts, and blowers. These ventilation system components are connected to the rooms and corridors of the facility to form amore » complete network for moving air through the structure and, perhaps, maintaining pressure levels in certain areas. The material transport capability in TORAC is very basic and includes convection, depletion, entrainment, and filtration of material.« less

Novel Hedgehog pathway targets against basal cell carcinoma

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

Tang, Jean Y.; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA; So, P.-L.

2007-11-01

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting thatmore » agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.« less

Temporal transcriptional response to ethylene gas drives growth hormone cross-regulation in Arabidopsis

DOE PAGES

Chang, Katherine Noelani; Zhong, Shan; Weirauch, Matthew T.; ...

2013-06-11

The gaseous plant hormone ethylene regulates a multitude of growth and developmental processes. How the numerous growth control pathways are coordinated by the ethylene transcriptional response remains elusive. We characterized the dynamic ethylene transcriptional response by identifying targets of the master regulator of the ethylene signaling pathway, ETHYLENE INSENSITIVE3 (EIN3), using chromatin immunoprecipitation sequencing and transcript sequencing during a timecourse of ethylene treatment. Ethylene-induced transcription occurs in temporal waves regulated by EIN3, suggesting distinct layers of transcriptional control. EIN3 binding was found to modulate a multitude of downstream transcriptional cascades, including a major feedback regulatory circuitry of the ethylene signalingmore » pathway, as well as integrating numerous connections between most of the hormone mediated growth response pathways. These findings provide direct evidence linking each of the major plant growth and development networks in novel ways.« less

Comparison of different two-pathway models for describing the combined effect of DO and nitrite on the nitrous oxide production by ammonia-oxidizing bacteria.

PubMed

Lang, Longqi; Pocquet, Mathieu; Ni, Bing-Jie; Yuan, Zhiguo; Spérandio, Mathieu

2017-02-01

The aim of this work is to compare the capability of two recently proposed two-pathway models for predicting nitrous oxide (N 2 O) production by ammonia-oxidizing bacteria (AOB) for varying ranges of dissolved oxygen (DO) and nitrite. The first model includes the electron carriers whereas the second model is based on direct coupling of electron donors and acceptors. Simulations are confronted to extensive sets of experiments (43 batches) from different studies with three different microbial systems. Despite their different mathematical structures, both models could well and similarly describe the combined effect of DO and nitrite on N 2 O production rate and emission factor. The model-predicted contributions for nitrifier denitrification pathway and hydroxylamine pathway also matched well with the available isotopic measurements. Based on sensitivity analysis, calibration procedures are described and discussed for facilitating the future use of those models.

Temporal transcriptional response to ethylene gas drives growth hormone cross-regulation in Arabidopsis

PubMed Central

Chang, Katherine Noelani; Zhong, Shan; Weirauch, Matthew T; Hon, Gary; Pelizzola, Mattia; Li, Hai; Huang, Shao-shan Carol; Schmitz, Robert J; Urich, Mark A; Kuo, Dwight; Nery, Joseph R; Qiao, Hong; Yang, Ally; Jamali, Abdullah; Chen, Huaming; Ideker, Trey; Ren, Bing; Bar-Joseph, Ziv; Hughes, Timothy R; Ecker, Joseph R

2013-01-01

The gaseous plant hormone ethylene regulates a multitude of growth and developmental processes. How the numerous growth control pathways are coordinated by the ethylene transcriptional response remains elusive. We characterized the dynamic ethylene transcriptional response by identifying targets of the master regulator of the ethylene signaling pathway, ETHYLENE INSENSITIVE3 (EIN3), using chromatin immunoprecipitation sequencing and transcript sequencing during a timecourse of ethylene treatment. Ethylene-induced transcription occurs in temporal waves regulated by EIN3, suggesting distinct layers of transcriptional control. EIN3 binding was found to modulate a multitude of downstream transcriptional cascades, including a major feedback regulatory circuitry of the ethylene signaling pathway, as well as integrating numerous connections between most of the hormone mediated growth response pathways. These findings provide direct evidence linking each of the major plant growth and development networks in novel ways. DOI: http://dx.doi.org/10.7554/eLife.00675.001 PMID:23795294

Comparative physiological and proteomic analyses reveal the actions of melatonin in the reduction of oxidative stress in Bermuda grass (Cynodon dactylon (L). Pers.).

PubMed

Shi, Haitao; Wang, Xin; Tan, Dun-Xian; Reiter, Russel J; Chan, Zhulong

2015-08-01

The fact of melatonin as an important antioxidant in animals led plant researchers to speculate that melatonin also acts in the similar manner in plants. Although melatonin has significant effects on alleviating stress-triggered reactive oxygen species (ROS), the involvement of melatonin in direct oxidative stress and the underlying physiological and molecular mechanisms remain unclear in plants. In this study, we found that exogenous melatonin significantly alleviated hydrogen peroxide (H2O2)-modulated plant growth, cell damage, and ROS accumulation in Bermuda grass. Additionally, 76 proteins significantly influenced by melatonin during mock or H2O2 treatment were identified by gel-free proteomics using iTRAQ (isobaric tags for relative and absolute quantitation). Metabolic pathway analysis showed that several pathways were markedly enhanced by melatonin and H2O2 treatments, including polyamine metabolism, ribosome pathway, major carbohydrate metabolism, photosynthesis, redox, and amino acid metabolism. Taken together, this study provides more comprehensive insights into the physiological and molecular mechanisms of melatonin in Bermuda grass responses to direct oxidative stress. This may relate to the activation of antioxidants, modulation of metabolic pathways, and extensive proteome reprograming. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bladder Cancer Recovery Pathways: A Systematic Review

PubMed Central

Maloney, Ian; Parker, Daniel C.; Cookson, Michael S.; Patel, Sanjay

2017-01-01

Background: Enhanced recovery pathways, also known as fast-track protocols, have been adopted since the early 2000s by various surgical specialties with the goal of improving patient outcomes and reducing the cost burden of major surgery on the health care system. Objective: To review the scientific literature on the origin of enhanced recovery pathways, track the contemporary utilization of such practices for patients undergoing radical cystectomy, and analyze the available data regarding their effect on morbidity, mortality, and treatment cost. Methods: A literature search of multiple electronic databases was undertaken. Manuscripts including patients undergoing radical cystectomy were chosen based on predefined criteria with an emphasis on randomized controlled trials and cohort studies. Strength of evidence for each study that met inclusion criteria was assessed based on the risk of bias, consistency, directness, and precision. Results: Database searches resulted in 1,236 potentially relevant articles. A total of 485 articles were selected for full-text dual review and 106 studies in 52 publications met the inclusion criteria. Conclusion: The utilization of enhanced recovery pathways with the goal of improving overall patient morbidity and mortality is well supported in the literature, however standardization of implementation and adherence across institutions is lacking, and their direct efficacy on reducing preventable treatment related expenditures is unconfirmed. PMID:29152551

Pathways to PTSD, Part II: Sexually Abused Children

PubMed Central

Kaplow, Julie B.; Dodge, Kenneth A.; Amaya-Jackson, Lisa; Saxe, Glenn N.

2009-01-01

Objective The goal of this research was to develop and test a prospective model of posttraumatic stress symptoms in sexually abused children that includes pretrauma, trauma, and disclosure-related pathways. Method At time 1, several measures were used to assess pretrauma variables, trauma variables, and stress reactions upon disclosure for 156 sexually abused children ages 8 to 13 years. At the time 2 follow-up (7 to 36 months following the initial interview), the children were assessed for posttraumatic stress disorder (PTSD) symptoms. Results A path analysis involving a series of hierarchically nested ordinary least squares multiple regression analyses indicated three direct paths to PTSD symptoms: avoidant coping, anxiety/arousal, and dissociation, all measured during or immediately after disclosure of sexual abuse. Additionally, age and gender predicted avoidant coping, while life stress and age at abuse onset predicted symptoms of anxiety/arousal. Taken together, these pathways accounted for approximately 57% of the variance in PTSD symptoms. Conclusions Symptoms measured at the time of disclosure constitute direct, independent pathways by which sexually abused children are likely to develop later PTSD symptoms. These findings speak to the importance of assessing children during the disclosure of abuse in order to identify those at greatest risk for later PTSD symptoms. PMID:15994713

Validation of theoretical pathway between discrimination, diabetes self-care and glycemic control.

PubMed

Dawson, Aprill Z; Walker, Rebekah J; Campbell, Jennifer A; Egede, Leonard E

2016-07-01

This study examined the mechanisms through which discrimination influences diabetes self-care and glycemic control in patients with diabetes by using structured equation modeling. 615 patients were recruited from two adult primary care clinics in the southeastern United States. Measures were based on a theoretical model and included perceived discrimination, social support, social cohesion, and perceived stress. Structured equation modeling examined the relationship with diabetes self-care and glycemic control. The final model (chi2(211)=328.82, p<0.0001, R(2)=0.99, RMSEA=0.03 and CFI=0.98) shows that higher stress is directly significantly related to a decreased self-care (r=-0.59, p <0.001) and increased HbA1c (r=0.27, p<0.05). There was no significant direct association between discrimination, social support or social cohesion, and glycemic control or self-care. There was, however, a direct significant association between increased discrimination (r=0.46, p<0.001), decreased social support (r=-0.34, p<0.001), increased social cohesion (r=0.14, p<0.05) and increased stress. These results support the hypothesized pathway of discrimination on health outcomes, showing both a direct and indirect influence through stress on HbA1c in adults with diabetes. Understanding the pathways through which discrimination influences diabetes outcomes is important for providing more comprehensive and effective care. These results suggest future interventions targeting patients with diabetes should take discrimination-induced stress into account. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessing co-regulation of directly linked genes in biological networks using microarray time series analysis.

PubMed

Del Sorbo, Maria Rosaria; Balzano, Walter; Donato, Michele; Draghici, Sorin

2013-11-01

Differential expression of genes detected with the analysis of high throughput genomic experiments is a commonly used intermediate step for the identification of signaling pathways involved in the response to different biological conditions. The impact analysis was the first approach for the analysis of signaling pathways involved in a certain biological process that was able to take into account not only the magnitude of the expression change of the genes but also the topology of signaling pathways including the type of each interactions between the genes. In the impact analysis, signaling pathways are represented as weighted directed graphs with genes as nodes and the interactions between genes as edges. Edges weights are represented by a β factor, the regulatory efficiency, which is assumed to be equal to 1 in inductive interactions between genes and equal to -1 in repressive interactions. This study presents a similarity analysis between gene expression time series aimed to find correspondences with the regulatory efficiency, i.e. the β factor as found in a widely used pathway database. Here, we focused on correlations among genes directly connected in signaling pathways, assuming that the expression variations of upstream genes impact immediately downstream genes in a short time interval and without significant influences by the interactions with other genes. Time series were processed using three different similarity metrics. The first metric is based on the bit string matching; the second one is a specific application of the Dynamic Time Warping to detect similarities even in presence of stretching and delays; the third one is a quantitative comparative analysis resulting by an evaluation of frequency domain representation of time series: the similarity metric is the correlation between dominant spectral components. These three approaches are tested on real data and pathways, and a comparison is performed using Information Retrieval benchmark tools, indicating the frequency approach as the best similarity metric among the three, for its ability to detect the correlation based on the correspondence of the most significant frequency components. Copyright © 2013. Published by Elsevier Ireland Ltd.

Bidirectional Plasticity in Striatonigral Synapses: A Switch to Balance Direct and Indirect Basal Ganglia Pathways

ERIC Educational Resources Information Center

Aceves, Jose J.; Rueda-Orozco, Pavel E.; Hernandez-Martinez, Ricardo; Galarraga, Elvira; Bargas, Jose

2011-01-01

There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral…

Dynamics Sampling in Transition Pathway Space.

PubMed

Zhou, Hongyu; Tao, Peng

2018-01-09

The minimum energy pathway contains important information describing the transition between two states on a potential energy surface (PES). Chain-of-states methods were developed to efficiently calculate minimum energy pathways connecting two stable states. In the chain-of-states framework, a series of structures are generated and optimized to represent the minimum energy pathway connecting two states. However, multiple pathways may exist connecting two existing states and should be identified to obtain a full view of the transitions. Therefore, we developed an enhanced sampling method, named as the direct pathway dynamics sampling (DPDS) method, to facilitate exploration of a PES for multiple pathways connecting two stable states as well as addition minima and their associated transition pathways. In the DPDS method, molecular dynamics simulations are carried out on the targeting PES within a chain-of-states framework to directly sample the transition pathway space. The simulations of DPDS could be regulated by two parameters controlling distance among states along the pathway and smoothness of the pathway. One advantage of the chain-of-states framework is that no specific reaction coordinates are necessary to generate the reaction pathway, because such information is implicitly represented by the structures along the pathway. The chain-of-states setup in a DPDS method greatly enhances the sufficient sampling in high-energy space between two end states, such as transition states. By removing the constraint on the end states of the pathway, DPDS will also sample pathways connecting minima on a PES in addition to the end points of the starting pathway. This feature makes DPDS an ideal method to directly explore transition pathway space. Three examples demonstrate the efficiency of DPDS methods in sampling the high-energy area important for reactions on the PES.

A competing, dual mechanism for catalytic direct benzene hydroxylation from combined experimental-DFT studies† †Electronic supplementary information (ESI) available: For experimental catalytic details and mechanistic procedures, including GC and GC-MS traces, additional figures (Fig. S1–S25), computational data including Cartesian coordinates and energies of all stationary points reported in the text. See DOI: 10.1039/c7sc02898a

PubMed Central

Vilella, Laia; Conde, Ana

2017-01-01

A dual mechanism for direct benzene catalytic hydroxylation is described. Experimental studies and DFT calculations have provided a mechanistic explanation for the acid-free, TpxCu-catalyzed hydroxylation of benzene with hydrogen peroxide (Tpx = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene ring following two different, competitive routes: (a) electrophilic aromatic substitution, with the copper-oxyl species acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu–O moiety prior to the C–O bond formation. Both pathways contribute to the global transformation albeit to different extents, the electrophilic substitution route seeming to be largely favoured. PMID:29619184

Child and adolescent risk factors that differentially predict violent versus nonviolent crime.

PubMed

Kalvin, Carla B; Bierman, Karen L

2017-11-01

While most research on the development of antisocial and criminal behavior has considered nonviolent and violent crime together, some evidence points to differential risk factors for these separate types of crime. The present study explored differential risk for nonviolent and violent crime by investigating the longitudinal associations between three key child risk factors (aggression, emotion dysregulation, and social isolation) and two key adolescent risk factors (parent detachment and deviant peer affiliation) predicting violent and nonviolent crime outcomes in early adulthood. Data on 754 participants (46% African American, 50% European American, 4% other; 58% male) oversampled for aggressive-disruptive behavior were collected across three time points. Parents and teachers rated aggression, emotion dysregulation, and social isolation in fifth grade (middle childhood, age 10-11); parents and youth rated parent detachment and deviant peer affiliation in seventh and eighth grade (early adolescence, age 12-14) and arrest data were collected when participants were 22-23 years old (early adulthood). Different pathways to violent and nonviolent crime emerged. The severity of child dysfunction in late childhood, including aggression, emotion dysregulation, and social isolation, was a powerful and direct predictor of violent crime. Although child dysfunction also predicted nonviolent crime, the direct pathway accounted for half as much variance as the direct pathway to violent crime. Significant indirect pathways through adolescent socialization experiences (peer deviancy) emerged for nonviolent crime, but not for violent crime, suggesting adolescent socialization plays a more distinctive role in predicting nonviolent than violent crime. The clinical implications of these findings are discussed. © 2017 Wiley Periodicals, Inc.

Striatal Direct and Indirect Pathway Output Structures are Differentially Altered in Mouse Models of Huntington's Disease.

PubMed

Barry, Joshua; Akopian, Garnik; Cepeda, Carlos; Levine, Michael S

2018-04-24

The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre-recombination, optogenetics, and whole-cell patch clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 days) and pre- (2 months) or symptomatic (10-12 months) YAC128 mice. Cell membrane capacitance was decreased whereas input resistance was increased in SNr neurons from R6/2, but not YAC128 mice. The amplitude of GABAergic responses evoked by optogenetic stimulation of direct pathway terminals was reduced in SNr neurons of symptomatic mice of both models. A decrease in spontaneous GABA synaptic activity, in particular large-amplitude events, in SNr neurons also was observed. Passive membrane properties of GPe neurons were not different between R6/2 or YAC128 mice and their control littermates. Similarly, the amplitude of GABA responses evoked by activation of indirect pathway MSN terminals and the frequency of spontaneous GABA synaptic activity were similar in HD and control animals. In contrast, the decay time of the evoked GABA response was significantly longer in cells from HD mice. Interestingly, activation of indirect pathway MSNs within the striatum evoked larger-amplitude responses in direct pathway MSNs. Together, these results demonstrate differential alterations in responses evoked by direct and indirect pathway terminals in SNr and GPe leading to striatal output imbalance and motor dysfunction. SIGNIFICANCE STATEMENT Previous work on Huntington's disease (HD) focused on striatal medium-sized spiny neurons (MSNs) almost exclusively. Little is known about the effects that alterations in the striatum have on output structures of the direct and indirect pathways, the substantia nigra pars reticulata (SNr) and the external segment of the globus pallidus (GPe), respectively. We combined electrophysiological and optogenetic methods to examine responses evoked by selective activation of terminals of direct and indirect pathway MSNs in SNr and GPe neurons in two mouse models of HD. We show a differential disruption of synaptic communication between the direct and indirect output pathways of the striatum with their target regions leading to an imbalance of striatal output, which will contribute to motor dysfunction. Copyright © 2018 the authors.

Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection.

PubMed

O'Hara, Samantha D; Garcea, Robert L

2016-11-01

Virus binding to the cell surface triggers an array of host responses, including activation of specific signaling pathways that facilitate steps in virus entry. Using mouse polyomavirus (MuPyV), we identified host signaling pathways activated upon virus binding to mouse embryonic fibroblasts (MEFs). Pathways activated by MuPyV included the phosphatidylinositol 3-kinase (PI3K), FAK/SRC, and mitogen-activated protein kinase (MAPK) pathways. Gangliosides and α4-integrin are required receptors for MuPyV infection. MuPyV binding to both gangliosides and the α4-integrin receptors was required for activation of the PI3K pathway; however, either receptor interaction alone was sufficient for activation of the MAPK pathway. Using small-molecule inhibitors, we confirmed that the PI3K and FAK/SRC pathways were required for MuPyV infection, while the MAPK pathway was dispensable. Mechanistically, the PI3K pathway was required for MuPyV endocytosis, while the FAK/SRC pathway enabled trafficking of MuPyV along microtubules. Thus, MuPyV interactions with specific cell surface receptors facilitate activation of signaling pathways required for virus entry and trafficking. Understanding how different viruses manipulate cell signaling pathways through interactions with host receptors could lead to the identification of new therapeutic targets for viral infection. Virus binding to cell surface receptors initiates outside-in signaling that leads to virus endocytosis and subsequent virus trafficking. How different viruses manipulate cell signaling through interactions with host receptors remains unclear, and elucidation of the specific receptors and signaling pathways required for virus infection may lead to new therapeutic targets. In this study, we determined that gangliosides and α4-integrin mediate mouse polyomavirus (MuPyV) activation of host signaling pathways. Of these pathways, the PI3K and FAK/SRC pathways were required for MuPyV infection. Both the PI3K and FAK/SRC pathways have been implicated in human diseases, such as heart disease and cancer, and inhibitors directed against these pathways are currently being investigated as therapies. It is possible that these pathways play a role in human PyV infections and could be targeted to inhibit PyV infection in immunosuppressed patients. Copyright © 2016 O’Hara and Garcea.

Cognitive mechanisms underlying third graders' arithmetic skills: Expanding the pathways to mathematics model.

PubMed

Träff, Ulf; Olsson, Linda; Skagerlund, Kenny; Östergren, Rickard

2018-03-01

A modified pathways to mathematics model was used to examine the cognitive mechanisms underlying arithmetic skills in third graders. A total of 269 children were assessed on tasks tapping the four pathways and arithmetic skills. A path analysis showed that symbolic number processing was directly supported by the linguistic and approximate quantitative pathways. The direct contribution from the four pathways to arithmetic proficiency varied; the linguistic pathway supported single-digit arithmetic and word problem solving, whereas the approximate quantitative pathway supported only multi-digit calculation. The spatial processing and verbal working memory pathways supported only arithmetic word problem solving. The notion of hierarchical levels of arithmetic was supported by the results, and the different levels were supported by different constellations of pathways. However, the strongest support to the hierarchical levels of arithmetic were provided by the proximal arithmetic skills. Copyright © 2017 Elsevier Inc. All rights reserved.

The Endoplasmic Reticulum and the Unfolded Protein Response

PubMed Central

Malhotra, Jyoti D.; Kaufman, Randal J.

2009-01-01

The endoplasmic reticulum (ER) is the site where proteins enter the secretory pathway. Proteins are translocated into the ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to attain their final appropriate conformation. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed towards a degradative pathway. In addition, those processes that prevent accumulation of unfolded proteins in the ER lumen are highly regulated by an intracellular signaling pathway known as the unfolded protein response (UPR). The UPR provides a mechanism by which cells can rapidly adapt to alterations in client protein-folding load in the ER lumen by expanding the capacity for protein folding. In addition, a variety of insults that disrupt protein folding in the ER lumen also activate the UPR. These include changes in intralumenal calcium, altered glycosylation, nutrient deprivation, pathogen infection, expression of folding-defective proteins, and changes in redox status. Persistent protein misfolding initiates apoptotic cascades that are now known to play fundamental roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis and neurodegenerative diseases. PMID:18023214

Metabolic engineering of Saccharomyces cerevisiae for production of fatty acid-derived hydrocarbons.

PubMed

Zhang, Yiming; Nielsen, Jens; Liu, Zihe

2018-06-05

Fatty acid-derived hydrocarbons attract increasing attention as biofuels due to their immiscibility with water, high-energy content, low freezing point, and high compatibility with existing refineries and end-user infrastructures. Yeast Saccharomyces cerevisiae has advantages for production of fatty acid-derived hydrocarbons as its native routes toward fatty acid synthesis involve only a few reactions that allow more efficient conversion of carbon substrates. Here we describe major biosynthetic pathways of fatty acid-derived hydrocarbons in yeast, and summarize key metabolic engineering strategies, including enhancing precursor supply, eliminating competing pathways, and expressing heterologous pathways. With recent advances in yeast production of fatty acid-derived hydrocarbons, our review identifies key research challenges and opportunities for future optimization, and concludes with perspectives and outlooks for further research directions. © 2018 Wiley Periodicals, Inc.

A new neural framework for visuospatial processing

PubMed Central

Kravitz, Dwight J.; Saleem, Kadharbatcha S.; Baker, Chris I.; Mishkin, Mortimer

2012-01-01

The division of cortical visual processing into distinct dorsal and ventral streams is a key framework that has guided visual neuroscience. The characterization of the ventral stream as a ‘What’ pathway is relatively uncontroversial, but the nature of dorsal stream processing is less clear. Originally proposed as mediating spatial perception (‘Where’), more recent accounts suggest it primarily serves non-conscious visually guided action (‘How’). Here, we identify three pathways emerging from the dorsal stream that consist of projections to the prefrontal and premotor cortices, and a major projection to the medial temporal lobe that courses both directly and indirectly through the posterior cingulate and retrosplenial cortices. These three pathways support both conscious and non-conscious visuospatial processing, including spatial working memory, visually guided action and navigation, respectively. PMID:21415848

Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling

PubMed Central

Clay, Hayley B.; Parl, Angelika K.; Mitchell, Sabrina L.; Singh, Larry; Bell, Lauren N.; Murdock, Deborah G.

2016-01-01

Despite the presence of a cytosolic fatty acid synthesis pathway, mitochondria have retained their own means of creating fatty acids via the mitochondrial fatty acid synthesis (mtFASII) pathway. The reason for its conservation has not yet been elucidated. Therefore, to better understand the role of mtFASII in the cell, we used thin layer chromatography to characterize the contribution of the mtFASII pathway to the fatty acid composition of selected mitochondrial lipids. Next, we performed metabolomic analysis on HeLa cells in which the mtFASII pathway was either hypofunctional (through knockdown of mitochondrial acyl carrier protein, ACP) or hyperfunctional (through overexpression of mitochondrial enoyl-CoA reductase, MECR). Our results indicate that the mtFASII pathway contributes little to the fatty acid composition of mitochondrial lipid species examined. Additionally, loss of mtFASII function results in changes in biochemical pathways suggesting alterations in glucose utilization and redox state. Interestingly, levels of bioactive lipids, including lysophospholipids and sphingolipids, directly correlate with mtFASII function, indicating that mtFASII may be involved in the regulation of bioactive lipid levels. Regulation of bioactive lipid levels by mtFASII implicates the pathway as a mediator of intracellular signaling. PMID:26963735

Redox and Nitric Oxide-Mediated Regulation of Sensory Neuron Ion Channel Function

PubMed Central

2015-01-01

Abstract Significance: Reactive oxygen and nitrogen species (ROS and RNS, respectively) can intimately control neuronal excitability and synaptic strength by regulating the function of many ion channels. In peripheral sensory neurons, such regulation contributes towards the control of somatosensory processing; therefore, understanding the mechanisms of such regulation is necessary for the development of new therapeutic strategies and for the treatment of sensory dysfunctions, such as chronic pain. Recent Advances: Tremendous progress in deciphering nitric oxide (NO) and ROS signaling in the nervous system has been made in recent decades. This includes the recognition of these molecules as important second messengers and the elucidation of their metabolic pathways and cellular targets. Mounting evidence suggests that these targets include many ion channels which can be directly or indirectly modulated by ROS and NO. However, the mechanisms specific to sensory neurons are still poorly understood. This review will therefore summarize recent findings that highlight the complex nature of the signaling pathways involved in redox/NO regulation of sensory neuron ion channels and excitability; references to redox mechanisms described in other neuron types will be made where necessary. Critical Issues: The complexity and interplay within the redox, NO, and other gasotransmitter modulation of protein function are still largely unresolved. Issues of specificity and intracellular localization of these signaling cascades will also be addressed. Future Directions: Since our understanding of ROS and RNS signaling in sensory neurons is limited, there is a multitude of future directions; one of the most important issues for further study is the establishment of the exact roles that these signaling pathways play in pain processing and the translation of this understanding into new therapeutics. Antioxid. Redox Signal. 22, 486–504. PMID:24735331

Viral Sequestration of Antigen Subverts Cross Presentation to CD8+ T Cells

PubMed Central

Tewalt, Eric F.; Grant, Jean M.; Granger, Erica L.; Palmer, Douglas C.; Heuss, Neal D.; Gregerson, Dale S.; Restifo, Nicholas P.; Norbury, Christopher C.

2009-01-01

Virus-specific CD8+ T cells (TCD8+) are initially triggered by peptide-MHC Class I complexes on the surface of professional antigen presenting cells (pAPC). Peptide-MHC complexes are produced by two spatially distinct pathways during virus infection. Endogenous antigens synthesized within virus-infected pAPC are presented via the direct-presentation pathway. Many viruses have developed strategies to subvert direct presentation. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from virus-infected cells to uninfected pAPC, is thought to compensate and allow the generation of effector TCD8+. Direct presentation of vaccinia virus (VACV) antigens driven by late promoters does not occur, as an abortive infection of pAPC prevents production of these late antigens. This lack of direct presentation results in a greatly diminished or ablated TCD8+ response to late antigens. We demonstrate that late poxvirus antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, since late antigen that is not cross-presented efficiently enters the MHC Class II presentation pathway. These data are the first to describe an evasion mechanism employed by pathogens to prevent entry into the cross-presentation pathway. In the absence of direct presentation, this evasion mechanism leads to a complete ablation of the TCD8+ response and a potential replicative advantage for the virus. Such mechanisms of viral modulation of antigen presentation must also be taken into account during the rational design of antiviral vaccines. PMID:19478869

A novel approach to select differential pathways associated with hypertrophic cardiomyopathy based on gene co‑expression analysis.

PubMed

Chen, Xiao-Min; Feng, Ming-Jun; Shen, Cai-Jie; He, Bin; Du, Xian-Feng; Yu, Yi-Bo; Liu, Jing; Chu, Hui-Min

2017-07-01

The present study was designed to develop a novel method for identifying significant pathways associated with human hypertrophic cardiomyopathy (HCM), based on gene co‑expression analysis. The microarray dataset associated with HCM (E‑GEOD‑36961) was obtained from the European Molecular Biology Laboratory‑European Bioinformatics Institute database. Informative pathways were selected based on the Reactome pathway database and screening treatments. An empirical Bayes method was utilized to construct co‑expression networks for informative pathways, and a weight value was assigned to each pathway. Differential pathways were extracted based on weight threshold, which was calculated using a random model. In order to assess whether the co‑expression method was feasible, it was compared with traditional pathway enrichment analysis of differentially expressed genes, which were identified using the significance analysis of microarrays package. A total of 1,074 informative pathways were screened out for subsequent investigations and their weight values were also obtained. According to the threshold of weight value of 0.01057, 447 differential pathways, including folding of actin by chaperonin containing T‑complex protein 1 (CCT)/T‑complex protein 1 ring complex (TRiC), purine ribonucleoside monophosphate biosynthesis and ubiquinol biosynthesis, were obtained. Compared with traditional pathway enrichment analysis, the number of pathways obtained from the co‑expression approach was increased. The results of the present study demonstrated that this method may be useful to predict marker pathways for HCM. The pathways of folding of actin by CCT/TRiC and purine ribonucleoside monophosphate biosynthesis may provide evidence of the underlying molecular mechanisms of HCM, and offer novel therapeutic directions for HCM.

Direct Observation of Parallel Folding Pathways Revealed Using a Symmetric Repeat Protein System

PubMed Central

Aksel, Tural; Barrick, Doug

2014-01-01

Although progress has been made to determine the native fold of a polypeptide from its primary structure, the diversity of pathways that connect the unfolded and folded states has not been adequately explored. Theoretical and computational studies predict that proteins fold through parallel pathways on funneled energy landscapes, although experimental detection of pathway diversity has been challenging. Here, we exploit the high translational symmetry and the direct length variation afforded by linear repeat proteins to directly detect folding through parallel pathways. By comparing folding rates of consensus ankyrin repeat proteins (CARPs), we find a clear increase in folding rates with increasing size and repeat number, although the size of the transition states (estimated from denaturant sensitivity) remains unchanged. The increase in folding rate with chain length, as opposed to a decrease expected from typical models for globular proteins, is a clear demonstration of parallel pathways. This conclusion is not dependent on extensive curve-fitting or structural perturbation of protein structure. By globally fitting a simple parallel-Ising pathway model, we have directly measured nucleation and propagation rates in protein folding, and have quantified the fluxes along each path, providing a detailed energy landscape for folding. This finding of parallel pathways differs from results from kinetic studies of repeat-proteins composed of sequence-variable repeats, where modest repeat-to-repeat energy variation coalesces folding into a single, dominant channel. Thus, for globular proteins, which have much higher variation in local structure and topology, parallel pathways are expected to be the exception rather than the rule. PMID:24988356

Autophagy dictates metabolism and differentiation of inflammatory immune cells

PubMed Central

Riffelmacher, Thomas; Richter, Felix Clemens; Simon, Anna Katharina

2018-01-01

ABSTRACT The role of macroautophagy/autophagy, a conserved lysosomal degradation pathway, during cellular differentiation has been well studied over the last decade. In particular, evidence for its role during immune cell differentiation is growing. Despite the description of a variety of dramatic immune phenotypes in tissue-specific autophagy knockout models, the underlying mechanisms are still under debate. One of the proposed mechanisms is the impact of autophagy on the altered metabolic states during immune cell differentiation. This concept is strengthened through novel molecular insights into how AMPK and MTOR signaling cascades affect both autophagy and metabolism. In this review, we discuss direct and indirect evidence linking autophagy, metabolic pathways and immune cell differentiation including T, B, and innate lymphocytes as well as in myeloid cells that are direct mediators of inflammation. Herein, we propose a model for autophagy-driven immunometabolism controlling immune cell differentiation. PMID:28806133

Formation pathways of mesoporous silica nanoparticles with dodecagonal tiling

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

Sun, Yao; Ma, Kai; Kao, Teresa

Considerable progress in the fabrication of quasicrystals demonstrates that they can be realized in a broad range of materials. However, the development of chemistries enabling direct experimental observation of early quasicrystal growth pathways remains challenging. Here, we report the synthesis of four surfactant-directed mesoporous silica nanoparticle structures, including dodecagonal quasicrystalline nanoparticles, as a function of micelle pore expander concentration or stirring rate. We demonstrate that the early formation stages of dodecagonal quasicrystalline mesoporous silica nanoparticles can be preserved, where precise control of mesoporous silica nanoparticle size down to <30 nm facilitates comparison between mesoporous silica nanoparticles and simulated single-particle growthmore » trajectories beginning with a single tiling unit. Our results reveal details of the building block size distributions during early growth and how they promote quasicrystal formation. This work identifies simple synthetic parameters, such as stirring rate, that may be exploited to design other quasicrystal-forming self-assembly chemistries and processes.« less

Formation pathways of mesoporous silica nanoparticles with dodecagonal tiling

DOE PAGES

Sun, Yao; Ma, Kai; Kao, Teresa; ...

2017-08-15

Considerable progress in the fabrication of quasicrystals demonstrates that they can be realized in a broad range of materials. However, the development of chemistries enabling direct experimental observation of early quasicrystal growth pathways remains challenging. Here, we report the synthesis of four surfactant-directed mesoporous silica nanoparticle structures, including dodecagonal quasicrystalline nanoparticles, as a function of micelle pore expander concentration or stirring rate. We demonstrate that the early formation stages of dodecagonal quasicrystalline mesoporous silica nanoparticles can be preserved, where precise control of mesoporous silica nanoparticle size down to <30 nm facilitates comparison between mesoporous silica nanoparticles and simulated single-particle growthmore » trajectories beginning with a single tiling unit. Our results reveal details of the building block size distributions during early growth and how they promote quasicrystal formation. This work identifies simple synthetic parameters, such as stirring rate, that may be exploited to design other quasicrystal-forming self-assembly chemistries and processes.« less

Extracellular Matrix Signaling from the Cellular Membrane Skeleton to the Nuclear Skeleton: A Model of Gene Regulation

PubMed Central

Lelièvre, Sophie; Weaver, Valerie M.; Bissell, Mina J.

2010-01-01

It is well established that cells must interact with their microenvironment and that such interaction is crucial for coordinated function and homeostasis. However, how cells receive and integrate external signals leading to gene regulation is far from understood. It is now appreciated that two classes of cooperative signals are implicated: a soluble class including hormones and growth factors and a class of insoluble signals emanating from the extracellular matrix (ECM) directly through contact with the cell surface. Using 3-dimensional culture systems and transgenic mice, we have been able to identify some of the elements of this ECM-signaling pathway responsible for gene regulation in rodent mammary gland differentiation and involution. Our major observations are 1) the requirement for a laminin-rich basement membrane; 2) the existence of a cooperative signaling pathway between basement membrane and the lactogenic hormone prolactin (PRL); 3) the importance of β1-integrins and bHLH transcription factor(s) and the presence of DNA response elements (exemplified by BCE-1, located on a milk protein gene, β-casein); and 4) the induction of mammary epithelial cell programmed cell death following degradation of basement membrane. We hypothesize that this cooperative signaling between ECM and PRL may be achieved through integrin- and laminin-directed restructuring of the cytoskeleton leading to profound changes in nuclear architecture and transcription factor localization. We postulate that the latter changes allow the prolactin signal to activate transcription of the β-casein gene. To further understand the molecular mechanisms underlying ECM and hormonal cooperative signaling, we are currently investigating ECM regulation of a “solid-state” signaling pathway including ECM fiber proteins, plasma membrane receptors, cytoskeleton, nuclear matrix and chromatin. We further postulate that disruption of such a pathway may be implicated in cell disorders including transformation and carcinogenesis. PMID:8701089

Identification of transcriptional factors and key genes in primary osteoporosis by DNA microarray.

PubMed

Xie, Wengui; Ji, Lixin; Zhao, Teng; Gao, Pengfei

2015-05-09

A number of genes have been identified to be related with primary osteoporosis while less is known about the comprehensive interactions between regulating genes and proteins. We aimed to identify the differentially expressed genes (DEGs) and regulatory effects of transcription factors (TFs) involved in primary osteoporosis. The gene expression profile GSE35958 was obtained from Gene Expression Omnibus database, including 5 primary osteoporosis and 4 normal bone tissues. The differentially expressed genes between primary osteoporosis and normal bone tissues were identified by the same package in R language. The TFs of these DEGs were predicted with the Essaghir A method. DAVID (The Database for Annotation, Visualization and Integrated Discovery) was applied to perform the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of DEGs. After analyzing regulatory effects, a regulatory network was built between TFs and the related DEGs. A total of 579 DEGs was screened, including 310 up-regulated genes and 269 down-regulated genes in primary osteoporosis samples. In GO terms, more up-regulated genes were enriched in transcription regulator activity, and secondly in transcription factor activity. A total 10 significant pathways were enriched in KEGG analysis, including colorectal cancer, Wnt signaling pathway, Focal adhesion, and MAPK signaling pathway. Moreover, total 7 TFs were enriched, of which CTNNB1, SP1, and TP53 regulated most up-regulated DEGs. The discovery of the enriched TFs might contribute to the understanding of the mechanism of primary osteoporosis. Further research on genes and TFs related to the WNT signaling pathway and MAPK pathway is urgent for clinical diagnosis and directing treatment of primary osteoporosis.

Metabolic Reconstruction for Metagenomic Data and Its Application to the Human Microbiome

PubMed Central

Abubucker, Sahar; Segata, Nicola; Goll, Johannes; Schubert, Alyxandria M.; Izard, Jacques; Cantarel, Brandi L.; Rodriguez-Mueller, Beltran; Zucker, Jeremy; Thiagarajan, Mathangi; Henrissat, Bernard; White, Owen; Kelley, Scott T.; Methé, Barbara; Schloss, Patrick D.; Gevers, Dirk; Mitreva, Makedonka; Huttenhower, Curtis

2012-01-01

Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities' metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as well as their relative abundances, directly from short sequence reads. We validated this methodology using a collection of synthetic metagenomes, recovering the presence and abundance both of large pathways and of small functional modules with high accuracy. We subsequently applied this method, HUMAnN, to the microbial communities of 649 metagenomes drawn from seven primary body sites on 102 individuals as part of the Human Microbiome Project (HMP). This provided a means to compare functional diversity and organismal ecology in the human microbiome, and we determined a core of 24 ubiquitously present modules. Core pathways were often implemented by different enzyme families within different body sites, and 168 functional modules and 196 metabolic pathways varied in metagenomic abundance specifically to one or more niches within the microbiome. These included glycosaminoglycan degradation in the gut, as well as phosphate and amino acid transport linked to host phenotype (vaginal pH) in the posterior fornix. An implementation of our methodology is available at http://huttenhower.sph.harvard.edu/humann. This provides a means to accurately and efficiently characterize microbial metabolic pathways and functional modules directly from high-throughput sequencing reads, enabling the determination of community roles in the HMP cohort and in future metagenomic studies. PMID:22719234

Impact of a critical pathway on postoperative length of stay and outcomes after infrainguinal bypass.

PubMed

Stanley, A C; Barry, M; Scott, T E; LaMorte, W W; Woodson, J; Menzoian, J O

1998-06-01

To determine the effect of a critical pathway on postoperative length of stay and outcomes after infrainguinal bypass. A critical pathway for care of patients after infrainguinal bypass was introduced in December 1995 to coordinate postoperative care at our institution. We compared care of 67 consecutively treated patients before institution of the pathway with care of 69 consecutively treated patients with the critical pathway in place. Data collection was done by means of chart review. Univariate analyses were used to identify differences between prepathway and postpathway patients and to identify factors influencing postoperative length of stay. Multivariate analysis was used to identify factors that influenced length of stay and to examine the effect of use of the pathway after adjusting for other factors. Patients on the pathway were similar to prepathway controls with respect to comorbid illnesses, vascular risk factors, indications for surgical treatment, type of conduit, and type of operation. Factors associated with longer postoperative stays included distal anastomoses to tibial rather than popliteal vessels (p = 0.02), preexisting cardiac disease (p = 0.005), postoperative complications (p = 0.0003), lower preoperative hematocrit (p = 0.01), and elevated preoperative creatinine level (p = 0.006). Overall, pathway patients had somewhat shorter postoperative lengths of stay (median value 7 days; range 2 to 29 days) than prepathway patients (median value 6 days; range 2 to 35; p = 0.01), and the two groups had similar frequencies of postoperative complications, readmission, and 6-month mortality. However, patients on the pathway were more likely to be discharged to an intermediate-care facility rather than directly home. After 12 patients with extraordinarily prolonged postoperative stays were excluded, multivariate analysis indicated that pathway patients had significantly shorter postoperative stays (p = 0.001). However, the difference was not significant if patients with extraordinarily long postoperative stays were included in the analysis (p = 0.28). Use of a critical pathway was associated with a modest decrease in postoperative length of stay for most patients. This was accomplished without an adverse effect on readmission, complication, or mortality rates. However, the decrease in stay may have been achieved primarily by discharging more patients to intermediate-care facilities. The pathway did not appear to have any effect when the subset of patients with extraordinarily long stays because of complex medical problems was included.

MicroRNA-directed siRNA biogenesis in Caenorhabditis elegans.

PubMed

Corrêa, Régis L; Steiner, Florian A; Berezikov, Eugene; Ketting, René F

2010-04-08

RNA interference (RNAi) is a post-transcriptional silencing process, triggered by double-stranded RNA (dsRNA), leading to the destabilization of homologous mRNAs. A distinction has been made between endogenous RNAi-related pathways and the exogenous RNAi pathway, the latter being essential for the experimental use of RNAi. Previous studies have shown that, in Caenorhabditis elegans, a complex containing the enzymes Dicer and the Argonaute RDE-1 process dsRNA. Dicer is responsible for cleaving dsRNA into short interfering RNAs (siRNAs) while RDE-1 acts as the siRNA acceptor. RDE-1 then guides a multi-protein complex to homologous targets to trigger mRNA destabilization. However, endogenous role(s) for RDE-1, if any, have remained unexplored. We here show that RDE-1 functions as a scavenger protein, taking up small RNA molecules from many different sources, including the microRNA (miRNA) pathway. This is in striking contrast to Argonaute proteins functioning directly in the miRNA pathway, ALG-1 and ALG-2: these proteins exclusively bind miRNAs. While playing no significant role in the biogenesis of the main pool of miRNAs, RDE-1 binds endogenous miRNAs and triggers RdRP activity on at least one perfectly matching, endogenous miRNA target. The resulting secondary siRNAs are taken up by a set of Argonaute proteins known to act as siRNA acceptors in exogenous RNAi, resulting in strong mRNA destabilization. Our results show that RDE-1 in an endogenous setting is actively screening the transcriptome using many different small RNAs, including miRNAs, as a guide, with implications for the evolution of transcripts with a potential to be recognized by Dicer.

MicroRNA–Directed siRNA Biogenesis in Caenorhabditis elegans

PubMed Central

Corrêa, Régis L.; Steiner, Florian A.; Berezikov, Eugene; Ketting, René F.

2010-01-01

RNA interference (RNAi) is a post-transcriptional silencing process, triggered by double-stranded RNA (dsRNA), leading to the destabilization of homologous mRNAs. A distinction has been made between endogenous RNAi–related pathways and the exogenous RNAi pathway, the latter being essential for the experimental use of RNAi. Previous studies have shown that, in Caenorhabditis elegans, a complex containing the enzymes Dicer and the Argonaute RDE-1 process dsRNA. Dicer is responsible for cleaving dsRNA into short interfering RNAs (siRNAs) while RDE-1 acts as the siRNA acceptor. RDE-1 then guides a multi-protein complex to homologous targets to trigger mRNA destabilization. However, endogenous role(s) for RDE-1, if any, have remained unexplored. We here show that RDE-1 functions as a scavenger protein, taking up small RNA molecules from many different sources, including the microRNA (miRNA) pathway. This is in striking contrast to Argonaute proteins functioning directly in the miRNA pathway, ALG-1 and ALG-2: these proteins exclusively bind miRNAs. While playing no significant role in the biogenesis of the main pool of miRNAs, RDE-1 binds endogenous miRNAs and triggers RdRP activity on at least one perfectly matching, endogenous miRNA target. The resulting secondary siRNAs are taken up by a set of Argonaute proteins known to act as siRNA acceptors in exogenous RNAi, resulting in strong mRNA destabilization. Our results show that RDE-1 in an endogenous setting is actively screening the transcriptome using many different small RNAs, including miRNAs, as a guide, with implications for the evolution of transcripts with a potential to be recognized by Dicer. PMID:20386745

Inhibition of IκB Kinase-Nuclear Factor-κB Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin*

PubMed Central

Kasinski, Andrea L.; Du, Yuhong; Thomas, Shala L.; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R.; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P.; Liotta, Dennis; Fu, Haian

2009-01-01

The nuclear factor-κB (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-κB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway through direct action on IκB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-κB, with an IC50 value of 1.3 μM compared with curcumin, with an IC50 value of 13 μM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-α-induced IκB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-α-induced NF-κB signaling by EF24 extends the therapeutic application of EF24 to other NF-κB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis. PMID:18577686

Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin.

PubMed

Kasinski, Andrea L; Du, Yuhong; Thomas, Shala L; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P; Liotta, Dennis; Fu, Haian

2008-09-01

The nuclear factor-kappaB (NF-kappaB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-kappaB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-kappaB signaling pathway through direct action on IkappaB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-kappaB, with an IC(50) value of 1.3 microM compared with curcumin, with an IC(50) value of 13 microM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced IkappaB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-alpha-induced NF-kappaB signaling by EF24 extends the therapeutic application of EF24 to other NF-kappaB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Modulation of neurotrophic signaling pathways by polyphenols

PubMed Central

Moosavi, Fatemeh; Hosseini, Razieh; Saso, Luciano; Firuzi, Omidreza

2016-01-01

Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk) receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Finally, the antioxidant activity of polyphenols reflected in the activation of Nrf2 pathway and the consequent upregulation of detoxification enzymes such as heme oxygenase-1 as well as the contribution of these effects to the neurotrophic activity have also been discussed. In conclusion, a better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases. PMID:26730179

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

Ma, Xiang; Zhang, Shuai; Jiao, Fang

Two-step nucleation pathways in which disordered, amorphous, or dense liquid states precede appearance of crystalline phases have been reported for a wide range of materials, but the dynamics of such pathways are poorly understood. Moreover, whether these pathways are general features of crystallizing systems or a consequence of system-specific structural details that select for direct vs two-step processes is unknown. Using atomic force microscopy to directly observe crystallization of sequence-defined polymers, we show that crystallization pathways are indeed sequence dependent. When a short hydrophobic region is added to a sequence that directly forms crystalline particles, crystallization instead follows a two-stepmore » pathway that begins with creation of disordered clusters of 10-20 molecules and is characterized by highly non-linear crystallization kinetics in which clusters transform into ordered structures that then enter the growth phase. The results shed new light on non-classical crystallization mechanisms and have implications for design of self-assembling polymer systems.« less

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action

PubMed Central

Carvalho Poyraz, Fernanda; Holzner, Eva; Bailey, Matthew R.; Meszaros, Jozsef; Kenney, Lindsay; Kheirbek, Mazen A.

2016-01-01

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal “no-go” pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization. SIGNIFICANCE STATEMENT Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease. PMID:27251620

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action.

PubMed

Carvalho Poyraz, Fernanda; Holzner, Eva; Bailey, Matthew R; Meszaros, Jozsef; Kenney, Lindsay; Kheirbek, Mazen A; Balsam, Peter D; Kellendonk, Christoph

2016-06-01

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization. Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease. Copyright © 2016 the authors 0270-6474/16/365989-14$15.00/0.

A multi-group path analysis of the relationship between perceived racial discrimination and self-rated stress: how does it vary across racial/ethnic groups?

PubMed

Yang, Tse-Chuan; Chen, Danhong

2018-04-01

The objective of this study was to answer three questions: (1) Is perceived discrimination adversely related to self-rated stress via the social capital and health care system distrust pathways? (2) Does the relationship between perceived discrimination and self-rated stress vary across race/ethnicity groups? and (3) Do the two pathways differ by one's race/ethnicity background? Using the Philadelphia Health Management Corporation's Southeastern Pennsylvania Household Survey, we classified 9831 respondents into 4 race/ethnicity groups: non-Hispanic White (n = 6621), non-Hispanic Black (n = 2359), Hispanic (n = 505), and non-Hispanic other races (n = 346). Structural equation modeling was employed to simultaneously estimate five sets of equations, including the confirmatory factor analysis for both social capital and health care distrust and both direct and indirect effects from perceived discrimination to self-rated stress. The key findings drawn from the analysis include the following: (1) in general, people who experienced racial discrimination have higher distrust and weaker social capital than those without perceived discrimination and both distrust and social capital are ultimately related to self-rated stress. (2) The direct relationship between perceived discrimination and self-rated stress is found for all race/ethnicity groups (except non-Hispanic other races) and it does not vary across groups. (3) The two pathways can be applied to non-Hispanic White and Black, but for Hispanic and non-Hispanic other races, we found little evidence for the social capital pathway. For non-Hispanic White, non-Hispanic Black, and Hispanic, perceived discrimination is negatively related to self-rated stress. This finding highlights the importance of reducing interpersonal discriminatory behavior even for non-Hispanic White. The health care system distrust pathway can be used to address the racial health disparity in stress as it holds true for all four race/ethnicity groups. On the other hand, the social capital pathway seems to better help non-Hispanic White and Black to mediate the adverse effect of perceived discrimination on stress.

Environmental estrogens inhibit mRNA and functional expression of growth hormone receptors as well as growth hormone signaling pathways in vitro in rainbow trout (Oncorhynchus mykiss).

PubMed

Hanson, Andrea M; Ickstadt, Alicia T; Marquart, Dillon J; Kittilson, Jeffrey D; Sheridan, Mark A

2017-05-15

Fish in aquatic habitats are exposed to increasing concentrations and types of environmental contaminants, including environmental estrogens (EE). While there is growing evidence to support the observation that endocrine-disrupting compounds (EDCs) possess growth-inhibiting effects, the mechanisms by which these physiological effects occur are poorly understood. In this study, we examined the direct effects of EE, specifically 17β-estradiol (E2), β-sitosterol (βS), and 4-n-nonylphenol (NP), on GH sensitivity as assessed by mRNA expression and functional expression of growth hormone receptor in hepatocytes, gill filaments, and muscle in rainbow trout (Oncorhynchus mykiss). Additionally, we examined the effects of EE on signaling cascades related to growth hormone signal transduction (i.e., JAK-STAT, MAPK, and PI3K-Akt). Environmental estrogens directly suppressed the expression of GHRs in a tissue- and compound-related manner. The potency and efficacy varied with EE; effects were most pronounced with E2 in liver. EE treatment deactivated the JAK-STAT, MAPK, and PI3K-Akt pathways in liver a time-, EE- and concentration-dependent manner. Generally, E2 and NP were most effective in deactivating pathway elements; maximum suppression for each pathway was rapid, typically occurring at 10-30min. The observed effects occurred via an estrogen-dependent pathway, as indicated by treatment with an ER antagonist, ICI 182,780. These findings suggest that EEs suppress growth by reducing GH sensitivity in terms of reduced GHR synthesis and reduced surface GHR expression and by repressing GH signaling pathways. Copyright © 2016. Published by Elsevier Inc.

Characterization of Cell Surface and EPS Remodeling of Azospirillum brasilense Chemotaxis-like 1 Signal Transduction Pathway mutants by Atomic Force Microscopy

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

Billings, Amanda N; Siuti, Piro; Bible, Amber

2011-01-01

To compete in complex microbial communities, bacteria must quickly sense environmental changes and adjust cellular functions for optimal growth. Chemotaxis-like signal transduction pathways are implicated in the modulation of multiple cellular responses, including motility, EPS production, and cell-to-cell interactions. Recently, the Che1 chemotaxis-like pathway from Azospirillum brasilense was shown to modulate flocculation. In A. brasilense, cell surface properties, including EPS production, are thought to play a direct role in promoting flocculation. Using atomic force microscopy (AFM), we have detected distinct changes in the surface morphology of flocculating A. brasilense Che1 mutant strains that are absent in the wild type strain.more » Whereas the wild type strain produces a smooth mucosal extracellular matrix, the flocculating Che1 mutant strains produce distinctive extracellular fibril structures. Further analyses using flocculation inhibition and lectin-binding assays suggest that the composition of EPS components in the extracellular matrix differs between the cheA1 and cheY1 mutants, despite an apparent similarity in the macroscopic floc structures. Collectively, these data indicate that mutations in the Che1 pathway that result in increased flocculation are correlated with distinctive changes in the extracellular matrix structure produced by the mutants, including likely changes in the EPS structure and/or composition.« less

Academic Genealogy and Direct Calorimetry: A Personal Account

ERIC Educational Resources Information Center

Jackson, Donald C.

2011-01-01

Each of us as a scientist has an academic legacy that consists of our mentors and their mentors continuing back for many generations. Here, I describe two genealogies of my own: one through my PhD advisor, H. T. (Ted) Hammel, and the other through my postdoctoral mentor, Knut Schmidt-Nielsen. Each of these pathways includes distingished scientists…

Natural Products with Antiplatelet Action.

PubMed

Hirsch, Gabriela Elisa; Viecili, Paulo Ricardo Nazario; de Almeida, Amanda Spring; Nascimento, Sabrina; Porto, Fernando Garcez; Otero, Juliana; Schmidt, Aline; da Silva, Brenda; Parisi, Mariana Migliorini; Klafke, Jonatas Zeni

2017-01-01

Complex hemostatic mechanisms are involved in the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activity is linked to the progression of atherosclerosis and mainly involves platelet aggregation and a decrease in blood flow in the vascular endothelium. The major platelet activation pathways mediated by agonists involve the arachidonic acid pathway, adenosine diphosphate pathway, serotonin pathway, nitric oxide pathway, and action of free radicals on molecules involved in platelet aggregation. These mechanisms have been widely studied and discussed because they are inhibited by the use of medicinal plants in complementary and alternative medicine, thus reducing platelet aggregation. Of the main plants discussed in this review, which have antiplatelet activity, some include saffron, garlic, green tea, St. John's wort, ginger, ginkgo biloba, ginseng, and guavirova. These herbal medicines have phytochemical components, which are directly related to the antiplatelet activity of the plant, such as flavonoids, curcumins, catechins, terpenoids, polyphenols, and saponins. While the majority of the medicinal plants mentioned here were native to the Asian continents, some are distributed worldwide, and found to a smaller extent throughout the American continent, European continent, Mediterranean, African continent, and the Middle East. This review showed that several plants and/or compounds exhibit anti-platelet activity, and are therefore potential research targets for developing drugs to treat diseases related to aggregation disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

N-(3-Oxo-acyl)-homoserine lactone induces apoptosis primarily through a mitochondrial pathway in fibroblasts.

PubMed

Neely, Aaron M; Zhao, Guoping; Schwarzer, Christian; Stivers, Nicole S; Whitt, Aaron G; Meng, Shuhan; Burlison, Joseph A; Machen, Terry E; Li, Chi

2018-01-01

N-(3-Oxododecanoyl)-l-homoserine lactone (C12) is produced by Pseudomonas aeruginosa to function as a quorum-sensing molecule for bacteria-bacteria communication. C12 is also known to influence many aspects of human host cell physiology, including induction of cell death. However, the signalling pathway(s) leading to C12-triggered cell death is (are) still not completely known. To clarify cell death signalling induced by C12, we examined mouse embryonic fibroblasts deficient in "initiator" caspases or "effector" caspases. Our data indicate that C12 selectively induces the mitochondria-dependent intrinsic apoptotic pathway by quickly triggering mitochondrial outer membrane permeabilisation. Importantly, the activities of C12 to permeabilise mitochondria are independent of activation of both "initiator" and "effector" caspases. Furthermore, C12 directly induces mitochondrial outer membrane permeabilisation in vitro. Overall, our study suggests a mitochondrial apoptotic signalling pathway triggered by C12, in which C12 or its metabolite(s) acts on mitochondria to permeabilise mitochondria, leading to activation of apoptosis. © 2017 John Wiley & Sons Ltd.

Connectome imaging for mapping human brain pathways

PubMed Central

Shi, Y; Toga, A W

2017-01-01

With the fast advance of connectome imaging techniques, we have the opportunity of mapping the human brain pathways in vivo at unprecedented resolution. In this article we review the current developments of diffusion magnetic resonance imaging (MRI) for the reconstruction of anatomical pathways in connectome studies. We first introduce the background of diffusion MRI with an emphasis on the technical advances and challenges in state-of-the-art multi-shell acquisition schemes used in the Human Connectome Project. Characterization of the microstructural environment in the human brain is discussed from the tensor model to the general fiber orientation distribution (FOD) models that can resolve crossing fibers in each voxel of the image. Using FOD-based tractography, we describe novel methods for fiber bundle reconstruction and graph-based connectivity analysis. Building upon these novel developments, there have already been successful applications of connectome imaging techniques in reconstructing challenging brain pathways. Examples including retinofugal and brainstem pathways will be reviewed. Finally, we discuss future directions in connectome imaging and its interaction with other aspects of brain imaging research. PMID:28461700

RBP-Jκ-Dependent Notch Signaling Is Dispensable for Mouse Early Embryonic Development

PubMed Central

Souilhol, Céline; Cormier, Sarah; Tanigaki, Kenji; Babinet, Charles; Cohen-Tannoudji, Michel

2006-01-01

The Notch signaling pathway is an evolutionarily conserved signaling system which has been shown to be essential in cell fate specification and in numerous aspects of embryonic development in all metazoans thus far studied. We recently demonstrated that several components of the Notch signaling pathway, including the four Notch receptors and their five ligands known in mammals, are expressed in mouse oocytes, in mouse preimplantation embryos, or both. This suggested a possible implication of the Notch pathway in the first cell fate specification of the dividing mouse embryo, which results in the formation of the blastocyst. To address this issue directly, we generated zygotes in which both the maternal and the zygotic expression of Rbpsuh, a key element of the core Notch signaling pathway, were abrogated. We find that such zygotes give rise to blastocysts which implant and develop normally. Nevertheless, after gastrulation, these embryos die around midgestation, similarly to Rbpsuh-null mutants. This demonstrates that the RBP-Jκ-dependent pathway, otherwise called the canonical Notch pathway, is dispensable for blastocyst morphogenesis and the establishment of the three germ layers, ectoderm, endoderm, and mesoderm. These results are discussed in the light of recent observations which have challenged this conclusion. PMID:16782866

RBP-Jkappa-dependent notch signaling is dispensable for mouse early embryonic development.

PubMed

Souilhol, Céline; Cormier, Sarah; Tanigaki, Kenji; Babinet, Charles; Cohen-Tannoudji, Michel

2006-07-01

The Notch signaling pathway is an evolutionarily conserved signaling system which has been shown to be essential in cell fate specification and in numerous aspects of embryonic development in all metazoans thus far studied. We recently demonstrated that several components of the Notch signaling pathway, including the four Notch receptors and their five ligands known in mammals, are expressed in mouse oocytes, in mouse preimplantation embryos, or both. This suggested a possible implication of the Notch pathway in the first cell fate specification of the dividing mouse embryo, which results in the formation of the blastocyst. To address this issue directly, we generated zygotes in which both the maternal and the zygotic expression of Rbpsuh, a key element of the core Notch signaling pathway, were abrogated. We find that such zygotes give rise to blastocysts which implant and develop normally. Nevertheless, after gastrulation, these embryos die around midgestation, similarly to Rbpsuh-null mutants. This demonstrates that the RBP-Jkappa-dependent pathway, otherwise called the canonical Notch pathway, is dispensable for blastocyst morphogenesis and the establishment of the three germ layers, ectoderm, endoderm, and mesoderm. These results are discussed in the light of recent observations which have challenged this conclusion.

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

PubMed

Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

2015-01-02

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease.

PubMed

Holleran, Grainne; Lopetuso, Loris; Petito, Valentina; Graziani, Cristina; Ianiro, Gianluca; McNamara, Deirdre; Gasbarrini, Antonio; Scaldaferri, Franco

2017-09-21

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date.

Cellular Mechanosensing: Getting to the nucleus of it all

PubMed Central

Fedorchak, Gregory R.; Kaminski, Ashley; Lammerding, Jan

2014-01-01

Cells respond to mechanical forces by activating specific genes and signaling pathways that allow the cells to adapt to their physical environment. Examples include muscle growth in response to exercise, bone remodeling based on their mechanical load, or endothelial cells aligning under fluid shear stress. While the involved downstream signaling pathways and mechanoresponsive genes are generally well characterized, many of the molecular mechanisms of the initiating ‘mechanosensing’ remain still elusive. In this review, we discuss recent findings and accumulating evidence suggesting that the cell nucleus plays a crucial role in cellular mechanotransduction, including processing incoming mechanoresponsive signals and even directly responding to mechanical forces. Consequently, mutations in the involved proteins or changes in nuclear envelope composition can directly impact mechanotransduction signaling and contribute to the development and progression of a variety of human diseases, including muscular dystrophy, cancer, and the focus of this review, dilated cardiomyopathy. Improved insights into the molecular mechanisms underlying nuclear mechanotransduction, brought in part by the emergence of new technologies to study intracellular mechanics at high spatial and temporal resolution, will not only result in a better understanding of cellular mechanosensing in normal cells but may also lead to the development of novel therapies in the many diseases linked to defects in nuclear envelope proteins. PMID:25008017

The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease

PubMed Central

Holleran, Grainne; Lopetuso, Loris; Petito, Valentina; Graziani, Cristina; Ianiro, Gianluca; McNamara, Deirdre; Gasbarrini, Antonio; Scaldaferri, Franco

2017-01-01

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date. PMID:28934123

A network model shows the importance of coupled processes in the microbial N cycle in the Cape Fear River Estuary

NASA Astrophysics Data System (ADS)

Hines, David E.; Lisa, Jessica A.; Song, Bongkeun; Tobias, Craig R.; Borrett, Stuart R.

2012-06-01

Estuaries serve important ecological and economic functions including habitat provision and the removal of nutrients. Eutrophication can overwhelm the nutrient removal capacity of estuaries and poses a widely recognized threat to the health and function of these ecosystems. Denitrification and anaerobic ammonium oxidation (anammox) are microbial processes responsible for the removal of fixed nitrogen and diminish the effects of eutrophication. Both of these microbial removal processes can be influenced by direct inputs of dissolved inorganic nitrogen substrates or supported by microbial interactions with other nitrogen transforming pathways such as nitrification and dissimilatory nitrate reduction to ammonium (DNRA). The coupling of nitrogen removal pathways to other transformation pathways facilitates the removal of some forms of inorganic nitrogen; however, differentiating between direct and coupled nitrogen removal is difficult. Network modeling provides a tool to examine interactions among microbial nitrogen cycling processes and to determine the within-system history of nitrogen involved in denitrification and anammox. To examine the coupling of nitrogen cycling processes, we built a nitrogen budget mass balance network model in two adjacent 1 cm3 sections of bottom water and sediment in the oligohaline portion of the Cape Fear River Estuary, NC, USA. Pathway, flow, and environ ecological network analyses were conducted to characterize the organization of nitrogen flow in the estuary and to estimate the coupling of nitrification to denitrification and of nitrification and DNRA to anammox. Centrality analysis indicated NH4+ is the most important form of nitrogen involved in removal processes. The model analysis further suggested that direct denitrification and coupled nitrification-denitrification had similar contributions to nitrogen removal while direct anammox was dominant to coupled forms of anammox. Finally, results also indicated that partial nitrification-anammox may play an important role in anammox nitrogen removal in the Cape Fear River Estuary.

Pathways Between Discrimination and Quality of Life in Patients with Type 2 Diabetes

PubMed Central

Achuko, Obinna; Walker, Rebekah J.; Campbell, Jennifer A.; Dawson, Aprill Z.

2016-01-01

Abstract Background: Discrimination is a social determinant that has been linked to poor physical and mental health outcomes. This study aimed to examine the pathway whereby discrimination influences quality of life in patients with type 2 diabetes. Subjects and Methods: Six hundred fifteen patients were recruited from two adult primary care clinics in the southeastern United States. Measures included perceived discrimination, perceived stress, social support, and social cohesion and were based on a theoretical model for the pathways by which perceived discrimination influences mental and physical health. Quality of life was measured using the SF-12 questionnaire. Results: The final model [χ2(106) = 157.35, P = 0.009, R2 = 0.99, root mean square error of approximation = 0.03, comparative fit index = 0.99] indicates direct effects of higher perceived stress (r = −1.02, P < 0.05) and lower social support (r = 0.36, P < 0.001) significantly related to decreased mental health component score (MCS) of quality of life. Discrimination and social cohesion were not significantly directly related to MCS. However, higher discrimination (r = 0.47, P < 0.001), higher social cohesion (r = 0.14, P < 0.05), and lower social support (r = −0.43, P < 0.001) were significantly directly related to increased stress. No significant paths were found for the physical component score of quality of life. Conclusions: Perceived discrimination was significantly associated with stress and served as a pathway to influence the mental health component of quality of life (MCS). Social support had a direct and an indirect effect on MCS through a negative association with stress. These results suggest that future interventions should be developed to decrease stress and increase social support surrounding discrimination to improve the MCS of quality of life in patients with diabetes. PMID:26866351

Pathways Between Discrimination and Quality of Life in Patients with Type 2 Diabetes.

PubMed

Achuko, Obinna; Walker, Rebekah J; Campbell, Jennifer A; Dawson, Aprill Z; Egede, Leonard E

2016-03-01

Discrimination is a social determinant that has been linked to poor physical and mental health outcomes. This study aimed to examine the pathway whereby discrimination influences quality of life in patients with type 2 diabetes. Six hundred fifteen patients were recruited from two adult primary care clinics in the southeastern United States. Measures included perceived discrimination, perceived stress, social support, and social cohesion and were based on a theoretical model for the pathways by which perceived discrimination influences mental and physical health. Quality of life was measured using the SF-12 questionnaire. The final model [χ(2)(106) = 157.35, P = 0.009, R(2) = 0.99, root mean square error of approximation = 0.03, comparative fit index = 0.99] indicates direct effects of higher perceived stress (r = -1.02, P < 0.05) and lower social support (r = 0.36, P < 0.001) significantly related to decreased mental health component score (MCS) of quality of life. Discrimination and social cohesion were not significantly directly related to MCS. However, higher discrimination (r = 0.47, P < 0.001), higher social cohesion (r = 0.14, P < 0.05), and lower social support (r = -0.43, P < 0.001) were significantly directly related to increased stress. No significant paths were found for the physical component score of quality of life. Perceived discrimination was significantly associated with stress and served as a pathway to influence the mental health component of quality of life (MCS). Social support had a direct and an indirect effect on MCS through a negative association with stress. These results suggest that future interventions should be developed to decrease stress and increase social support surrounding discrimination to improve the MCS of quality of life in patients with diabetes.

Triazole induced concentration-related gene signatures in rat whole embryo culture.

PubMed

Robinson, Joshua F; Tonk, Elisa C M; Verhoef, Aart; Piersma, Aldert H

2012-09-01

Commonly used as antifungal agents in agriculture and medicine, triazoles have been shown to cause teratogenicity in a diverse set of animal models. Here, we evaluated the dose-dependent impacts of flusilazole, cyproconazole and triadimefon, on global gene expression in relation to effects on embryonic development using the rat whole embryo culture (WEC) model. After 4 h exposure, we identified changes in gene expression due to triazole exposure which preceded morphological alterations observed at 48 h. In general, across the three triazoles, we observed similar directionality of regulation in gene expression and the magnitude of effects on gene expression correlated with the degree of induced developmental toxicity. Significantly regulated genes included key members of steroid/cholesterol and retinoic acid metabolism and hindbrain developmental pathways. Direct comparisons with previous studies suggest that triazole-gene signatures identified in the WEC overlap with zebrafish and mouse, and furthermore, triazoles impact gene expression in a similar manner as retinoic acid exposures in rat embryos. In summary, we further differentiate pathways underlying triazole-developmental toxicity using WEC and demonstrate the conservation of these response-pathways across model systems. Copyright © 2012 Elsevier Inc. All rights reserved.

Therapeutic targets and new directions for antibodies developed for ovarian cancer

PubMed Central

Bax, Heather J.; Josephs, Debra H.; Pellizzari, Giulia; Spicer, James F.; Montes, Ana; Karagiannis, Sophia N.

2016-01-01

ABSTRACT Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential. PMID:27494775

Developmental Programming, a Pathway to Disease

PubMed Central

Cardoso, Rodolfo C.; Puttabyatappa, Muraly

2016-01-01

Accumulating evidence suggests that insults occurring during the perinatal period alter the developmental trajectory of the fetus/offspring leading to long-term detrimental outcomes that often culminate in adult pathologies. These perinatal insults include maternal/fetal disease states, nutritional deficits/excess, stress, lifestyle choices, exposure to environmental chemicals, and medical interventions. In addition to reviewing the various insults that contribute to developmental programming and the benefits of animal models in addressing underlying mechanisms, this review focuses on the commonalities in disease outcomes stemming from various insults, the convergence of mechanistic pathways via which various insults can lead to common outcomes, and identifies the knowledge gaps in the field and future directions. PMID:26859334

Oncogenic Viruses and Tumor Glucose Metabolism: Like Kids in a Candy Store

PubMed Central

Noch, Evan; Khalili, Kamel

2011-01-01

Oncogenic viruses represent a significant public health burden in light of the multitude of malignancies resulting from chronic or spontaneous viral infection and transformation. Though many of the molecular signaling pathways underlying virus-mediated cellular transformation are known, the impact of these viruses on metabolic signaling and phenotype within proliferating tumor cells is less well understood. Whether the interaction of oncogenic viruses with metabolic signaling pathways involves enhanced glucose uptake and glycolysis, both hallmark features of transformed cells, or dysregulation of molecular pathways regulating oxidative stress, viruses are adept at facilitating tumor expansion. Through their effects on cell proliferation pathways, such as the PI3K and MAPK pathways, the cell cycle regulatory proteins, p53 and ATM, and the cell stress response proteins, HIF-1α and AMPK, viruses exert control over critical metabolic signaling cascades. Additionally, oncogenic viruses modulate the tumor metabolomic profile through direct and indirect interaction with glucose transporters, such as GLUT1, and specific glycolytic enzymes, including pyruvate kinase, glucose 6-phosphate dehydrogenase, and hexokinase. Through these pathways, oncogenic viruses alter the phenotypic characteristics of transformed cells and their methods of energy utilization, and it may be possible to develop novel anti-glycolytic therapies to target these dysregulated pathways in virus-derived malignancies. PMID:22234809

Changes in Neuronal Signaling and Cell Stress Response Pathways are Associated with a Multigenic Response of Drosophila melanogaster to DDT Selection

PubMed Central

Coates, Brad S; Sun, Weilin; Clark, John M; Pittendrigh, Barry R

2017-01-01

Abstract The adaptation of insect populations to insecticidal control is a continual threat to human health and sustainable agricultural practices, but many complex genomic mechanisms involved in this adaption remain poorly understood. This study applied a systems approach to investigate the interconnections between structural and functional variance in response to dichlorodiphenyltrichloroethane (DDT) within the Drosophila melanogaster strain 91-R. Directional selection in 6 selective sweeps coincided with constitutive gene expression differences in DDT resistant flies, including the most highly upregulated transcript, Unc-115 b, which plays a central role in axon guidance, and the most highly downregulated transcript, the angiopoietin-like CG31832, which is involved in directing vascular branching and dendrite outgrowth but likely may be under trans-regulatory control. Direct functions and protein–protein interactions mediated by differentially expressed transcripts control changes in cell migration, signal transduction, and gene regulatory cascades that impact the nervous system. Although changes to cellular stress response pathways involve 8 different cytochrome P450s, stress response, and apoptosis is controlled by a multifacetted regulatory mechanism. These data demonstrate that DDT selection in 91-R may have resulted in genome-wide adaptations that impacts genetic and signal transduction pathways that converge to modify stress response, cell survival, and neurological functions. This study implicates the involvement of a multigenic mechanism in the adaptation to a chemical insecticide, which impact interconnected regulatory cascades. We propose that DDT selection within 91-R might act systemically, wherein pathway interactions function to reinforce the epistatic effects of individual adaptive changes on an additive or nonadditive basis. PMID:29211847

Direct and indirect pathways for choosing objects and actions.

PubMed

Hikosaka, Okihide; Kim, Hyoung F; Amita, Hidetoshi; Yasuda, Masaharu; Isoda, Masaki; Tachibana, Yoshihisa; Yoshida, Atsushi

2018-02-23

A prominent target of the basal ganglia is the superior colliculus (SC) which controls gaze orientation (saccadic eye movement in primates) to an important object. This 'object choice' is crucial for choosing an action on the object. SC is innervated by the substantia nigra pars reticulata (SNr) which is controlled mainly by the caudate nucleus (CD). This CD-SNr-SC circuit is sensitive to the values of individual objects and facilitates saccades to good objects. The object values are processed differently in two parallel circuits: flexibly by the caudate head (CDh) and stably by the caudate tail (CDt). To choose good objects, we need to reject bad objects. In fact, these contrasting functions are accomplished by the circuit originating from CDt: The direct pathway focuses on good objects and facilitates saccades to them; the indirect pathway focuses on bad objects and suppresses saccades to them. Inactivation of CDt deteriorated the object choice, because saccades to bad objects were no longer suppressed. This suggests that the indirect pathway is important for object choice. However, the direct and indirect pathways for 'object choice', which aim at the same action (i.e., saccade), may not work for 'action choice'. One possibility is that circuits controlling different actions are connected through the indirect pathway. Additional connections of the indirect pathway with brain areas outside the basal ganglia may also provide a wider range of behavioral choice. In conclusion, basal ganglia circuits are composed of the basic direct/indirect pathways and additional connections and thus have acquired multiple functions. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Analysis of Membrane Protein Topology in the Plant Secretory Pathway.

PubMed

Guo, Jinya; Miao, Yansong; Cai, Yi

2017-01-01

Topology of membrane proteins provides important information for the understanding of protein function and intermolecular associations. Integrate membrane proteins are generally transported from endoplasmic reticulum (ER) to Golgi and downstream compartments in the plant secretory pathway. Here, we describe a simple method to study membrane protein topology along the plant secretory pathway by transiently coexpressing a fluorescent protein (XFP)-tagged membrane protein and an ER export inhibitor protein, ARF1 (T31N), in tobacco BY-2 protoplast. By fractionation, microsome isolation, and trypsin digestion, membrane protein topology could be easily detected by either direct confocal microscopy imaging or western-blot analysis using specific XFP antibodies. A similar strategy in determining membrane protein topology could be widely adopted and applied to protein analysis in a broad range of eukaryotic systems, including yeast cells and mammalian cells.

Genetic Alterations in Glioma

PubMed Central

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. PMID:24212656

Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

PubMed Central

Thaker, Nikhil G; Pollack, Ian F

2010-01-01

Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

Analyses of the Large Subunit Histidine-Rich Motif Expose an Alternative Proton Transfer Pathway in [NiFe] Hydrogenases

PubMed Central

Szőri-Dorogházi, Emma; Maróti, Gergely; Szőri, Milán; Nyilasi, Andrea; Rákhely, Gábor; Kovács, Kornél L.

2012-01-01

A highly conserved histidine-rich region with unknown function was recognized in the large subunit of [NiFe] hydrogenases. The HxHxxHxxHxH sequence occurs in most membrane-bound hydrogenases, but only two of these histidines are present in the cytoplasmic ones. Site-directed mutagenesis of the His-rich region of the T. roseopersicina membrane-attached Hyn hydrogenase disclosed that the enzyme activity was significantly affected only by the replacement of the His104 residue. Computational analysis of the hydrogen bond network in the large subunits indicated that the second histidine of this motif might be a component of a proton transfer pathway including Arg487, Asp103, His104 and Glu436. Substitutions of the conserved amino acids of the presumed transfer route impaired the activity of the Hyn hydrogenase. Western hybridization was applied to demonstrate that the cellular level of the mutant hydrogenases was similar to that of the wild type. Mostly based on theoretical modeling, few proton transfer pathways have already been suggested for [NiFe] hydrogenases. Our results propose an alternative route for proton transfer between the [NiFe] active center and the surface of the protein. A novel feature of this model is that this proton pathway is located on the opposite side of the large subunit relative to the position of the small subunit. This is the first study presenting a systematic analysis of an in silico predicted proton translocation pathway in [NiFe] hydrogenases by site-directed mutagenesis. PMID:22511957

The sensory transduction pathways in bacterial chemotaxis

NASA Technical Reports Server (NTRS)

Taylor, Barry L.

1989-01-01

Bacterial chemotaxis is a useful model for investigating in molecular detail the behavioral response of cells to changes in their environment. Peritrichously flagellated bacteria such as coli and typhimurium swim by rotating helical flagella in a counterclockwise direction. If flagellar rotation is briefly reversed, the bacteria tumble and change the direction of swimming. The bacteria continuously sample the environment and use a temporal sensing mechanism to compare the present and immediate past environments. Bacteria respond to a broad range of stimuli including changes in temperature, oxygen concentration, pH and osmotic strength. Bacteria are attracted to potential sources of nutrition such as sugars and amino acids and are repelled by other chemicals. In the methylation-dependent pathways for sensory transduction and adaptation in E. coli and S. typhimurium, chemoeffectors bind to transducing proteins that span the plasma membrane. The transducing proteins are postulated to control the rate of autophosphorylation of the CheA protein, which in turn phosphorylates the CheY protein. The phospho-CheY protein binds to the switch on the flagellar motor and is the signal for clockwise rotation of the motor. Adaptation to an attractant is achieved by increasing methylation of the transducing protein until the attractant stimulus is cancelled. Responses to oxygen and certain sugars involve methylation-independent pathways in which adaption occurs without methylation of a transducing protein. Taxis toward oxygen is mediated by the electron transport system and changes in the proton motive force. Recent studies have shown that the methylation-independent pathway converges with the methylation-dependent pathway at or before the CheA protein.

A Cyber Security Self-Assessment Method for Nuclear Power Plants

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

Glantz, Clifford S.; Coles, Garill A.; Bass, Robert B.

2004-11-01

A cyber security self-assessment method (the Method) has been developed by Pacific Northwest National Laboratory. The development of the Method was sponsored and directed by the U.S. Nuclear Regulatory Commission. Members of the Nuclear Energy Institute Cyber Security Task Force also played a substantial role in developing the Method. The Method's structured approach guides nuclear power plants in scrutinizing their digital systems, assessing the potential consequences to the plant of a cyber exploitation, identifying vulnerabilities, estimating cyber security risks, and adopting cost-effective protective measures. The focus of the Method is on critical digital assets. A critical digital asset is amore » digital device or system that plays a role in the operation, maintenance, or proper functioning of a critical system (i.e., a plant system that can impact safety, security, or emergency preparedness). A critical digital asset may have a direct or indirect connection to a critical system. Direct connections include both wired and wireless communication pathways. Indirect connections include sneaker-net pathways by which software or data are manually transferred from one digital device to another. An indirect connection also may involve the use of instructions or data stored on a critical digital asset to make adjustments to a critical system. The cyber security self-assessment begins with the formation of an assessment team, and is followed by a six-stage process.« less

Network design and analysis for multi-enzyme biocatalysis.

PubMed

Blaß, Lisa Katharina; Weyler, Christian; Heinzle, Elmar

2017-08-10

As more and more biological reaction data become available, the full exploration of the enzymatic potential for the synthesis of valuable products opens up exciting new opportunities but is becoming increasingly complex. The manual design of multi-step biosynthesis routes involving enzymes from different organisms is very challenging. To harness the full enzymatic potential, we developed a computational tool for the directed design of biosynthetic production pathways for multi-step catalysis with in vitro enzyme cascades, cell hydrolysates and permeabilized cells. We present a method which encompasses the reconstruction of a genome-scale pan-organism metabolic network, path-finding and the ranking of the resulting pathway candidates for proposing suitable synthesis pathways. The network is based on reaction and reaction pair data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the thermodynamics calculator eQuilibrator. The pan-organism network is especially useful for finding the most suitable pathway to a target metabolite from a thermodynamic or economic standpoint. However, our method can be used with any network reconstruction, e.g. for a specific organism. We implemented a path-finding algorithm based on a mixed-integer linear program (MILP) which takes into account both topology and stoichiometry of the underlying network. Unlike other methods we do not specify a single starting metabolite, but our algorithm searches for pathways starting from arbitrary start metabolites to a target product of interest. Using a set of biochemical ranking criteria including pathway length, thermodynamics and other biological characteristics such as number of heterologous enzymes or cofactor requirement, it is possible to obtain well-designed meaningful pathway alternatives. In addition, a thermodynamic profile, the overall reactant balance and potential side reactions as well as an SBML file for visualization are generated for each pathway alternative. We present an in silico tool for the design of multi-enzyme biosynthetic production pathways starting from a pan-organism network. The method is highly customizable and each module can be adapted to the focus of the project at hand. This method is directly applicable for (i) in vitro enzyme cascades, (ii) cell hydrolysates and (iii) permeabilized cells.

Integrated turbomachine oxygen plant

DOEpatents

Anand, Ashok Kumar; DePuy, Richard Anthony; Muthaiah, Veerappan

2014-06-17

An integrated turbomachine oxygen plant includes a turbomachine and an air separation unit. One or more compressor pathways flow compressed air from a compressor through one or more of a combustor and a turbine expander to cool the combustor and/or the turbine expander. An air separation unit is operably connected to the one or more compressor pathways and is configured to separate the compressed air into oxygen and oxygen-depleted air. A method of air separation in an integrated turbomachine oxygen plant includes compressing a flow of air in a compressor of a turbomachine. The compressed flow of air is flowed through one or more of a combustor and a turbine expander of the turbomachine to cool the combustor and/or the turbine expander. The compressed flow of air is directed to an air separation unit and is separated into oxygen and oxygen-depleted air.

Lipotoxicity: Effects of Dietary Saturated and Transfatty Acids

PubMed Central

Estadella, Débora; da Penha Oller do Nascimento, Claudia M.; Oyama, Lila M.; Ribeiro, Eliane B.; Dâmaso, Ana R.; de Piano, Aline

2013-01-01

The ingestion of excessive amounts of saturated fatty acids (SFAs) and transfatty acids (TFAs) is considered to be a risk factor for cardiovascular diseases, insulin resistance, dyslipidemia, and obesity. The focus of this paper was to elucidate the influence of dietary SFA and TFA intake on the promotion of lipotoxicity to the liver and cardiovascular, endothelial, and gut microbiota systems, as well as on insulin resistance and endoplasmic reticulum stress. The saturated and transfatty acids favor a proinflammatory state leading to insulin resistance. These fatty acids can be involved in several inflammatory pathways, contributing to disease progression in chronic inflammation, autoimmunity, allergy, cancer, atherosclerosis, hypertension, and heart hypertrophy as well as other metabolic and degenerative diseases. As a consequence, lipotoxicity may occur in several target organs by direct effects, represented by inflammation pathways, and through indirect effects, including an important alteration in the gut microbiota associated with endotoxemia. Interactions between these pathways may perpetuate a feedback process that exacerbates an inflammatory state. The importance of lifestyle modification, including an improved diet, is recommended as a strategy for treatment of these diseases. PMID:23509418

Studying emotion theories through connectivity analysis: Evidence from generalized psychophysiological interactions and graph theory.

PubMed

Huang, Yun-An; Jastorff, Jan; Van den Stock, Jan; Van de Vliet, Laura; Dupont, Patrick; Vandenbulcke, Mathieu

2018-05-15

Psychological construction models of emotion state that emotions are variable concepts constructed by fundamental psychological processes, whereas according to basic emotion theory, emotions cannot be divided into more fundamental units and each basic emotion is represented by a unique and innate neural circuitry. In a previous study, we found evidence for the psychological construction account by showing that several brain regions were commonly activated when perceiving different emotions (i.e. a general emotion network). Moreover, this set of brain regions included areas associated with core affect, conceptualization and executive control, as predicted by psychological construction models. Here we investigate directed functional brain connectivity in the same dataset to address two questions: 1) is there a common pathway within the general emotion network for the perception of different emotions and 2) if so, does this common pathway contain information to distinguish between different emotions? We used generalized psychophysiological interactions and information flow indices to examine the connectivity within the general emotion network. The results revealed a general emotion pathway that connects neural nodes involved in core affect, conceptualization, language and executive control. Perception of different emotions could not be accurately classified based on the connectivity patterns from the nodes of the general emotion pathway. Successful classification was achieved when connections outside the general emotion pathway were included. We propose that the general emotion pathway functions as a common pathway within the general emotion network and is involved in shared basic psychological processes across emotions. However, additional connections within the general emotion network are required to classify different emotions, consistent with a constructionist account. Copyright © 2018 Elsevier Inc. All rights reserved.

Quantitative Profiling of DNA Damage and Apoptotic Pathways in UV Damaged Cells Using PTMScan Direct

PubMed Central

Stokes, Matthew P.; Silva, Jeffrey C.; Jia, Xiaoying; Lee, Kimberly A.; Polakiewicz, Roberto D.; Comb, Michael J.

2013-01-01

Traditional methods for analysis of peptides using liquid chromatography and tandem mass spectrometry (LC-MS/MS) lack the specificity to comprehensively monitor specific biological processes due to the inherent duty cycle limitations of the MS instrument and the stochastic nature of the analytical platform. PTMScan Direct is a novel, antibody-based method that allows quantitative LC-MS/MS profiling of specific peptides from proteins that reside in the same signaling pathway. New PTMScan Direct reagents have been produced that target peptides from proteins involved in DNA Damage/Cell Cycle and Apoptosis/Autophagy pathways. Together, the reagents provide access to 438 sites on 237 proteins in these signaling cascades. These reagents have been used to profile the response to UV damage of DNA in human cell lines. UV damage was shown to activate canonical DNA damage response pathways through ATM/ATR-dependent signaling, stress response pathways and induce the initiation of apoptosis, as assessed by an increase in the abundance of peptides corresponding to cleaved, activated caspases. These data demonstrate the utility of PTMScan Direct as a multiplexed assay for profiling specific cellular responses to various stimuli, such as UV damage of DNA. PMID:23344034

Mitochondrial DNA and trade data support multiple origins of Helicoverpa armigera (Lepidoptera, Noctuidae) in Brazil

PubMed Central

Tay, Wee Tek; Walsh, Thomas K.; Downes, Sharon; Anderson, Craig; Jermiin, Lars S.; Wong, Thomas K. F.; Piper, Melissa C.; Chang, Ester Silva; Macedo, Isabella Barony; Czepak, Cecilia; Behere, Gajanan T.; Silvie, Pierre; Soria, Miguel F.; Frayssinet, Marie; Gordon, Karl H. J.

2017-01-01

The Old World bollworm Helicoverpa armigera is now established in Brazil but efforts to identify incursion origin(s) and pathway(s) have met with limited success due to the patchiness of available data. Using international agricultural/horticultural commodity trade data and mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) and cytochrome b (Cyt b) gene markers, we inferred the origins and incursion pathways into Brazil. We detected 20 mtDNA haplotypes from six Brazilian states, eight of which were new to our 97 global COI-Cyt b haplotype database. Direct sequence matches indicated five Brazilian haplotypes had Asian, African, and European origins. We identified 45 parsimoniously informative sites and multiple substitutions per site within the concatenated (945 bp) nucleotide dataset, implying that probabilistic phylogenetic analysis methods are needed. High diversity and signatures of uniquely shared haplotypes with diverse localities combined with the trade data suggested multiple incursions and introduction origins in Brazil. Increasing agricultural/horticultural trade activities between the Old and New Worlds represents a significant biosecurity risk factor. Identifying pest origins will enable resistance profiling that reflects countries of origin to be included when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots including national ports. PMID:28350004

Mitochondrial DNA and trade data support multiple origins of Helicoverpa armigera (Lepidoptera, Noctuidae) in Brazil.

PubMed

Tay, Wee Tek; Walsh, Thomas K; Downes, Sharon; Anderson, Craig; Jermiin, Lars S; Wong, Thomas K F; Piper, Melissa C; Chang, Ester Silva; Macedo, Isabella Barony; Czepak, Cecilia; Behere, Gajanan T; Silvie, Pierre; Soria, Miguel F; Frayssinet, Marie; Gordon, Karl H J

2017-03-28

The Old World bollworm Helicoverpa armigera is now established in Brazil but efforts to identify incursion origin(s) and pathway(s) have met with limited success due to the patchiness of available data. Using international agricultural/horticultural commodity trade data and mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) and cytochrome b (Cyt b) gene markers, we inferred the origins and incursion pathways into Brazil. We detected 20 mtDNA haplotypes from six Brazilian states, eight of which were new to our 97 global COI-Cyt b haplotype database. Direct sequence matches indicated five Brazilian haplotypes had Asian, African, and European origins. We identified 45 parsimoniously informative sites and multiple substitutions per site within the concatenated (945 bp) nucleotide dataset, implying that probabilistic phylogenetic analysis methods are needed. High diversity and signatures of uniquely shared haplotypes with diverse localities combined with the trade data suggested multiple incursions and introduction origins in Brazil. Increasing agricultural/horticultural trade activities between the Old and New Worlds represents a significant biosecurity risk factor. Identifying pest origins will enable resistance profiling that reflects countries of origin to be included when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots including national ports.

Mitochondrial DNA and trade data support multiple origins of Helicoverpa armigera (Lepidoptera, Noctuidae) in Brazil

NASA Astrophysics Data System (ADS)

Tay, Wee Tek; Walsh, Thomas K.; Downes, Sharon; Anderson, Craig; Jermiin, Lars S.; Wong, Thomas K. F.; Piper, Melissa C.; Chang, Ester Silva; Macedo, Isabella Barony; Czepak, Cecilia; Behere, Gajanan T.; Silvie, Pierre; Soria, Miguel F.; Frayssinet, Marie; Gordon, Karl H. J.

2017-03-01

The Old World bollworm Helicoverpa armigera is now established in Brazil but efforts to identify incursion origin(s) and pathway(s) have met with limited success due to the patchiness of available data. Using international agricultural/horticultural commodity trade data and mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) and cytochrome b (Cyt b) gene markers, we inferred the origins and incursion pathways into Brazil. We detected 20 mtDNA haplotypes from six Brazilian states, eight of which were new to our 97 global COI-Cyt b haplotype database. Direct sequence matches indicated five Brazilian haplotypes had Asian, African, and European origins. We identified 45 parsimoniously informative sites and multiple substitutions per site within the concatenated (945 bp) nucleotide dataset, implying that probabilistic phylogenetic analysis methods are needed. High diversity and signatures of uniquely shared haplotypes with diverse localities combined with the trade data suggested multiple incursions and introduction origins in Brazil. Increasing agricultural/horticultural trade activities between the Old and New Worlds represents a significant biosecurity risk factor. Identifying pest origins will enable resistance profiling that reflects countries of origin to be included when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots including national ports.

Bioreactors to Influence Stem Cell Fate: Augmentation of Mesenchymal Stem Cell Signaling Pathways via Dynamic Culture Systems

PubMed Central

Yeatts, Andrew B.; Choquette, Daniel T.; Fisher, John P.

2012-01-01

Background Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro. Scope of Review This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems. Major Conclusions The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased. General Significance Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. PMID:22705676

Whole-Genome Analysis of the SHORT-ROOT Developmental Pathway in Arabidopsis

PubMed Central

Busch, Wolfgang; Cui, Hongchang; Wang, Jean Y; Blilou, Ikram; Hassan, Hala; Nakajima, Keiji; Matsumoto, Noritaka; Lohmann, Jan U; Scheres, Ben

2006-01-01

Stem cell function during organogenesis is a key issue in developmental biology. The transcription factor SHORT-ROOT (SHR) is a critical component in a developmental pathway regulating both the specification of the root stem cell niche and the differentiation potential of a subset of stem cells in the Arabidopsis root. To obtain a comprehensive view of the SHR pathway, we used a statistical method called meta-analysis to combine the results of several microarray experiments measuring the changes in global expression profiles after modulating SHR activity. Meta-analysis was first used to identify the direct targets of SHR by combining results from an inducible form of SHR driven by its endogenous promoter, ectopic expression, followed by cell sorting and comparisons of mutant to wild-type roots. Eight putative direct targets of SHR were identified, all with expression patterns encompassing subsets of the native SHR expression domain. Further evidence for direct regulation by SHR came from binding of SHR in vivo to the promoter regions of four of the eight putative targets. A new role for SHR in the vascular cylinder was predicted from the expression pattern of several direct targets and confirmed with independent markers. The meta-analysis approach was then used to perform a global survey of the SHR indirect targets. Our analysis suggests that the SHR pathway regulates root development not only through a large transcription regulatory network but also through hormonal pathways and signaling pathways using receptor-like kinases. Taken together, our results not only identify the first nodes in the SHR pathway and a new function for SHR in the development of the vascular tissue but also reveal the global architecture of this developmental pathway. PMID:16640459

Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning

PubMed Central

Dunovan, Kyle; Verstynen, Timothy

2016-01-01

The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning. PMID:27047328

Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning.

PubMed

Dunovan, Kyle; Verstynen, Timothy

2016-01-01

The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning.

A spiking neural network based on the basal ganglia functional anatomy.

PubMed

Baladron, Javier; Hamker, Fred H

2015-07-01

We introduce a spiking neural network of the basal ganglia capable of learning stimulus-action associations. We model learning in the three major basal ganglia pathways, direct, indirect and hyperdirect, by spike time dependent learning and considering the amount of dopamine available (reward). Moreover, we allow to learn a cortico-thalamic pathway that bypasses the basal ganglia. As a result the system develops new functionalities for the different basal ganglia pathways: The direct pathway selects actions by disinhibiting the thalamus, the hyperdirect one suppresses alternatives and the indirect pathway learns to inhibit common mistakes. Numerical experiments show that the system is capable of learning sets of either deterministic or stochastic rules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exposure assessment of veterinary medicines in aquatic systems

USGS Publications Warehouse

Metcalfe, Chris; Boxall, Alistair; Fenner, Kathrin; Kolpin, Dana W.; Silberhorn, Eric; Staveley, Jane

2008-01-01

The release of veterinary medicines into the aquatic environment may occur through direct or indirect pathways. An example of direct release is the use of medicines in aquaculture (Armstrong et al. 2005; Davies et al. 1998), where chemicals used to treat fish are added directly to water. Indirect releases, in which medicines make their way to water through transport from other matrices, include the application of animal manure to land or direct excretion of residues onto pasture land, from which the therapeutic chemicals may be transported into the aquatic environment (Jørgensen and Halling-Sørensen 2000; Boxall et al. 2003, 2004). Veterinary medicines used to treat companion animals may also be transported into the aquatic environment through disposal of unused medicines, veterinary waste, or animal carcasses (Daughton and Ternes 1999, Boxall et al. 2004). The potential for a veterinary medicine to be released to the aquatic environment will be determined by several different criteria, including the method of treatment, agriculture or aquaculture practices, environmental conditions, and the properties of the veterinary medicine.

Fanconi Anemia Proteins, DNA Interstrand Crosslink Repair Pathways, and Cancer Therapy

PubMed Central

Andreassen, Paul R.; Ren, Keqin

2016-01-01

DNA interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and DNA intrastrand crosslinks, are extensively utilized for cancer therapy. Understanding the cellular response to DNA damage induced by these agents is critical for more effective utilization of these compounds and for the identification of novel therapeutic targets. Importantly, the repair of DNA interstrand crosslinks (ICLs) involves many distinct DNA repair pathways, including nucleotide excision repair, translesion synthesis (TLS), and homologous recombination (HR). Additionally, proteins implicated in the pathophysiology of the multigenic disease Fanconi anemia (FA) have a role in the repair of ICLs that is not well understood. Cells from FA patients are hypersensitive to agents that induce ICLs, therefore FA proteins are potentially novel therapeutic targets. Here we will review current research directed at identifying FA genes and understanding the function of FA proteins in DNA damage responses. We will also examine interactions of FA proteins with other repair proteins and pathways, including signaling networks, which are potentially involved in ICL repair. Potential approaches to the modulation of FA protein function to enhance therapeutic outcome will be discussed. Also, mutation of many genes that encode proteins involved in ICL repair, including FA genes, increases susceptibility to cancer. A better understanding of these pathways is therefore critical for the design of individualized therapies tailored to the genetic profile of a particular malignancy. For this purpose, we will also review evidence for the association of mutation of FA genes with cancer in non-FA patients. PMID:19200054

Ars Moriendi; the art of dying well - new insights into the molecular pathways of necroptotic cell death.

PubMed

Murphy, James M; Silke, John

2014-02-01

When our time comes to die most people would probably opt for a quick, peaceful and painless exit. But the manner and timing are rarely under our direct control. Hence the Ars moriendi, literally, "The Art of Dying", two texts written in Latin around the 15th century that offered advice on how to die well according to the Christian ideals of the time. In contrast, for individual cells, the death process is frequently under their control and several signaling pathways that cause cell death, including apoptosis, pyroptosis and necroptosis, have been described. Furthermore the manner in which cells die can have good or bad consequences for the organism. In this review we will discuss how cells die via the necroptotic signaling pathway, with emphasis on recent structural work and place this work in a biological context by discussing relevant studies with knock-out animals.

Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol.

PubMed

Ahn, Sang-Il; Lee, Jun-Kyung; Youn, Hyung-Sun

2009-02-28

Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B (NF-kappaB). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of NF-kappaB activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.

Pharmacogenetic study focused on fluoxetine pharmacodynamics in children and adolescent patients: impact of the serotonin pathway.

PubMed

Mas, Sergi; Blázquez, Ana; Rodríguez, Natalia; Boloc, Daniel; Lafuente, Amalia; Arnaiz, Joan A; Lázaro, Luisa; Gassó, Patricia

2016-11-01

Pharmacogenetic studies of fluoxetine in children and adolescents are scarce. After reporting the effect of genetic variants in genes related to the fluoxetine pharmacokinetics on clinical response in a pediatric population, we now evaluate the impact of genetic markers involved in its pharmacodynamics. The assessment was performed in 83 patients after 12 weeks of fluoxetine treatment. The genetic association analysis included a total of 316 validated single nucleotide polymorphisms in 45 candidate genes involved in six different pathways. Clinical improvement after treatment with fluoxetine in our pediatric population was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B (HTR1B) and the tryptophan 5-hydroxylase 2 (TPH2). Although a wide range of candidate genes related to different pathways were assessed, the results show that genetic markers directly related to serotonin have an important effect on fluoxetine response.

Reconstruction of a metabolic regulatory network in Escherichia coli for purposeful switching from cell growth mode to production mode in direct GABA fermentation from glucose.

PubMed

Soma, Yuki; Fujiwara, Yuri; Nakagawa, Takuya; Tsuruno, Keigo; Hanai, Taizo

2017-09-01

γ-aminobutyric acid (GABA) is a drug and functional food additive and is used as a monomer for producing the biodegradable plastic, polyamide 4. Recently, direct GABA fermentation from glucose has been developed as an alternative to glutamate-based whole cell bioconversion. Although total productivity in fermentation is determined by the specific productivity and cell amount responsible for GABA production, the optimal metabolic state for GABA production conflicts with that for bacterial cell growth. Herein, we demonstrated metabolic state switching from the cell growth mode based on the metabolic pathways of the wild type strain to a GABA production mode based on a synthetic metabolic pathway in Escherichia coli through rewriting of the metabolic regulatory network and pathway engineering. The GABA production mode was achieved by multiple strategies such as conditional interruption of the TCA and glyoxylate cycles, engineering of GABA production pathway including a bypass for precursor metabolite supply, and upregulation of GABA transporter. As a result, we achieved 3-fold improvement in total GABA production titer and yield (4.8g/L, 49.2% (mol/mol glucose)) in batch fermentation compared to the case without metabolic state switching (1.6g/L, 16.4% (mol/mol glucose)). This study reports the highest GABA production performance among previous reports on GABA fermentation from glucose using engineered E. coli. Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Implications of Cancer Stem Cell Theory for Cancer Chemoprevention by Natural Dietary Compounds

PubMed Central

Li, Yanyan; Wicha, Max S.; Schwartz, Steven J.; Sun, Duxin

2011-01-01

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anti-cancer drugs targeting cancer stem cells. Naturally-occurring dietary compounds have received increasing attention in cancer chemoprevention. The anti-cancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog, and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine, and vitamin D3, are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival. PMID:21295962

Evolutionary Importance of the Intramolecular Pathways of Hydrolysis of Phosphate Ester Mixed Anhydrides with Amino Acids and Peptides

NASA Astrophysics Data System (ADS)

Liu, Ziwei; Beaufils, Damien; Rossi, Jean-Christophe; Pascal, Robert

2014-12-01

Aminoacyl adenylates (aa-AMPs) constitute essential intermediates of protein biosynthesis. Their polymerization in aqueous solution has often been claimed as a potential route to abiotic peptides in spite of a highly efficient CO2-promoted pathway of hydrolysis. Here we investigate the efficiency and relevance of this frequently overlooked pathway from model amino acid phosphate mixed anhydrides including aa-AMPs. Its predominance was demonstrated at CO2 concentrations matching that of physiological fluids or that of the present-day ocean, making a direct polymerization pathway unlikely. By contrast, the occurrence of the CO2-promoted pathway was observed to increase the efficiency of peptide bond formation owing to the high reactivity of the N-carboxyanhydride (NCA) intermediate. Even considering CO2 concentrations in early Earth liquid environments equivalent to present levels, mixed anhydrides would have polymerized predominantly through NCAs. The issue of a potential involvement of NCAs as biochemical metabolites could even be raised. The formation of peptide-phosphate mixed anhydrides from 5(4H)-oxazolones (transiently formed through prebiotically relevant peptide activation pathways) was also observed as well as the occurrence of the reverse cyclization process in the reactions of these mixed anhydrides. These processes constitute the core of a reaction network that could potentially have evolved towards the emergence of translation.

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

PubMed Central

Miele, Lucio; Harris, Pamela Jo; Jeong, Woondong; Bando, Hideaki; Kahn, Michael; Yang, Sherry X.

2015-01-01

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents. PMID:25850553

miR-958 inhibits Toll signaling and Drosomycin expression via direct targeting of Toll and Dif in Drosophila melanogaster.

PubMed

Li, Shengjie; Li, Yao; Shen, Li; Jin, Ping; Chen, Liming; Ma, Fei

2017-02-01

Drosophila melanogaster is widely used as a model system to study innate immunity and signaling pathways related to innate immunity, including the Toll signaling pathway. Although this pathway is well studied, the precise mechanisms of posttranscriptional regulation of key components of the Toll signaling pathway by microRNAs (miRNAs) remain obscure. In this study, we used an in silico strategy in combination with the Gal80 ts -Gal4 driver system to identify microRNA-958 (miR-958) as a candidate Toll pathway regulating miRNA in Drosophila We report that overexpression of miR-958 significantly reduces the expression of Drosomycin, a key antimicrobial peptide involved in Toll signaling and the innate immune response. We further demonstrate in vitro and in vivo that miR-958 targets the Toll and Dif genes, key components of the Toll signaling pathway, to negatively regulate Drosomycin expression. In addition, a miR-958 sponge rescued the expression of Toll and Dif, resulting in increased expression of Drosomycin. These results, not only revealed a novel function and modulation pattern of miR-958, but also provided a new insight into the underlying molecular mechanisms of Toll signaling in regulation of innate immunity. Copyright © 2017 the American Physiological Society.

Regulation of CaV2 calcium channels by G protein coupled receptors

PubMed Central

Zamponi, Gerald W.; Currie, Kevin P.M.

2012-01-01

Voltage gated calcium channels (Ca2+ channels) are key mediators of depolarization induced calcium influx into excitable cells, and thereby play pivotal roles in a wide array of physiological responses. This review focuses on the inhibition of CaV2 (N- and P/Q-type) Ca2+-channels by G protein coupled receptors (GPCRs), which exerts important autocrine/paracrine control over synaptic transmission and neuroendocrine secretion. Voltage-dependent inhibition is the most widespread mechanism, and involves direct binding of the G protein βγ dimer (Gβγ) to the α1 subunit of CaV2 channels. GPCRs can also recruit several other distinct mechanisms including phosphorylation, lipid signaling pathways, and channel trafficking that result in voltage-independent inhibition. Current knowledge of Gβγ-mediated inhibition is reviewed, including the molecular interactions involved, determinants of voltage-dependence, and crosstalk with other cell signaling pathways. A summary of recent developments in understanding the voltage-independent mechanisms prominent in sympathetic and sensory neurons is also included. PMID:23063655

The neurology of mTOR.

PubMed

Lipton, Jonathan O; Sahin, Mustafa

2014-10-22

The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.

Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets.

PubMed

Lindsay, Cameron; Seikaly, Hadi; Biron, Vincent L

2017-01-31

Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Balancing repair and tolerance of DNA damage caused by alkylating agents.

PubMed

Fu, Dragony; Calvo, Jennifer A; Samson, Leona D

2012-01-12

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

PubMed Central

Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

2013-01-01

Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID:22237395

Pain Amplification Syndrome: A Biopsychosocial Approach.

PubMed

Namerow, Lisa B; Kutner, Emily C; Wakefield, Emily C; Rzepski, Barbara R; Sahl, Robert A

2016-08-01

Pediatric neurologists frequently encounter patients who present with significant musculoskeletal pain that cannot be attributed to a specific injury or illness, which can often be defined as pain amplification syndrome (PAS). PAS in children and adolescents is the result of a heightened pain sensitivity pathway, which is intensified by significant biological, psychological, and social contributors. Appropriate assessment and multimodal intervention of PAS are crucial to treatment success, including neurology and behavioral health collaborative treatment plans to restore patient function and reduce pain perception. Pediatric neurologists are imperative in the identification of patients with PAS, providing the family assurance in diagnosis and validation of pain, and directing patients to the appropriate multidisciplinary treatment pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Photodegradation of Mefenamic Acid in Aqueous Media: Kinetics, Toxicity and Photolysis Products.

PubMed

Chen, Ping; Wang, Feng Liang; Yao, Kun; Ma, Jing Shuai; Li, Fu Hua; Lv, Wen Ying; Liu, Guo Guang

2016-02-01

The present study investigated the photolytic behavior and photodegradation products of mefenamic acid (MEF) under ultraviolet-C irradiation. The results demonstrated that the photodegradation of MEF followed pseudo-first-order kinetics and the direct photolysis quantum yield of mefenamic acid was observed to be 2.63 ± 0.28 × 10⁻³. Photodegradation of MEF included degradation by direct photolysis and by self-sensitization that the contribution rates of self-sensitized photodegradation were 5.70, 11.25 and 18.96 % for ·OH, ¹O₂ and O·₂⁻ , respectively. Primary transformation products of MEF were identified using ultra performance liquid chromatography and quadrupole time-of-flight mass spectrometer (UPLC-Q-TOF-MS). The identified transformation products suggested three possible pathways of MEF photodegradation: dehydrogenation, hydroxylation, and ketonized reactions. Toxicity of phototransformation products were evaluated using the Microtox test, which revealed that photodegradation likely provides a critical pathway for MEF toxicity reduction in drinking water and wastewater treatment facilities.

MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health

PubMed Central

Kubinak, Jason L.; Petersen, Charisse; Stephens, W. Zac; Soto, Ray; Bake, Erin; O’Connell, Ryan M.; Round, June L.

2015-01-01

SUMMARY Altered commensal communities are associated with human disease. IgA mediates intestinal homeostasis and regulates microbiota composition. Intestinal IgA is produced at high levels as a result of T follicular helper cell (TFH) and B cell interactions in germinal centers. However, the pathways directing host IgA responses towards the microbiota remain unknown. Here, we report that signaling through the innate adaptor MyD88 in gut T cells coordinates germinal center responses, including TFH and IgA+ B cell development. TFH development is deficient in germfree mice and can be restored by feeding TLR2 agonists that activate T cell intrinsic MyD88 signaling. Loss of this pathway diminishes high affinity IgA targeting of the microbiota and fails to control the bacterial community, leading to worsened disease. Our findings identify that T cells converge innate and adaptive immune signals to coordinate IgA against the microbiota, constraining microbial community membership to promote symbiosis. PMID:25620548

The geometric phase controls ultracold chemistry

DOE PAGES

Kendrick, B. K.; Hazra, Jisha; Balakrishnan, N.

2015-07-30

In this study, the geometric phase is shown to control the outcome of an ultracold chemical reaction. The control is a direct consequence of the sign change on the interference term between two scattering pathways (direct and looping), which contribute to the reactive collision process in the presence of a conical intersection (point of degeneracy between two Born–Oppenheimer electronic potential energy surfaces). The unique properties of the ultracold energy regime lead to an effective quantization of the scattering phase shift enabling maximum constructive or destructive interference between the two pathways. By taking the O + OH → H + Omore » 2 reaction as an illustrative example, it is shown that inclusion of the geometric phase modifies ultracold reaction rates by nearly two orders of magnitude. Interesting experimental control possibilities include the application of external electric and magnetic fields that might be used to exploit the geometric phase effect reported here and experimentally switch on or off the reactivity.« less

Ventral Fronto-Temporal Pathway Supporting Cognitive Control of Episodic Memory Retrieval

PubMed Central

Barredo, Jennifer; Öztekin, Ilke; Badre, David

2015-01-01

Achieving our goals often requires guiding access to relevant information from memory. Such goal-directed retrieval requires interactions between systems supporting cognitive control, including ventrolateral prefrontal cortex (VLPFC), and those supporting declarative memory, such as the medial temporal lobes (MTL). However, the pathways by which VLPFC interacts with MTL during retrieval are underspecified. Prior neuroanatomical evidence suggests that a polysynaptic ventral fronto-temporal pathway may support VLPFC–MTL interactions. To test this hypothesis, human participants were scanned using fMRI during performance of a source-monitoring task. The strength of source information was varied via repetition during encoding. Single encoding events should produce a weaker memory trace, thus recovering source information about these items should demand greater cognitive control. Results demonstrated that cortical targets along the ventral path—anterior VLPFC, temporal pole, anterior parahippocampus, and hippocampus—exhibited increases in univariate BOLD response correlated with increases in controlled retrieval demand, independent of factors related to response selection. Further, a functional connectivity analysis indicated that these regions functionally couple and are distinguishable from a dorsal pathway related to response selection demands. These data support a ventral retrieval pathway linking PFC and MTL. PMID:24177990

The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism

PubMed Central

Inserte, Javier; Garcia-Dorado, David

2015-01-01

Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca2+ handling, sarcoplasmic reticulum-mediated Ca2+ oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca2+ oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction. PMID:25297462

The Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Transforming Growth Factor-β Signaling by Destabilizing Ski and Inducing Smad7*

PubMed Central

Band, Arja M.; Björklund, Mia; Laiho, Marikki

2009-01-01

Ski is an oncoprotein that negatively regulates transforming growth factor (TGF)-β signaling. It acts as a transcriptional co-repressor by binding to TGF-β signaling molecules, Smads. Efficient TGF-β signaling is facilitated by rapid proteasome-mediated degradation of Ski by TGF-β. Here we report that Ski is phosphorylated by Akt/PKB kinase. Akt phosphorylates Ski on a highly conserved Akt motif at threonine 458 both in vitro and in vivo. The phosphorylation of Ski at threonine 458 is induced by Akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of Ski causes its destabilization and reduces Ski-mediated inhibition of expression of another negative regulator of TGF-β, Smad7. Induction of Smad7 levels leads to inactivation of TGF-β receptors and TGF-β signaling cascade, as indicated by reduced induction of TGF-β target p15. Therefore, Akt modulates TGF-β signaling by temporarily adjusting the levels of two TGF-β pathway negative regulators, Ski and Smad7. These novel findings demonstrate that Akt pathway activation directly impacts TGF-β pathway. PMID:19875456

Adenosine receptor desensitization and trafficking.

PubMed

Mundell, Stuart; Kelly, Eamonn

2011-05-01

As with the majority of G-protein-coupled receptors, all four of the adenosine receptor subtypes are known to undergo agonist-induced regulation in the form of desensitization and trafficking. These processes can limit the ability of adenosine receptors to couple to intracellular signalling pathways and thus reduce the ability of adenosine receptor agonists as well as endogenous adenosine to produce cellular responses. In addition, since adenosine receptors couple to multiple signalling pathways, these pathways may desensitize differentially, while the desensitization of one pathway could even trigger signalling via another. Thus, the overall picture of adenosine receptor regulation can be complex. For all adenosine receptor subtypes, there is evidence to implicate arrestins in agonist-induced desensitization and trafficking, but there is also evidence for other possible forms of regulation, including second messenger-dependent kinase regulation, heterologous effects involving G proteins, and the involvement of non-clathrin trafficking pathways such as caveolae. In this review, the evidence implicating these mechanisms is summarized for each adenosine receptor subtype, and we also discuss those issues of adenosine receptor regulation that remain to be resolved as well as likely directions for future research in this field. Copyright © 2010 Elsevier B.V. All rights reserved.

Quantitative proteomic analysis of milk fat globule membrane (MFGM) proteins in human and bovine colostrum and mature milk samples through iTRAQ labeling.

PubMed

Yang, Mei; Cong, Min; Peng, Xiuming; Wu, Junrui; Wu, Rina; Liu, Biao; Ye, Wenhui; Yue, Xiqing

2016-05-18

Milk fat globule membrane (MFGM) proteins have many functions. To explore the different proteomics of human and bovine MFGM, MFGM proteins were separated from human and bovine colostrum and mature milk, and analyzed by the iTRAQ proteomic approach. A total of 411 proteins were recognized and quantified. Among these, 232 kinds of differentially expressed proteins were identified. These differentially expressed proteins were analyzed based on multivariate analysis, gene ontology (GO) annotation and KEGG pathway. Biological processes involved were response to stimulus, localization, establishment of localization, and the immune system process. Cellular components engaged were the extracellular space, extracellular region parts, cell fractions, and vesicles. Molecular functions touched upon were protein binding, nucleotide binding, and enzyme inhibitor activity. The KEGG pathway analysis showed several pathways, including regulation of the actin cytoskeleton, focal adhesion, neurotrophin signaling pathway, leukocyte transendothelial migration, tight junction, complement and coagulation cascades, vascular endothelial growth factor signaling pathway, and adherens junction. These results enhance our understanding of different proteomes of human and bovine MFGM across different lactation phases, which could provide important information and potential directions for the infant milk powder and functional food industries.

The Co-Occurring Development of Executive Function Skills and Receptive Vocabulary in Preschool-Aged Children: A Look at the Direction of the Developmental Pathways

ERIC Educational Resources Information Center

Weiland, Christina; Barata, M. Clara; Yoshikawa, Hirokazu

2014-01-01

Despite consensus in the developmental literature regarding the role of executive function (EF) skills in supporting the development of language skills during the preschool years, we know relatively little about the associations between EF skills, including all EF components, and vocabulary skills among preschool-aged children. In this paper, we…

Asthma as a disruption in iron homeostasis | Science ...

EPA Pesticide Factsheets

Over several decades, asthma has evolved from being recognized as a single disease to include a diverse group of phenotypes with dissimilar natural histories, pathophysiologies, responses to treatment, and distinctive molecular pathways. With the application of Occam’s razor to asthma, it is proposed that there is one cause underlying the numerous phenotypes of this disease and that the responsible molecular pathway is a deficiency of iron in the lung tissues. This deficiency can be either absolute (e.g. asthma in the neonate and during both pregnancy and menstruation) or functional (e.g. asthma associated with infections, smoking, and obesity). Comparable associations between asthma co-morbidity (e.g. eczema, urticaria, restless leg syndrome, and pulmonary hypertension) with iron deficiency support such a shared mechanistic pathway. Therapies directed at asthma demonstrate a capacity to impact iron homeostasis, further strengthening the relationship. Finally, pathophysiologic events producing asthma, including inflammation, increases in Th2 cells, and muscle contraction, can correlate with iron availability. Recognition of a potential association between asthma and an absolute and/or functional iron deficiency suggests specific therapeutic interventions including inhaled iron. Asthma is a public health issue that has environmental triggers. Iron homeostasis is an essential mechanism whereby the body manages the impact of environmental agents on overall

Developmental pathways from prenatal marijuana exposure to Cannabis Use Disorder in young adulthood.

PubMed

Sonon, Kristen; Richardson, Gale A; Cornelius, Jack; Kim, Kevin H; Day, Nancy L

Earlier studies reported an association between prenatal marijuana exposure (PME) and cognitive and behavioral problems in the offspring. A recent publication demonstrated the relation between PME and offspring marijuana use at age 22. There are no reports of the association between PME and Cannabis Use Disorder (CUD) at 22years, the age when use of marijuana and CUD peak. Subjects are from the Maternal Health Practices and Child Development Study, a longitudinal study of PME and other exposures during pregnancy. The cohort of mothers and their offspring has been followed since the fourth prenatal month through 22years of age. A path analysis was conducted on 590 mother-child pairs, representing 77% of the birth cohort, to examine potential pathways from PME to CUD in offspring at 22years of age. There is no direct effect of PME on CUD. There are, however, two indirect pathways from PME to CUD. In the first, the pathway from PME to CUD goes through offspring early age of marijuana onset. In the second, offspring depression at age 10 and early age of marijuana onset predict CUD. Although there is no direct effect of PME on CUD, there are significant indirect pathways from PME to CUD that affect the rate of CUD in the population. Thus, PME, offspring depression, and an early age of marijuana initiation, are significant points for intervention. As marijuana is legalized in more states, the rates of marijuana use will increase significantly, including during pregnancy, and the consequences of the association between PME and CUD will become even more significant from a public health perspective. Copyright © 2016 Elsevier Inc. All rights reserved.

Site Environmental Report for Calendar Year 2000. DOE Operations at The Boeing Company, Rocketdyne Propulsion & Power

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

Rutherford, Phil; Samuels, Sandy; Lee, Majelle

2001-09-01

This Annual Site Environmental Report (ASER) for 2000 describes the environmental conditions related to work performed for the Department of Energy (DOE) at Area IV of the Rocketdyne Santa Susana Field Laboratory (SSFL). In the past, these operations included development, fabrication, and disassembly of nuclear reactors, reactor fuel, and other radioactive materials, under the former Atomics International (AI) Division. Other activities included the operation of large-scale liquid metal facilities for testing of liquid metal fast breeder components at the Energy Technology Engineering Center (ETEC), a government-owned company-operated, test facility within Area IV. All nuclear work was terminated in 1988, andmore » subsequently, all radiological work has been directed toward decontamination and decommissioning (D&D) of the previously used nuclear facilities and associated site areas. Large-scale D&D activities of the sodium test facilities began in 1996. Results of the radiological monitoring program for the calendar year of 2000 continue to indicate no significant releases of radioactive material from Rocketdyne sites. All potential exposure pathways are sampled and/or monitored, including air, soil, surface water, groundwater, direct radiation, transfer of property (land, structures, waste), and recycling. All radioactive wastes are processed for disposal at DOE disposal sites and other sites approved by DOE and licensed for radioactive waste. Liquid radioactive wastes are not released into the environment and do not constitute an exposure pathway.« less

Pericytes of the neurovascular unit: Key functions and signaling pathways

PubMed Central

Sweeney, Melanie D.; Ayyadurai, Shiva; Zlokovic, Berislav V.

2017-01-01

Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles, and post-capillary venules. The central nervous system (CNS) pericytes are uniquely positioned within the neurovascular unit between endothelial cells, astrocytes, and neurons. They integrate, coordinate, and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation, and stem cell activity. Here, we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes, and neurons that control neurovascular functions. We also review the role of pericytes in different CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies. PMID:27227366

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases.

PubMed

Choudhary, Mayur; Malek, Goldis

2016-12-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

PubMed Central

Choudhary, Mayur; Malek, Goldis

2017-01-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment. PMID:27455994

Does Breastfeeding Protect Against Childhood Obesity? Moving Beyond Observational Evidence.

PubMed

Woo, Jessica G; Martin, Lisa J

2015-06-01

Human milk is the optimal feeding choice for infants, as it dynamically provides the nutrients, immunity support, and other bioactive factors needed for infants at specific stages during development. Observational studies and several meta-analyses have suggested that breastfeeding is protective against development of obesity in childhood and beyond. However, these findings are not without significant controversy. This review includes an overview of observational findings to date, then focuses on three specific pathways that connect human milk and infant physiology: maternal obesity, microbiome development in the infant, and the development of taste preference and diet quality. Each of these pathways involves complex interactions between mother and infant, includes both biologic and non-biologic factors, and may have both direct and indirect effects on obesity risk in the offspring. This type of integrated approach to examining breastfeeding and childhood obesity is necessary to advance research in this area beyond observational findings.

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

PubMed

Peng, Changmin; Zhu, Yue; Zhang, Wanjun; Liao, Qinchao; Chen, Yali; Zhao, Xinyuan; Guo, Qiang; Shen, Pan; Zhen, Bei; Qian, Xiaohong; Yang, Dong; Zhang, Jin-San; Xiao, Dongguang; Qin, Weijie; Pei, Huadong

2017-11-02

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

A Weighted and Directed Interareal Connectivity Matrix for Macaque Cerebral Cortex

PubMed Central

Markov, N. T.; Ercsey-Ravasz, M. M.; Ribeiro Gomes, A. R.; Lamy, C.; Magrou, L.; Vezoli, J.; Misery, P.; Falchier, A.; Quilodran, R.; Gariel, M. A.; Sallet, J.; Gamanut, R.; Huissoud, C.; Clavagnier, S.; Giroud, P.; Sappey-Marinier, D.; Barone, P.; Dehay, C.; Toroczkai, Z.; Knoblauch, K.; Van Essen, D. C.; Kennedy, H.

2014-01-01

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks. PMID:23010748

Family boundary structures and child adjustment: the indirect role of emotional reactivity.

PubMed

Lindahl, Kristin M; Bregman, Hallie R; Malik, Neena M

2012-12-01

Structural and system theories propose that disruptions in family subsystem functioning increase risk for youth maladjustment. While there is growing evidence to support this proposition, studies that specifically focus on the larger family system remain relatively rare. Furthermore, the pathways that connect problems in family subsystem alliances to externalizing or internalizing problems in youth are as yet largely unexplored. This study examined youth emotional reactivity (anger and sadness) to family conflict as an indirect pathway of the association between family boundary disturbances and youth adjustment in a sample of two-parent families (N = 270). Observational coding was used to group families into Balanced, Dyadic, or Disengaged family alliance structures and to assess youth emotional reactivity, and parent-report was used to assess youth psychopathology. Structural equation modeling indicated both anger and sadness served as indirect pathways through which family boundary disturbances are linked with youth adjustment. In addition, gender was tested as a moderator and important gender differences were found. Specifically, boys were directly impacted by dyadic disturbances while girls were directly impacted by family disengagement. The findings help target goals for intervention and indicate that worthwhile objectives may include realigning family subsystem boundaries, changing family communication patterns, and improving affective coping skills for youth. PsycINFO Database Record (c) 2012 APA, all rights reserved.

Spatially-explicit life cycle assessment of sun-to-wheels transportation pathways in the U.S.

PubMed

Geyer, Roland; Stoms, David; Kallaos, James

2013-01-15

Growth in biofuel production, which is meant to reduce greenhouse gas (GHG) emissions and fossil energy demand, is increasingly seen as a threat to food supply and natural habitats. Using photovoltaics (PV) to directly convert solar radiation into electricity for battery electric vehicles (BEVs) is an alternative to photosynthesis, which suffers from a very low energy conversion efficiency. Assessments need to be spatially explicit, since solar insolation and crop yields vary widely between locations. This paper therefore compares direct land use, life cycle GHG emissions and fossil fuel requirements of five different sun-to-wheels conversion pathways for every county in the contiguous U.S.: Ethanol from corn or switchgrass for internal combustion vehicles (ICVs), electricity from corn or switchgrass for BEVs, and PV electricity for BEVs. Even the most land-use efficient biomass-based pathway (i.e., switchgrass bioelectricity in U.S. counties with hypothetical crop yields of over 24 tonnes/ha) requires 29 times more land than the PV-based alternative in the same locations. PV BEV systems also have the lowest life cycle GHG emissions throughout the U.S. and the lowest fossil fuel inputs, except for locations with hypothetical switchgrass yields of 16 or more tonnes/ha. Including indirect land use effects further strengthens the case for PV.

Deep Conservation of Genes Required for Both Drosophila melanogaster and Caenorhabditis elegans Sleep Includes a Role for Dopaminergic Signaling

PubMed Central

Singh, Komudi; Ju, Jennifer Y.; Walsh, Melissa B.; DiIorio, Michael A.; Hart, Anne C.

2014-01-01

Objectives: Cross-species conservation of sleep-like behaviors predicts the presence of conserved molecular mechanisms underlying sleep. However, limited experimental evidence of conservation exists. Here, this prediction is tested directly. Measurements and Results: During lethargus, Caenorhabditis elegans spontaneously sleep in short bouts that are interspersed with bouts of spontaneous locomotion. We identified 26 genes required for Drosophila melanogaster sleep. Twenty orthologous C. elegans genes were selected based on similarity. Their effect on C. elegans sleep and arousal during the last larval lethargus was assessed. The 20 most similar genes altered both the quantity of sleep and arousal thresholds. In 18 cases, the direction of change was concordant with Drosophila studies published previously. Additionally, we delineated a conserved genetic pathway by which dopamine regulates sleep and arousal. In C. elegans neurons, G-alpha S, adenylyl cyclase, and protein kinase A act downstream of D1 dopamine receptors to regulate these behaviors. Finally, a quantitative analysis of genes examined herein revealed that C. elegans arousal thresholds were directly correlated with amount of sleep during lethargus. However, bout duration varies little and was not correlated with arousal thresholds. Conclusions: The comprehensive analysis presented here suggests that conserved genes and pathways are required for sleep in invertebrates and, likely, across the entire animal kingdom. The genetic pathway delineated in this study implicates G-alpha S and previously known genes downstream of dopamine signaling in sleep. Quantitative analysis of various components of quiescence suggests that interdependent or identical cellular and molecular mechanisms are likely to regulate both arousal and sleep entry. Citation: Singh K, Ju JY, Walsh MB, Dilorio MA, Hart AC. Deep conservation of genes required for both Drosophila melanogaster and Caenorhabditis elegans sleep includes a role for dopaminergic signaling. SLEEP 2014;37(9):1439-1451. PMID:25142568

Different Roles of Direct and Indirect Frontoparietal Pathways for Individual Working Memory Capacity.

PubMed

Ekman, Matthias; Fiebach, Christian J; Melzer, Corina; Tittgemeyer, Marc; Derrfuss, Jan

2016-03-09

The ability to temporarily store and manipulate information in working memory is a hallmark of human intelligence and differs considerably across individuals, but the structural brain correlates underlying these differences in working memory capacity (WMC) are only poorly understood. In two separate studies, diffusion MRI data and WMC scores were collected for 70 and 109 healthy individuals. Using a combination of probabilistic tractography and network analysis of the white matter tracts, we examined whether structural brain network properties were predictive of individual WMC. Converging evidence from both studies showed that lateral prefrontal cortex and posterior parietal cortex of high-capacity individuals are more densely connected compared with low-capacity individuals. Importantly, our network approach was further able to dissociate putative functional roles associated with two different pathways connecting frontal and parietal regions: a corticocortical pathway and a subcortical pathway. In Study 1, where participants were required to maintain and update working memory items, the connectivity of the direct and indirect pathway was predictive of WMC. In contrast, in Study 2, where participants were required to maintain working memory items without updating, only the connectivity of the direct pathway was predictive of individual WMC. Our results suggest an important dissociation in the circuitry connecting frontal and parietal regions, where direct frontoparietal connections might support storage and maintenance, whereas subcortically mediated connections support the flexible updating of working memory content. Copyright © 2016 the authors 0270-6474/16/362894-10$15.00/0.

Novel Cysteine-Centered Sulfur Metabolic Pathway in the Thermotolerant Methylotrophic Yeast Hansenula polymorpha

PubMed Central

Oh, Doo-Byoung; Kwon, Ohsuk; Lee, Sang Yup; Sibirny, Andriy A.; Kang, Hyun Ah

2014-01-01

In yeast and filamentous fungi, sulfide can be condensed either with O-acetylhomoserine to generate homocysteine, the precursor of methionine, or with O-acetylserine to directly generate cysteine. The resulting homocysteine and cysteine can be interconverted through transsulfuration pathway. Here, we systematically analyzed the sulfur metabolic pathway of the thermotolerant methylotrophic yeast Hansenula polymorpha, which has attracted much attention as an industrial yeast strain for various biotechnological applications. Quite interestingly, the detailed sulfur metabolic pathway of H. polymorpha, which was reconstructed based on combined analyses of the genome sequences and validation by systematic gene deletion experiments, revealed the absence of de novo synthesis of homocysteine from inorganic sulfur in this yeast. Thus, the direct biosynthesis of cysteine from sulfide is the only pathway of synthesizing sulfur amino acids from inorganic sulfur in H. polymorpha, despite the presence of both directions of transsulfuration pathway Moreover, only cysteine, but no other sulfur amino acid, was able to repress the expression of a subset of sulfur genes, suggesting its central and exclusive role in the control of H. polymorpha sulfur metabolism. 35S-Cys was more efficiently incorporated into intracellular sulfur compounds such as glutathione than 35S-Met in H. polymorpha, further supporting the cysteine-centered sulfur pathway. This is the first report on the novel features of H. polymorpha sulfur metabolic pathway, which are noticeably distinct from those of other yeast and filamentous fungal species. PMID:24959887

Differential activation of human T cells to allogeneic endothelial cells, epithelial cells and fibroblasts in vitro

PubMed Central

2012-01-01

Background In the direct pathway, T cells recognize intact donor major histocompatability complexes and allogeneic peptide on the surface of donor antigen presenting cells (APCs). Indirect allorecognition results from the recognition of processed alloantigen by self MHC complexes on self APCs. In this study, we wished to evaluate the relative contribution of different intragraft cells to the alloactivation of nave and memory T cells though the direct and the indirect pathway of allorecognition. Methods The processing of membrane fragments from IFN-treated single donor endothelial cells (EC), fibroblasts or renal epithelial cells (RPTEC) was evaluated by DiOC labeling of each cell type and flow cytometry following interaction with PBMC. Direct pathway activation of nave CD45RA+ or memory CD45RO+ CD4+ T cells was evaluated following coculture with IFN-treated and MHC class II-expressing EC, fibroblasts or RPTEC. Indirect pathway activation was assessed using CD45RA+ or CD45RO+ CD4+ T cells cocultured with autologous irradiated APCs in the absence or presence of sonicates derived from IFN-treated allogeneic EC, fibroblasts or RPTEC. Activation of T cells was assessed by [3H]thymidine incorporation and by ELISpot assays. Results We find that CD14+ APCs readily acquire membrane fragments from fibroblasts and RPTEC, but fail to acquire membrane fragments from intact EC. However, APCs process membranes from EC undergoing apoptosis.There was a notable direct pathway alloproliferative response of CD45RO+ CD4+ T cells to IFN-treated EC, but not to fibroblasts or RPTEC. Also, there was a minimal direct pathway response of CD45RA+ CD4+ T cells to all cell types. In contrast, we found that both CD45RA+ and CD45RO+ CD4+ T cells proliferated following coculture with autologous APCs in the presence of sonicates derived from IFN-treated EC, fibroblasts or RPTEC. By ELISpot, we found that these T cells stimulated via the indirect pathway also produced the cytokines IFN, IL-2, IL-4 and IL-5. Conclusions Recipient APCs may readily process membrane fragments from allogeneic intragraft cells, but not from EC unless they are undergoing apoptosis. This processing is sufficient for indirect pathway alloactivation of both CD45RA+ and CD45RO+ CD4+ T cells. Only graft vascular EC mediate direct pathway reactivation of CD4+ T cells. PMID:23369287

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention.

PubMed

Cathcart, Mary-Clare; Lysaght, Joanne; Pidgeon, Graham P

2011-12-01

Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways leads to the generation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Eicosanoid expression levels vary during tumor development and progression of a range of malignancies, including colorectal cancer. The actions of these autocoids are also directly influenced by diet, as demonstrated by recent evidence for omega-3 fatty acids in colorectal cancer (CRC) prevention and/or treatment. Eicosanoids regulate CRC development and progression, while inhibition of these pathways has generally been shown to inhibit tumor growth/progression. A progressive sequence of colorectal cancer development has been identified, ranging from normal colon, to colitis, dysplasia, and carcinoma. While both COX and LOX inhibition are both promising candidates for colorectal cancer prevention and/or treatment, there is an urgent need to understand the mechanisms through which these signalling pathways mediate their effects on tumorigenesis. This will allow identification of safer, more effective strategies for colorectal cancer prevention and/or treatment. In particular, binding to/signalling through prostanoid receptors have recently been the subject of considerable interest in this area. In this review, we discuss the role of the eicosanoid signalling pathways in the development and progression of colorectal cancer. We discuss the effects of the eicosanoids on tumor cell proliferation, their roles in cell death induction, effects on angiogenesis, migration, invasion and their regulation of the immune response. Signal transduction pathways involved in these processes are also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of colorectal cancer are outlined.

ERK1/2/MAPK pathway-dependent regulation of the telomeric factor TRF2

PubMed Central

Picco, Vincent; Coste, Isabelle; Giraud-Panis, Marie-Josèphe; Renno, Toufic; Gilson, Eric; Pagès, Gilles

2016-01-01

Telomere stability is a hallmark of immortalized cells, including cancer cells. While the telomere length is maintained in most cases by the telomerase, the activity of a protein complex called Shelterin is required to protect telomeres against unsuitable activation of the DNA damage response pathway. Within this complex, telomeric repeat binding factor 2 (TRF2) plays an essential role by blocking the ataxia telangiectasia-mutated protein (ATM) signaling pathway at telomeres and preventing chromosome end fusion. We showed that TRF2 was phosphorylated in vitro and in vivo on serine 323 by extracellular signal-regulated kinase (ERK1/2) in both normal and cancer cells. Moreover, TRF2 and activated ERK1/2 unexpectedly interacted in the cytoplasm of tumor cells and human tumor tissues. The expression of non-phosphorylatable forms of TRF2 in melanoma cells induced the DNA damage response, leading to growth arrest and tumor reversion. These findings revealed that the telomere stability is under direct control of one of the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) via TRF2 phosphorylation. PMID:27366950

Obesity and psychiatric disorders: commonalities in dysregulated biological pathways and their implications for treatment.

PubMed

Lopresti, Adrian L; Drummond, Peter D

2013-08-01

Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus-pituitary-adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined. Copyright © 2013 Elsevier Inc. All rights reserved.

Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

PubMed

Lee, Erinna F; Clarke, Oliver B; Evangelista, Marco; Feng, Zhiping; Speed, Terence P; Tchoubrieva, Elissaveta B; Strasser, Andreas; Kalinna, Bernd H; Colman, Peter M; Fairlie, W Douglas

2011-04-26

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

PubMed Central

Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

2011-01-01

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment. PMID:21444803

Hippo, TGF-β, and Src-MAPK pathways regulate transcription of the upd3 cytokine in Drosophila enterocytes upon bacterial infection.

PubMed

Houtz, Philip; Bonfini, Alessandro; Liu, Xi; Revah, Jonathan; Guillou, Aurélien; Poidevin, Mickael; Hens, Korneel; Huang, Hsin-Yi; Deplancke, Bart; Tsai, Yu-Chen; Buchon, Nicolas

2017-11-01

Cytokine signaling is responsible for coordinating conserved epithelial regeneration and immune responses in the digestive tract. In the Drosophila midgut, Upd3 is a major cytokine, which is induced in enterocytes (EC) and enteroblasts (EB) upon oral infection, and initiates intestinal stem cell (ISC) dependent tissue repair. To date, the genetic network directing upd3 transcription remains largely uncharacterized. Here, we have identified the key infection-responsive enhancers of the upd3 gene and show that distinct enhancers respond to various stresses. Furthermore, through functional genetic screening, bioinformatic analyses and yeast one-hybrid screening, we determined that the transcription factors Scalloped (Sd), Mothers against dpp (Mad), and D-Fos are principal regulators of upd3 expression. Our study demonstrates that upd3 transcription in the gut is regulated by the activation of multiple pathways, including the Hippo, TGF-β/Dpp, and Src, as well as p38-dependent MAPK pathways. Thus, these essential pathways, which are known to control ISC proliferation cell-autonomously, are also activated in ECs to promote tissue turnover the regulation of upd3 transcription.

Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch

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

Howe, John A.; Xiao, Li; Fischmann, Thierry O.

2016-08-02

Bacterial riboswitches are non-coding RNA structural elements that direct gene expression in numerous metabolic pathways. The key regulatory roles of riboswitches, and the urgent need for new classes of antibiotics to treat multi-drug resistant bacteria, has led to efforts to develop small-molecules that mimic natural riboswitch ligands to inhibit metabolic pathways and bacterial growth. Recently, we reported the results of a phenotypic screen targeting the riboflavin biosynthesis pathway in the Gram-negative bacteria Escherichia coli that led to the identification of ribocil, a small molecule inhibitor of the flavin mononucleotide (FMN) riboswitch controlling expression of this biosynthetic pathway. Although ribocil ismore » structurally distinct from FMN, ribocil functions as a potent and highly selective synthetic mimic of the natural ligand to repress riboswitch-mediated ribB gene expression and inhibit bacterial growth both in vitro and in vivo. Herein, we expand our analysis of ribocil; including mode of binding in the FMN binding pocket of the riboswitch, mechanisms of resistance and structure-activity relationship guided efforts to generate more potent analogs.« less

Feasibility of a physical activity pathway for Irish primary care physiotherapy services.

PubMed

Barrett, Emer M; Hussey, Juliette; Darker, Catherine D

2017-03-01

To establish consensus on a physical activity pathway suitable for use by physiotherapists in Irish primary care. The physical activity pathway "Let's Get Moving" was examined to agree recruitment criteria and seek consensus on component parts. Modified Delphi approach which attempts to achieve a convergence of opinion, over a series of iterations. Three rounds of questionnaires were used. Primary care. 41 senior physiotherapists working in primary care for a median of 6 years (IQR 3.7 to 8.5). Statements achieving consensus; defined as at least 70% of participants scoring a 6 or a 7, indicating high agreement, on a 7 point Likert scale. The response rate was 98%. There was a high degree of consensus for many components of the pathway. Participants agreed that all patients attending physiotherapy should be eligible for recruitment onto the pathway as well as accepting referrals from other health professionals and direct access from the public. Private physiotherapists highlighted concerns about recruiting fee paying patients onto the pathway. The pathway should be integrated into other preventative and chronic disease programmes in primary care. Modifications to the original pathway included the use of a pedometer in addition to the General Practice Physical Activity Questionnaire. Training needs in physical activity screening and motivational interviewing, as well as additional staffing were identified to support implementation. The Physical Activity Pathway "Let's Get Moving" was accepted as a clinically feasible resource to primary care physiotherapists with some modifications and with the support of additional resources. Copyright © 2016 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Toward industrial production of isoprenoids in Escherichia coli: Lessons learned from CRISPR-Cas9 based optimization of a chromosomally integrated mevalonate pathway.

PubMed

Alonso-Gutierrez, Jorge; Koma, Daisuke; Hu, Qijun; Yang, Yuchen; Chan, Leanne J G; Petzold, Christopher J; Adams, Paul D; Vickers, Claudia E; Nielsen, Lars K; Keasling, Jay D; Lee, Taek S

2018-04-01

Escherichia coli has been the organism of choice for the production of different chemicals by engineering native and heterologous pathways. In the present study, we simultaneously address some of the main issues associated with E. coli as an industrial platform for isoprenoids, including an inability to grow on sucrose, a lack of endogenous control over toxic mevalonate (MVA) pathway intermediates, and the limited pathway engineering into the chromosome. As a proof of concept, we generated an E. coli DH1 strain able to produce the isoprenoid bisabolene from sucrose by integrating the cscAKB operon into the chromosome and by expressing a heterologous MVA pathway under stress-responsive control. Production levels dropped dramatically relative to plasmid-mediated expression when the entire pathway was integrated into the chromosome. In order to optimize the chromosomally integrated MVA pathway, we established a CRISPR-Cas9 system to rapidly and systematically replace promoter sequences. This strategy led to higher pathway expression and a fivefold improvement in bisabolene production. More interestingly, we analyzed proteomics data sets to understand and address some of the challenges associated with metabolic engineering of the chromosomally integrated pathway. This report shows that integrating plasmid-optimized operons into the genome and making them work optimally is not a straightforward task and any poor engineering choices on the chromosome may lead to cell death rather than just resulting in low titers. Based on these results, we also propose directions for chromosomal metabolic engineering. © 2017 Wiley Periodicals, Inc.

mir-30d Regulates multiple genes in the autophagy pathway and impairs autophagy process in human cancer cells

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

Yang, Xiaojun; Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 710000; Zhong, Xiaomin

2013-02-15

Highlights: ► Gene set enrichment analysis indicated mir-30d might regulate the autophagy pathway. ► mir-30d represses the expression of BECN1, BNIP3L, ATG12, ATG5 and ATG2. ► BECN1, BNIP3L, ATG12, ATG5 and ATG2 are direct targets of mir-30d. ► mir-30d inhibits autophagosome formation and LC3B-I conversion to LC3B-II. ► mir-30d regulates the autophagy process. -- Abstract: In human epithelial cancers, the microRNA (miRNA) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis, apoptosis, proliferation, and differentiation. Autophagy, a degradation pathway for long-lived protein and organelles, regulates the survival and death of many cell types. Increasingmore » evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression. Using a combined bioinformatics approach, gene set enrichment analysis, and miRNA target prediction, we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1, BNIP3L, ATG12, ATG5, and ATG2. Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells. Finally, we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II. Taken together, our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway. This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy.« less

CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea

PubMed Central

Marraffini, Luciano A.; Sontheimer, Erik J.

2010-01-01

Sequence-directed genetic interference pathways control gene expression and preserve genome integrity in all kingdoms of life. The importance of such pathways is highlighted by the extensive study of RNA interference (RNAi) and related processes in eukaryotes. In many bacteria and most archaea, clustered, regularly interspaced short palindromic repeats (CRISPRs) are involved in a more recently discovered interference pathway that protects cells from bacteriophages and conjugative plasmids. CRISPR sequences provide an adaptive, heritable record of past infections and express CRISPR RNAs — small RNAs that target invasive nucleic acids. Here, we review the mechanisms of CRISPR interference and its roles in microbial physiology and evolution. We also discuss potential applications of this novel interference pathway. PMID:20125085

DISCO interacting protein 2 determines direction of axon projection under the regulation of c-Jun N-terminal kinase in the Drosophila mushroom body

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

Nitta, Yohei; Brain Research Institute, Niigata University; Sugie, Atsushi

Precisely controlled axon guidance for complex neuronal wiring is essential for appropriate neuronal function. c-Jun N-terminal kinase (JNK) was found to play a role in axon guidance recently as well as in cell proliferation, protection and apoptosis. In spite of many genetic and molecular studies on these biological processes regulated by JNK, how JNK regulates axon guidance accurately has not been fully explained thus far. To address this question, we use the Drosophila mushroom body (MB) as a model since the α/β axons project in two distinct directions. Here we show that DISCO interacting protein 2 (DIP2) is required formore » the accurate direction of axonal guidance. DIP2 expression is under the regulation of Basket (Bsk), the Drosophila homologue of JNK. We additionally found that the Bsk/DIP2 pathway is independent from the AP-1 transcriptional factor complex pathway, which is directly activated by Bsk. In conclusion, our findings revealed DIP2 as a novel effector downstream of Bsk modulating the direction of axon projection. - Highlights: • DIP2 is required for accurate direction of axon guidance in Drosophila mushroom body. • DIP2 is a downstream of JNK in the axon guidance of Drosophila mushroom body neuron. • JNK/DIP2 pathway is independent from JNK/AP-1 transcriptional factor complex pathway.« less

Basal Ganglia Disorders Associated with Imbalances in the Striatal Striosome and Matrix Compartments

PubMed Central

Crittenden, Jill R.; Graybiel, Ann M.

2011-01-01

The striatum is composed principally of GABAergic, medium spiny striatal projection neurons (MSNs) that can be categorized based on their gene expression, electrophysiological profiles, and input–output circuits. Major subdivisions of MSN populations include (1) those in ventromedial and dorsolateral striatal regions, (2) those giving rise to the direct and indirect pathways, and (3) those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input–output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia, and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in these disorders. PMID:21941467

RNF11 is a multifunctional modulator of growth factor receptor signalling and transcriptional regulation.

PubMed

Azmi, Peter; Seth, Arun

2005-11-01

Our laboratory has found that the 154aa RING finger protein 11 (RNF11), has modular domains and motifs including a RING-H2 finger domain, a PY motif, an ubiquitin interacting motif (UIM), a 14-3-3 binding sequence and an AKT phosphorylation site. RNF11 represents a unique protein with no other known immediate family members yet described. Comparative genetic analysis has shown that RNF11 is highly conserved throughout evolution. This may indicate a conserved and non-redundant role for the RNF11 protein. Molecular binding assays using RNF11 have shown that RNF11 has important roles in growth factor signalling, ubiquitination and transcriptional regulation. RNF11 has been shown to interact with HECT-type E3 ubiquitin ligases Nedd4, AIP4, Smurf1 and Smurf2, as well as with Cullin1, the core protein in the multi-subunit SCF E3 ubiquitin ligase complex. Work done in our laboratory has shown that RNF11 is capable of antagonizing Smurf2-mediated inhibition of TGFbeta signalling. Furthermore, RNF11 is capable of degrading AMSH, a positive regulator of both TGFbeta and EGFR signalling pathways. Recently, we have found that RNF11 can directly enhance TGFbeta signalling through a direct association with Smad4, the common signal transducer and transcription factor in the TGFbeta, BMP, and Activin pathways. Through its association with Smad4 and other transcription factors, RNF11 may have a role in direct transcriptional regulation. Our laboratory and others have found nearly 80 protein interactions for RNF11, placing RNF11 at the cross-roads of cell signalling and transcriptional regulation. RNF11 is highly expressed in breast tumours. Deregulation of RNF11 function may prove to be harmful to patient therapeutic outcomes. RNF11 may therefore provide a novel target for cancer therapeutics. The purpose of this review is to discuss the role of RNF11 in cell signalling and transcription factor modulation with special attention given to the ubiquitin-proteasomal pathway, TGFbeta pathway and EGFR pathway.

Wnt ligands from the embryonic surface ectoderm regulate ‘bimetallic strip’ optic cup morphogenesis in mouse

PubMed Central

Carpenter, April C.; Smith, April N.; Wagner, Heidi; Cohen-Tayar, Yamit; Rao, Sujata; Wallace, Valerie; Ashery-Padan, Ruth; Lang, Richard A.

2015-01-01

The Wnt/β-catenin response pathway is central to many developmental processes. Here, we assessed the role of Wnt signaling in early eye development using the mouse as a model system. We showed that the surface ectoderm region that includes the lens placode expressed 12 out of 19 possible Wnt ligands. When these activities were suppressed by conditional deletion of wntless (Le-cre; Wlsfl/fl) there were dramatic consequences that included a saucer-shaped optic cup, ventral coloboma, and a deficiency of periocular mesenchyme. This phenotype shared features with that produced when the Wnt/β-catenin pathway co-receptor Lrp6 is mutated or when retinoic acid (RA) signaling in the eye is compromised. Consistent with this, microarray and cell fate marker analysis identified a series of expression changes in genes known to be regulated by RA or by the Wnt/β-catenin pathway. Using pathway reporters, we showed that Wnt ligands from the surface ectoderm directly or indirectly elicit a Wnt/β-catenin response in retinal pigment epithelium (RPE) progenitors near the optic cup rim. In Le-cre; Wlsfl/fl mice, the numbers of RPE cells are reduced and this can explain, using the principle of the bimetallic strip, the curvature of the optic cup. These data thus establish a novel hypothesis to explain how differential cell numbers in a bilayered epithelium can lead to shape change. PMID:25715397

Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining.

PubMed

Tang, Xiaoyu; Li, Jie; Millán-Aguiñaga, Natalie; Zhang, Jia Jia; O'Neill, Ellis C; Ugalde, Juan A; Jensen, Paul R; Mantovani, Simone M; Moore, Bradley S

2015-12-18

Recent genome sequencing efforts have led to the rapid accumulation of uncharacterized or "orphaned" secondary metabolic biosynthesis gene clusters (BGCs) in public databases. This increase in DNA-sequenced big data has given rise to significant challenges in the applied field of natural product genome mining, including (i) how to prioritize the characterization of orphan BGCs and (ii) how to rapidly connect genes to biosynthesized small molecules. Here, we show that by correlating putative antibiotic resistance genes that encode target-modified proteins with orphan BGCs, we predict the biological function of pathway specific small molecules before they have been revealed in a process we call target-directed genome mining. By querying the pan-genome of 86 Salinispora bacterial genomes for duplicated house-keeping genes colocalized with natural product BGCs, we prioritized an orphan polyketide synthase-nonribosomal peptide synthetase hybrid BGC (tlm) with a putative fatty acid synthase resistance gene. We employed a new synthetic double-stranded DNA-mediated cloning strategy based on transformation-associated recombination to efficiently capture tlm and the related ttm BGCs directly from genomic DNA and to heterologously express them in Streptomyces hosts. We show the production of a group of unusual thiotetronic acid natural products, including the well-known fatty acid synthase inhibitor thiolactomycin that was first described over 30 years ago, yet never at the genetic level in regards to biosynthesis and autoresistance. This finding not only validates the target-directed genome mining strategy for the discovery of antibiotic producing gene clusters without a priori knowledge of the molecule synthesized but also paves the way for the investigation of novel enzymology involved in thiotetronic acid natural product biosynthesis.

Direct Oral Anticoagulants: An Overview for the Interventional Radiologist

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

Kumar, Pradesh, E-mail: pradeshkumar@doctors.org.uk; Ravi, Rajeev, E-mail: rajeev.ravi@aintree.nhs.uk; Sundar, Gaurav, E-mail: gaurav.sundar@aintree.nhs.uk

The direct oral anticoagulants (DOACs) have emerged as a good alternative for the treatment of thromboembolic diseases, and their use in clinical practice is increasing rapidly. The DOACs act by blocking the activity of one single step in the coagulation cascade. These drugs act downstream in the common pathway of the coagulation cascade by directly antagonising the action of thrombin or factor Xa. The development of DOACs represents a paradigm shift from the oral vitamin K antagonists such as warfarin. This article aims to describe the properties of the currently available DOACs including pharmacology and dosing. We also address themore » strategies for periprocedural management and reversal of anticoagulation of patients treated with these agents.« less

Visual probes and methods for placing visual probes into subsurface areas

DOEpatents

Clark, Don T.; Erickson, Eugene E.; Casper, William L.; Everett, David M.

2004-11-23

Visual probes and methods for placing visual probes into subsurface areas in either contaminated or non-contaminated sites are described. In one implementation, the method includes driving at least a portion of a visual probe into the ground using direct push, sonic drilling, or a combination of direct push and sonic drilling. Such is accomplished without providing an open pathway for contaminants or fugitive gases to reach the surface. According to one implementation, the invention includes an entry segment configured for insertion into the ground or through difficult materials (e.g., concrete, steel, asphalt, metals, or items associated with waste), at least one extension segment configured to selectively couple with the entry segment, at least one push rod, and a pressure cap. Additional implementations are contemplated.

Designing On-Demand Education for Simultaneous Development of Domain-Specific and Self-Directed Learning Skills

ERIC Educational Resources Information Center

Taminiau, E. M. C.; Kester, L.; Corbalan, G.; Spector, J. M.; Kirschner, P. A.; Van Merriënboer, J. J. G.

2015-01-01

On-demand education enables individual learners to choose their learning pathways according to their own learning needs. They must use self-directed learning (SDL) skills involving self-assessment and task selection to determine appropriate pathways for learning. Learners who lack these skills must develop them because SDL skills are prerequisite…

In situ Proteomic Profiling of Curcumin Targets in HCT116 Colon Cancer Cell Line.

PubMed

Wang, Jigang; Zhang, Jianbin; Zhang, Chong-Jing; Wong, Yin Kwan; Lim, Teck Kwang; Hua, Zi-Chun; Liu, Bin; Tannenbaum, Steven R; Shen, Han-Ming; Lin, Qingsong

2016-02-26

To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQ(TM) quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway Analysis(TM) (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death.

In situ Proteomic Profiling of Curcumin Targets in HCT116 Colon Cancer Cell Line

PubMed Central

Wang, Jigang; Zhang, Jianbin; Zhang, Chong-Jing; Wong, Yin Kwan; Lim, Teck Kwang; Hua, Zi-Chun; Liu, Bin; Tannenbaum, Steven R.; Shen, Han-Ming; Lin, Qingsong

2016-01-01

To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQTM quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway AnalysisTM (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death. PMID:26915414

THE DEVELOPMENT OF SEXUAL DIMORPHISM: STUDIES OF THE C. ELEGANS MALE

PubMed Central

Emmons, Scott W.

2014-01-01

Studies of the development of the C. elegans male have been carried out with the aim of understanding the basis of sexual dimorphism. Postembryonic development of the two C. elegans sexes differs extensively. Development along either the hermaphrodite or male pathway is specified initially by the X to autosome ratio. The regulatory events initiated by this ratio include a male-determining paracrine intercellular signal. Expression of this signal leads to different consequences in three regions of the body: the non-gonadal soma, the somatic parts of the gonad, and the germ line. In the non-gonadal soma, activity of the key Zn-finger transcription factor TRA 1 determines hermaphrodite development; in its absence, the male pathway is followed. Only a few genes directly regulated by TRA 1 are currently known, including members of the evolutionarily conserved, male-determining DM domain Zn-finger transcription factors. In the somatic parts of the gonad and germ line, absence of TRA 1 activity is not sufficient for full expression of the male pathway. Several additional transcription factors involved have been identified. In the germ line, regulatory genes for sperm development that act at the level of RNA in the cytoplasm play a prominent role. PMID:25262817

Overlapping the Tryptophan Catabolite (TRYCAT) and Melatoninergic Pathways in Alzheimer's Disease.

PubMed

Maes, Michael; Anderson, George

2016-01-01

Activation of the trptophan catabolite (TRYCAT) pathways by oxidative and nitrosative stress and proinflammatory cytokine-driven indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) leads to the synthesis of a number of neuroregulatory TRYCATs, such as kynurenic acid and quinolinic acid. Such TRYCATs have significant impacts on neuronal functioning and survival contributing to the changes seen in Alzheimer's disease (AD), including in its association with depression as well as alterations in the reactivity of immune and glia cells. By decreasing the availability of tryptophan for serotonin synthesis, such IDO and TDO-driven TRYCATs, also decrease the availability of serotonin for N-acetylserotonin (NAS) and melatonin synthesis. The loss of NAS and melatonin has significant consequences for the etiology, course and treatment of AD, including via interactions with altered TRYCATs, but also by changing the levels of trophic support and modulating the patterning of immune activity. In this review, we look at how such interactions of the TRYCAT and melatoninergic pathways link a plethora of previously diffuse data in AD as well as the treatment implications and future research directions that such data would suggest.

p205, a potential tumor suppressor, inhibits cell proliferation via multiple pathways of cell cycle regulation.

PubMed

Asefa, Benyam; Dermott, Jonathan M; Kaldis, Philipp; Stefanisko, Karen; Garfinkel, David J; Keller, Jonathan R

2006-02-20

p205 is a member of the interferon-inducible p200 family of proteins that regulate cell proliferation. Over-expression of p205 inhibits cell growth, although its mechanism of action is currently unknown. Therefore, we evaluated the effect of p205 on the p53 and Rb-dependent pathways of cell cycle regulation. p205 expression results in elevated levels of p21, and activates the p21 promoter in vitro in a p53-dependent manner. In addition, p205 induces increased expression of Rb, and binds directly to Rb and p53. Interestingly, p205 also induces growth inhibition independent of p53 and Rb by delaying G2/M progression in proliferating cells, and is a substrate for Cdk2 kinase activity. Finally, we have identified other binding partners of p205 by a yeast two-hybrid screen, including the paired homeodomain protein HoxB2. Taken together, our results indicate that p205 induces growth arrest by interaction with multiple transcription factors that regulate the cell cycle, including but not entirely dependent on the Rb- and p53-mediated pathways of growth inhibition.

Biotransformation pathways of fluorotelomer-based polyfluoroalkyl substances: a review.

PubMed

Butt, Craig M; Muir, Derek C G; Mabury, Scott A

2014-02-01

The study reviews the current state of knowledge regarding the biotransformation of fluorotelomer-based compounds, with a focus on compounds that ultimately degrade to form perfluoroalkyl carboxylates (PFCAs). Most metabolism studies have been performed with either microbial systems or rats and mice, and comparatively few studies have used fish models. Furthermore, biotransformation studies thus far have predominately used the 8:2 fluorotelomer alcohol (FTOH) as the substrate. However, there have been an increasing number of studies investigating 6:2 FTOH biotransformation as a result of industry's transition to shorter-chain fluorotelomer chemistry. Studies with the 8:2 FTOH metabolism universally show the formation of perfluorooctanoate (PFOA) and, to a smaller fraction, perfluorononanoate (PFNA) and lower-chain-length PFCAs. In general, the overall yield of PFOA is low, presumably because of the multiple branches in the biotransformation pathways, including conjugation reactions in animal systems. There have been a few studies of non-FTOH biotransformation, which include polyfluoroalkyl phosphates (PAPs), 8:2 fluorotelomer acrylate (8:2 FTAC), and fluorotelomer carboxylates (FTCAs, FTUCAs). The PAPs compounds and 8:2 FTAC were shown to be direct precursors to FTOHs and thus follow similar degradation pathways. © 2013 SETAC.

Innervation of Extrahepatic Biliary Tract, With Special Reference to the Direct Bidirectional Neural Connections of the Gall Bladder, Sphincter of Oddi and Duodenum in Suncus murinus, in Whole-Mount Immunohistochemical Study.

PubMed

Yi, S-Q; Ren, K; Kinoshita, M; Takano, N; Itoh, M; Ozaki, N

2016-06-01

Sphincter of Oddi dysfunction is one of the most important symptoms in post-cholecystectomy syndrome. Using either electrical or mechanical stimulation and retrogradely transported neuronal dyes, it has been demonstrated that there are direct neural pathways connecting gall bladder and the sphincter of Oddi in the Australian opossum and the golden hamster. In the present study, we employed whole-mount immunohistochemistry staining to observe and verify that there are two different plexuses of the extrahepatic biliary tract in Suncus murinus. One, named Pathway One, showed a fine, irregular but dense network plexus that ran adhesively and resided on/in the extrahepatic biliary tract wall, and the plexus extended into the intrahepatic area. On the other hand, named Pathway Two, exhibiting simple, thicker and straight neural bundles, ran parallel to the surface of the extrahepatic biliary tract and passed between the gall bladder and duodenum, but did not give off any branches to the liver. Pathway Two was considered to involve direct bidirectional neural connections between the duodenum and the biliary tract system. For the first time, morphologically, we demonstrated direct neural connections between gall bladder and duodenum in S. murinus. Malfunction of the sphincter of Oddi may be caused by injury of the direct neural pathways between gall bladder and duodenum by cholecystectomy. From the viewpoint of preserving the function of the major duodenal papilla and common bile duct, we emphasize the importance of avoiding kocherization of the common bile duct so as to preserve the direct neural connections between gall bladder and sphincter of Oddi. © 2015 Blackwell Verlag GmbH.

Kisspeptin and energy balance in reproduction.

PubMed

De Bond, Julie-Ann P; Smith, Jeremy T

2014-03-01

Kisspeptin is vital for the neuroendocrine regulation of GNRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GNRH neurons. This pathway is likely to mediate the well-established link between energy balance and reproductive function. Thus, in states of severely altered energy balance (either negative or positive), fertility is compromised, as is Kiss1 expression in the arcuate nucleus. A number of metabolic modulators have been proposed as regulators of kisspeptin neurons including leptin, ghrelin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY). Whether these regulate kisspeptin neurons directly or indirectly will be discussed. Moreover, whether the stimulatory role of leptin on reproduction is mediated by kisspeptin directly will be questioned. Furthermore, in addition to being expressed in GNRH neurons, the kisspeptin receptor (Kiss1r) is also expressed in other areas of the brain, as well as in the periphery, suggesting alternative roles for kisspeptin signaling outside of reproduction. Interestingly, kisspeptin neurons are anatomically linked to, and can directly excite, anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, kisspeptin may have a direct role in regulating energy balance. Although data from Kiss1r knockout and WT mice found no differences in body weight, recent data indicate that kisspeptin may still play a role in food intake and glucose homeostasis. Thus, in addition to regulating reproduction, and mediating the effect of energy balance on reproductive function, kisspeptin signaling may also be a direct regulator of metabolism.

Automatically visualise and analyse data on pathways using PathVisioRPC from any programming environment.

PubMed

Bohler, Anwesha; Eijssen, Lars M T; van Iersel, Martijn P; Leemans, Christ; Willighagen, Egon L; Kutmon, Martina; Jaillard, Magali; Evelo, Chris T

2015-08-23

Biological pathways are descriptive diagrams of biological processes widely used for functional analysis of differentially expressed genes or proteins. Primary data analysis, such as quality control, normalisation, and statistical analysis, is often performed in scripting languages like R, Perl, and Python. Subsequent pathway analysis is usually performed using dedicated external applications. Workflows involving manual use of multiple environments are time consuming and error prone. Therefore, tools are needed that enable pathway analysis directly within the same scripting languages used for primary data analyses. Existing tools have limited capability in terms of available pathway content, pathway editing and visualisation options, and export file formats. Consequently, making the full-fledged pathway analysis tool PathVisio available from various scripting languages will benefit researchers. We developed PathVisioRPC, an XMLRPC interface for the pathway analysis software PathVisio. PathVisioRPC enables creating and editing biological pathways, visualising data on pathways, performing pathway statistics, and exporting results in several image formats in multiple programming environments. We demonstrate PathVisioRPC functionalities using examples in Python. Subsequently, we analyse a publicly available NCBI GEO gene expression dataset studying tumour bearing mice treated with cyclophosphamide in R. The R scripts demonstrate how calls to existing R packages for data processing and calls to PathVisioRPC can directly work together. To further support R users, we have created RPathVisio simplifying the use of PathVisioRPC in this environment. We have also created a pathway module for the microarray data analysis portal ArrayAnalysis.org that calls the PathVisioRPC interface to perform pathway analysis. This module allows users to use PathVisio functionality online without having to download and install the software and exemplifies how the PathVisioRPC interface can be used by data analysis pipelines for functional analysis of processed genomics data. PathVisioRPC enables data visualisation and pathway analysis directly from within various analytical environments used for preliminary analyses. It supports the use of existing pathways from WikiPathways or pathways created using the RPC itself. It also enables automation of tasks performed using PathVisio, making it useful to PathVisio users performing repeated visualisation and analysis tasks. PathVisioRPC is freely available for academic and commercial use at http://projects.bigcat.unimaas.nl/pathvisiorpc.

Direct uptake and degradation of DNA by lysosomes

PubMed Central

Fujiwara, Yuuki; Kikuchi, Hisae; Aizawa, Shu; Furuta, Akiko; Hatanaka, Yusuke; Konya, Chiho; Uchida, Kenko; Wada, Keiji; Kabuta, Tomohiro

2013-01-01

Lysosomes contain various hydrolases that can degrade proteins, lipids, nucleic acids and carbohydrates. We recently discovered “RNautophagy,” an autophagic pathway in which RNA is directly taken up by lysosomes and degraded. A lysosomal membrane protein, LAMP2C, a splice variant of LAMP2, binds to RNA and acts as a receptor for this pathway. In the present study, we show that DNA is also directly taken up by lysosomes and degraded. Like RNautophagy, this autophagic pathway, which we term “DNautophagy,” is dependent on ATP. The cytosolic sequence of LAMP2C also directly interacts with DNA, and LAMP2C functions as a receptor for DNautophagy, in addition to RNautophagy. Similarly to RNA, DNA binds to the cytosolic sequences of fly and nematode LAMP orthologs. Together with the findings of our previous study, our present findings suggest that RNautophagy and DNautophagy are evolutionarily conserved systems in Metazoa. PMID:23839276

Informatics approaches in the Biological Characterization of Adverse Outcome Pathways

EPA Science Inventory

Adverse Outcome Pathways (AOPs) are a conceptual framework to characterize toxicity pathways by a series of mechanistic steps from a molecular initiating event to population outcomes. This framework helps to direct risk assessment research, for example by aiding in computational ...

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT

NASA Astrophysics Data System (ADS)

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-07-01

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT.

PubMed

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-07-16

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.

Probing the Pathways and Interactions Controlling Crystallization by Particle Attachment

NASA Astrophysics Data System (ADS)

De Yoreo, J. J.; Li, D.; Chun, J.; Schenter, G.; Mundy, C.; Rosso, K. M.

2016-12-01

Crystallization by particle attachment appears to be a widespread mechanism of mineralization. Yet many long-standing questions surrounding nucleation and assembly of precursor particles remain unanswered, due in part to a lack of tools to probe mineralization dynamics with adequate spatial and temporal resolution. Here we report results of liquid phase TEM studies of nucleation and particle assembly in a number of mineral systems. We interpret the results within a framework that considers the impact of both the complexity of free energy landscapes and kinetic factors associated with high supersaturation or slow dynamics. In the calcium carbonate system, the need for high supersturations to overcome the high barrier to nucleation of calcite leads to simultaneous occurrence of multiple pathways, including direct formation of all the common ploymorphs, as well as two-step pathways through which initial precursors, particularly ACC, undergo a direct transformation to a more stable phase. Introduction of highly charged polymers that bind calcium inhibits nucleation, but directs the pathway to a metastable amorphous phase that no longer transforms to more stable polymorphs. Experiments in the iron oxide and oxyhydroxide systems show that, when high supersaturations lead to nucleation of many nanoprticles, further growth occurs through a combination of particle aggregation events and Ostwald ripening. In some cases, aggregation occurs only through oriented attachment on lattice matched faces, leading to single crystals with complex topologies and internal twin boundaries, while in others aggregation results initially in poor co-alignment, but over time the particles undergo atomic rearrangements to achieve a single crystal structure. AFM-based measurements of forces between phyllosilicate surfaces reveal the importance of long-range dispersion interactions in driving alignment, as well as the impact of electrolyte concentration and temperature on the competition of those attractive forces with repulsive electrostatic interactions. Taken together, the results help to define an emerging framework for understanding crystallization by particle attachment.

How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension

PubMed Central

Leenen, Frans H. H.; Chen, Ling; Golovina, Vera A.; Hamlyn, John M.; Pallone, Thomas L.; Van Huysse, James W.; Zhang, Jin; Wier, W. Gil

2012-01-01

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na+ and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na+]. This leads, via the Na+-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na+ pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na+]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na+ channels, EO, ouabain-sensitive α2 Na+ pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na+ channel-EO-α2 Na+ pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α2 Na+ pump-Na+/Ca2+ exchanger-Ca2+ signaling pathway. Circulating EO also activates an EO-α2 Na+ pump-Src kinase signaling cascade. This increases the expression of the Na+/Ca2+ exchanger-transient receptor potential cation channel Ca2+ signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP. PMID:22058154

Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

PubMed Central

Drago, J; Gerfen, C R; Lachowicz, J E; Steiner, H; Hollon, T R; Love, P E; Ooi, G T; Grinberg, A; Lee, E J; Huang, S P

1994-01-01

Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway. Images Fig. 2 Fig. 4 PMID:7809078

Stem cells: Balancing resistance and sensitivity to DNA damage

PubMed Central

Liu, Julia C.; Lerou, Paul H.; Lahav, Galit

2015-01-01

Embryonic stem cells are known to be very sensitive to DNA damage and undergo rapid apoptosis even after low damage doses. In contrast, adult stem cells show variable sensitivity to damage. Here we describe the multiple pathways that have been proposed to affect the sensitivity of stem cells to damage, including proximity to the apoptotic threshold (mitochondrial priming) and the p53 signaling pathway, through activation of transcription or direct interaction with pro apoptotic proteins in the cytoplasm. We also discuss which cellular factors might connect mitochondrial priming with pluripotency and the potential therapeutic advances that can be achieved by better understanding the molecular mechanisms leading to sensitivity or resistance of embryonic or adult stem cells from different tissues. PMID:24721782

Regulation of gonadotropin-releasing hormone neurons by glucose

PubMed Central

Roland, Alison V.; Moenter, Suzanne M.

2011-01-01

Reproduction is influenced by energy balance, but the physiological pathways mediating their relationship have not been fully elucidated. As the central regulators of fertility, gonadotropin-releasing hormone (GnRH) neurons integrate numerous physiological signals, including metabolic cues. Circulating glucose levels regulate GnRH release and may in part mediate the effects of negative energy balance on fertility. Existing evidence suggests that neural pathways originating in the hindbrain, as well as in the hypothalamic feeding nuclei, transmit information concerning glucose availability to GnRH neurons. Here we review recent evidence suggesting that GnRH neurons may directly sense changes in glucose availability by a mechanism involving adenosine monophosphate-activated protein kinase (AMPK). These findings expand our understanding of how metabolic signaling in the brain regulates reproduction. PMID:21855365

Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.

PubMed

Li, Yanyan; Wicha, Max S; Schwartz, Steven J; Sun, Duxin

2011-09-01

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival. Copyright © 2011 Elsevier Inc. All rights reserved.

Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia

PubMed Central

Fenske, Myles P.; Hewett Hazelton, Kristen D.; Hempton, Andrew K.; Shim, Jae Sung; Yamamoto, Breanne M.; Riffell, Jeffrey A.; Imaizumi, Takato

2015-01-01

Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening-expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia. PMID:26124104

Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia.

PubMed

Fenske, Myles P; Hewett Hazelton, Kristen D; Hempton, Andrew K; Shim, Jae Sung; Yamamoto, Breanne M; Riffell, Jeffrey A; Imaizumi, Takato

2015-08-04

Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening-expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia.

Socializing problems and low self-esteem enhance interpersonal models of eating disorders: Evidence from a clinical sample.

PubMed

Raykos, Bronwyn C; McEvoy, Peter M; Fursland, Anthea

2017-09-01

The present study evaluated the relative clinical validity of two interpersonal models of the maintenance of eating disorders, IPT-ED (Rieger et al., ) and the interpersonal model of binge eating (Wilfley, MacKenzie, Welch, Ayres, & Weissman, ; Wilfley, Pike, & Striegel-Moore, ). While both models propose an indirect relationship between interpersonal problems and eating disorder symptoms via negative affect, IPT-ED specifies negative social evaluation as the key interpersonal problem, and places greater emphasis on the role of low self-esteem as an intermediate variable between negative social evaluation and eating pathology. Treatment-seeking individuals (N = 306) with a diagnosed eating disorder completed measures of socializing problems, generic interpersonal problems, self-esteem, eating disorder symptoms, and negative affect (depression and anxiety). Structural equation models were run for both models. Consistent with IPT-ED, a significant indirect pathway was found from socializing problems to eating disorder symptoms via low self-esteem and anxiety symptoms. There was also a direct pathway from low self-esteem to eating disorder symptoms. Using a socializing problems factor in the model resulted in a significantly better fit than a generic interpersonal problems factor. Inconsistent with both interpersonal models, the direct pathway from socializing problems to eating disorder symptoms was not supported. Interpersonal models that included self-esteem and focused on socializing problems (rather than generic interpersonal problems) explained more variance in eating disorder symptoms. Future experimental, prospective, and treatment studies are required to strengthen the case that these pathways are causal. © 2017 Wiley Periodicals, Inc.

Pathways between Ecstasy Initiation and Other Drug Use

PubMed Central

Martins, Silvia S.; Ghandour, Lilian A.; Chilcoat, Howard D.

2007-01-01

This study aims to shed light on drug use pathways associated with ecstasy use initiation. Data from 54,573 respondents aged 12-21 years old from the 2002-2003 National Survey on Drug Use and Health (NSDUH) public use data files were analyzed via Cox proportional hazards models with time-dependent covariates. Our findings showed that marijuana, cocaine, and heroin were significant independent predictors of subsequent ecstasy use. Earlier ecstasy initiation was significantly associated with subsequent other illegal drug initiation (marijuana, cocaine and heroin). The strength of the association was greater for the pathway from earlier marijuana initiation to subsequent ecstasy initiation as compared to the pathway in the opposite direction. The pathway from earlier ecstasy initiation to subsequent cocaine and heroin initiation was also stronger as compared to pathways in the opposite directions. Pathways between ecstasy initiation and marijuana, cocaine and heroin initiation seem to be independent of the association between drug use and psychiatric symptoms/deviant behaviors. Ecstasy initiation seems to play a role in the subsequent initiation of cocaine and heroin. PMID:17174036

INDIRECT EXPOSURE ASSESSMENT AT THE U.S. EPA

EPA Science Inventory

In the early 1980s, exposures and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

Atypical regulators of Wnt/β-catenin signaling as potential therapeutic targets in Hepatocellular Carcinoma.

PubMed

Chen, Jianxiang; Rajasekaran, Muthukumar; Hui, Kam M

2017-06-01

Hepatocellular carcinoma is one of the most common causes of cancer-related death worldwide. Hepatocellular carcinoma development depends on the inhibition and activation of multiple vital pathways, including the Wnt signaling pathway. The Wnt/β-catenin pathway lies at the center of various signaling pathways that regulate embryonic development, tissue homeostasis and cancers. Activation of the Wnt/β-catenin pathway has been observed frequently in hepatocellular carcinoma. However, activating mutations in β-catenin, Axin and Adenomatous Polyposis Coli only contribute to a portion of the Wnt signaling hyper-activation observed in hepatocellular carcinoma. Therefore, besides mutations in the canonical Wnt components, there must be additional atypical regulation or regulators during Wnt signaling activation that promote liver carcinogenesis. In this mini-review, we have tried to summarize some of these well-established factors and to highlight some recently identified novel factors in the Wnt/β-catenin signaling pathway in hepatocellular carcinoma. Impact statement Early recurrence of human hepatocellular carcinoma (HCC) is a frequent cause of poor survival after potentially curative liver resection. Among the deregulated signaling cascades in HCC, evidence indicates that alterations in the Wnt/β-catenin signaling pathway play key roles in hepatocarcinogenesis. In this review, we summarize the potential molecular mechanisms how the microtubule-associated Protein regulator of cytokinesis 1 (PRC1), a direct Wnt signaling target previously identified in our laboratory to be up-regulated in HCC, in promoting cancer proliferation, stemness, metastasis and tumorigenesis through a complex regulatory circuitry of Wnt3a activities.

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor.

PubMed

Liu, Sheng; Nheu, Thao; Luwor, Rodney; Nicholson, Sandra E; Zhu, Hong-Jian

2015-07-17

Appropriate cellular signaling is essential to control cell proliferation, differentiation, and cell death. Aberrant signaling can have devastating consequences and lead to disease states, including cancer. The transforming growth factor-β (TGF-β) signaling pathway is a prominent signaling pathway that has been tightly regulated in normal cells, whereas its deregulation strongly correlates with the progression of human cancers. The regulation of the TGF-β signaling pathway involves a variety of physiological regulators. Many of these molecules act to alter the activity of Smad proteins. In contrast, the number of molecules known to affect the TGF-β signaling pathway at the receptor level is relatively low, and there are no known direct modulators for the TGF-β type II receptor (TβRII). Here we identify SPSB1 (a Spry domain-containing Socs box protein) as a novel regulator of the TGF-β signaling pathway. SPSB1 negatively regulates the TGF-β signaling pathway through its interaction with both endogenous and overexpressed TβRII (and not TβRI) via its Spry domain. As such, TβRII and SPSB1 co-localize on the cell membrane. SPSB1 maintains TβRII at a low level by enhancing the ubiquitination levels and degradation rates of TβRII through its Socs box. More importantly, silencing SPSB1 by siRNA results in enhanced TGF-β signaling and migration and invasion of tumor cells. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

PubMed

Nojima, Kuniharu; Hochegger, Helfrid; Saberi, Alihossein; Fukushima, Toru; Kikuchi, Koji; Yoshimura, Michio; Orelli, Brian J; Bishop, Douglas K; Hirano, Seiki; Ohzeki, Mioko; Ishiai, Masamichi; Yamamoto, Kazuhiko; Takata, Minoru; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Yamazoe, Mitsuyoshi; Kawamoto, Takuo; Araki, Kasumi; Takahashi, Jun A; Hashimoto, Nobuo; Takeda, Shunichi; Sonoda, Eiichiro

2005-12-15

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

Identification of prostate cancer modifier pathways using parental strain expression mapping

PubMed Central

Xu, Qing; Majumder, Pradip K.; Ross, Kenneth; Shim, Yeonju; Golub, Todd R.; Loda, Massimo; Sellers, William R.

2007-01-01

Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease. PMID:17978178

The endoplasmic reticulum is a hub to sort proteins toward unconventional traffic pathways and endosymbiotic organelles.

PubMed

Bellucci, Michele; De Marchis, Francesca; Pompa, Andrea

2017-12-18

The discovery that much of the extracellular proteome in eukaryotic cells consists of proteins lacking a signal peptide, which cannot therefore enter the secretory pathway, has led to the identification of alternative protein secretion routes bypassing the Golgi apparatus. However, proteins harboring a signal peptide for translocation into the endoplasmic reticulum can also be transported along these alternative routes, which are still far from being well elucidated in terms of the molecular machineries and subcellular/intermediate compartments involved. In this review, we first try to provide a definition of all the unconventional protein secretion pathways in eukaryotic cells, as those pathways followed by proteins directed to an 'external space' bypassing the Golgi, where 'external space' refers to the extracellular space plus the lumen of the secretory route compartments and the inner space of mitochondria and plastids. Then, we discuss the role of the endoplasmic reticulum in sorting proteins toward unconventional traffic pathways in plants. In this regard, various unconventional pathways exporting proteins from the endoplasmic reticulum to the vacuole, plasma membrane, apoplast, mitochondria, and plastids are described, including the short routes followed by the proteins resident in the endoplasmic reticulum. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Novel diagnostics of metabolic dysfunction detected in breath and plasma by selective isotope-assisted labeling.

PubMed

Haviland, Julia A; Tonelli, Marco; Haughey, Dermot T; Porter, Warren P; Assadi-Porter, Fariba M

2012-08-01

Metabolomics is the study of a unique fingerprint of small molecules present in biological systems under healthy and disease conditions. One of the major challenges in metabolomics is validation of fingerprint molecules to identify specifically perturbed pathways in metabolic aberrations. This step is crucial to the understanding of budding metabolic pathologies and the ability to identify early indicators of common diseases such as obesity, type 2 diabetes mellitus, metabolic syndrome, polycystic ovary syndrome, and cancer. We present a novel approach to diagnosing aberrations in glucose utilization including metabolic pathway switching in a disease state. We used a well-defined prenatally exposed glucocorticoid mouse model that results in adult females with metabolic dysfunction. We applied the complementary technologies of nuclear magnetic resonance spectroscopy and cavity ring-down spectroscopy to analyze serial plasma samples and real-time breath measurements following selective (13)C-isotope-assisted labeling. These platforms allowed us to trace metabolic markers in whole animals and identify key metabolic pathway switching in prenatally glucocorticoid-treated animals. Total glucose flux is significantly proportionally increased through the major oxidative pathways of glycolysis and the pentose phosphate pathway in the prenatally glucocorticoid-treated animals relative to the control animals. This novel diagnostics approach is fast, noninvasive, and sensitive for determining specific pathway utilization, and provides a direct translational application in the health care field. Copyright © 2012 Elsevier Inc. All rights reserved.

Integrated Transcriptomic and Epigenomic Analysis of Primary Human Lung Epithelial Cell Differentiation

PubMed Central

Marconett, Crystal N.; Zhou, Beiyun; Rieger, Megan E.; Selamat, Suhaida A.; Dubourd, Mickael; Fang, Xiaohui; Lynch, Sean K.; Stueve, Theresa Ryan; Siegmund, Kimberly D.; Berman, Benjamin P.

2013-01-01

Elucidation of the epigenetic basis for cell-type specific gene regulation is key to gaining a full understanding of how the distinct phenotypes of differentiated cells are achieved and maintained. Here we examined how epigenetic changes are integrated with transcriptional activation to determine cell phenotype during differentiation. We performed epigenomic profiling in conjunction with transcriptomic profiling using in vitro differentiation of human primary alveolar epithelial cells (AEC). This model recapitulates an in vivo process in which AEC transition from one differentiated cell type to another during regeneration following lung injury. Interrogation of histone marks over time revealed enrichment of specific transcription factor binding motifs within regions of changing chromatin structure. Cross-referencing of these motifs with pathways showing transcriptional changes revealed known regulatory pathways of distal alveolar differentiation, such as the WNT and transforming growth factor beta (TGFB) pathways, and putative novel regulators of adult AEC differentiation including hepatocyte nuclear factor 4 alpha (HNF4A), and the retinoid X receptor (RXR) signaling pathways. Inhibition of the RXR pathway confirmed its functional relevance for alveolar differentiation. Our incorporation of epigenetic data allowed specific identification of transcription factors that are potential direct upstream regulators of the differentiation process, demonstrating the power of this approach. Integration of epigenomic data with transcriptomic profiling has broad application for the identification of regulatory pathways in other models of differentiation. PMID:23818859

Differential miRNA expression in B cells is associated with inter-individual differences in humoral immune response to measles vaccination.

PubMed

Haralambieva, Iana H; Kennedy, Richard B; Simon, Whitney L; Goergen, Krista M; Grill, Diane E; Ovsyannikova, Inna G; Poland, Gregory A

2018-01-01

MicroRNAs are important mediators of post-transcriptional regulation of gene expression through RNA degradation and translational repression, and are emerging biomarkers of immune system activation/response after vaccination. We performed Next Generation Sequencing (mRNA-Seq) of intracellular miRNAs in measles virus-stimulated B and CD4+ T cells from high and low antibody responders to measles vaccine. Negative binomial generalized estimating equation (GEE) models were used for miRNA assessment and the DIANA tool was used for gene/target prediction and pathway enrichment analysis. We identified a set of B cell-specific miRNAs (e.g., miR-151a-5p, miR-223, miR-29, miR-15a-5p, miR-199a-3p, miR-103a, and miR-15a/16 cluster) and biological processes/pathways, including regulation of adherens junction proteins, Fc-receptor signaling pathway, phosphatidylinositol-mediated signaling pathway, growth factor signaling pathway/pathways, transcriptional regulation, apoptosis and virus-related processes, significantly associated with neutralizing antibody titers after measles vaccination. No CD4+ T cell-specific miRNA expression differences between high and low antibody responders were found. Our study demonstrates that miRNA expression directly or indirectly influences humoral immunity to measles vaccination and suggests that B cell-specific miRNAs may serve as useful predictive biomarkers of vaccine humoral immune response.

Stalking Higher Energy Conformers on the Potential Energy Surface of Charged Species.

PubMed

Brites, Vincent; Cimas, Alvaro; Spezia, Riccardo; Sieffert, Nicolas; Lisy, James M; Gaigeot, Marie-Pierre

2015-03-10

Combined theoretical DFT-MD and RRKM methodologies and experimental spectroscopic infrared predissociation (IRPD) strategies to map potential energy surfaces (PES) of complex ionic clusters are presented, providing lowest and high energy conformers, thresholds to isomerization, and cluster formation pathways. We believe this association not only represents a significant advance in the field of mapping minima and transition states on the PES but also directly measures dynamical pathways for the formation of structural conformers and isomers. Pathways are unraveled over picosecond (DFT-MD) and microsecond (RRKM) time scales while changing the amount of internal energy is experimentally achieved by changing the loss channel for the IRPD measurements, thus directly probing different kinetic and isomerization pathways. Demonstration is provided for Li(+)(H2O)3,4 ionic clusters. Nonstatistical formation of these ionic clusters by both direct and cascade processes, involving isomerization processes that can lead to trapping of high energy conformers along the paths due to evaporative cooling, has been unraveled.

Direct accumulation pathway of radioactive cesium to fruit-bodies of edible mushroom from contaminated wood logs

NASA Astrophysics Data System (ADS)

Ohnuki, Toshihiko; Aiba, Yukitoshi; Sakamoto, Fuminori; Kozai, Naofumi; Niizato, Tadafumi; Sasaki, Yoshito

2016-07-01

This paper presents the accumulation process of radioactive Cs in edible mushrooms. We here first report the direct accumulation pathway of radioactive Cs from contaminated wood logs to the fruit-bodies of shiitake mushrooms through the basal portion of the stipe. In this pathway, radioactive Cs is not transported through the hyphae. This pathway results in a high accumulation of radioactive Cs in the fruit-body, more by the excess accumulation of radioactive Cs from the wood logs than that through the hyphae. We grew the fruit-bodies of Shiitake mushroom from radioactive-Cs-contaminated wood logs. The spatial distributions of radioactive Cs and Prussian blue as a tracer of interstitial water in the cross section of the wood log measured after the harvest of the fruit-body from the inoculated sawdust spawn area indicated that some fraction of the radioactive Cs and Prussian blue were transported directly to the basal portion of the stipe during the growth of the fruit-bodies.

Separate elements of episodic memory subserved by distinct hippocampal-prefrontal connections.

PubMed

Barker, Gareth R I; Banks, Paul J; Scott, Hannah; Ralph, G Scott; Mitrophanous, Kyriacos A; Wong, Liang-Fong; Bashir, Zafar I; Uney, James B; Warburton, E Clea

2017-02-01

Episodic memory formation depends on information about a stimulus being integrated within a precise spatial and temporal context, a process dependent on the hippocampus and prefrontal cortex. Investigations of putative functional interactions between these regions are complicated by multiple direct and indirect hippocampal-prefrontal connections. Here application of a pharmacogenetic deactivation technique enabled us to investigate the mnemonic contributions of two direct hippocampal-medial prefrontal cortex (mPFC) pathways, one arising in the dorsal CA1 (dCA1) and the other in the intermediate CA1 (iCA1). While deactivation of either pathway impaired episodic memory, the resulting pattern of mnemonic deficits was different: deactivation of the dCA1→mPFC pathway selectively disrupted temporal order judgments while iCA1→mPFC pathway deactivation disrupted spatial memory. These findings reveal a previously unsuspected division of function among CA1 neurons that project directly to the mPFC. Such subnetworks may enable the distinctiveness of contextual information to be maintained in an episodic memory circuit.

Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

PubMed

Johnson, Norman A; Porter, Adam H

2007-01-01

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

Pathways and trajectories linking housing instability and poor health among low-income women experiencing intimate partner violence (IPV): Toward a conceptual framework.

PubMed

Daoud, Nihaya; Matheson, Flora I; Pedersen, Cheryl; Hamilton-Wright, Sarah; Minh, Anita; Zhang, Janice; O'Campo, Patricia

2016-01-01

We used grounded theory to understand pathways and trajectories to housing instability (HI) and poor health among low-income women with experiences of intimate partner violence (IPV). We conducted in-depth interviews during 2010-11 with forty-one women (ages 18-45 years) living in Ontario, Canada. All women reported depressive symptoms in combination with other health problems. In addition to the direct pathway of IPV to poor health, thematic analysis revealed an indirect multi-tiered pathway with complex trajectories among IPV, HI, and poor health. These trajectories included material HI (homelessness, high mobility, evictions, problems paying rent, hiding, and landlord discrimination), psychological HI (feeling unsafe, low self-esteem, and poor control), and social trajectories (financial problems, loss of employment, income, or social networks, and leaving school). These trajectories elevated stress and decreased self-care (unhealthy behaviors, substance abuse, and reduced medical compliance) and exacerbated poor health already compromised by IPV. Depending on her specific context, each woman experienced these pathways and trajectories differently. Moreover, the women's experiences differed across three time periods: before, immediately after, and long after leaving an abusive relationship. Finally, we found that for these women, achieving stable housing was crucial for stabilizing their health.

Direct and Indirect Effects of PM on the Cardiovascular System

PubMed Central

Nelin, Timothy D.; Joseph, Allan M.; Gorr, Matthew W.; Wold, Loren E.

2011-01-01

Human exposure to particulate matter (PM) elicits a variety of responses on the cardiovascular system through both direct and indirect pathways. Indirect effects of PM on the cardiovascular system are mediated through the autonomic nervous system, which controls heart rate variability, and inflammatory responses, which augment acute cardiovascular events and atherosclerosis. Recent research demonstrates that PM also affects the cardiovascular system directly by entry into the systemic circulation. This process causes myocardial dysfunction through mechanisms of reactive oxygen species production, calcium ion interference, and vascular dysfunction. In this review, we will present key evidence in both the direct and indirect pathways, suggest clinical applications of the current literature, and recommend directions for future research. PMID:22119171

INDIRECT EXPOSURE ASSESSMENT AT THE UNITED STATES ENRONMENTAL PROTECTION AGENCY

EPA Science Inventory

In the early 1980s, expousres and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies.

PubMed

Karmali, Reem; Dalovisio, Andrew; Borgia, Jeffrey A; Venugopal, Parameswaran; Kim, Brian W; Grant-Szymanski, Kelly; Hari, Parameswaran; Lazarus, Hillard

2015-03-01

Metabolic syndrome constitutes a constellation of findings including central obesity, insulin resistance/type 2 diabetes mellitus (DM), dyslipidemia and hypertension. Metabolic syndrome affects 1 in 4 adults in the United States and is rapidly rising in prevalence, largely driven by the dramatic rise in obesity and insulin resistance/DM. Being central to the development of metabolic syndrome and its other related diseases, much focus has been placed on identifying the mitogenic effects of obesity and insulin resistance/DM as mechanistic clues of the link between metabolic syndrome and cancer. Pertinent mechanisms identified include altered lipid signaling, adipokine and inflammatory cytokine effects, and activation of PI3K/Akt/mTOR and RAS/RAF/MAPK/ERK pathways via dysregulated insulin/insulin-like growth factor-1 (IGF-1) signaling. Through variable activation of these multiple pathways, obesity and insulin resistance/DM pre-dispose to hematologic malignancies, imposing the aggressive and chemo-resistant phenotypes typically seen in cancer patients with underlying metabolic syndrome. Growing understanding of these pathways has identified druggable cancer targets, rationalizing the development and testing of agents like PI3K inhibitor idelalisib, mTOR inhibitors everolimus and temsirolimus, and IGF-1 receptor inhibitor linsitinib. It has also led to exploration of obesity and diabetes-directed therapies including statins and oral hypoglycemic for the management of metabolic syndrome-related hematologic neoplasms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Using Answer Set Programming to Integrate RNA Expression with Signalling Pathway Information to Infer How Mutations Affect Ageing

PubMed Central

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M.

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects. PMID:23251396

Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

PubMed

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

Dependence of prevalence of contiguous pathways in proteins on structural complexity.

PubMed

Thayer, Kelly M; Galganov, Jesse C; Stein, Avram J

2017-01-01

Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible. A major difficulty for testing the two methods is the ability to definitively determine that a residue is directly involved in allosteric signal transduction. Statistical Coupling Analysis (SCA) is a method that has been successful at predicting pathways, and experimental tests involving mutagenesis or domain substitution provide the best available evidence of signaling pathways. However, ascertaining energetic pathways which need not be contiguous is far more difficult. To date, simple estimates of the statistical significance of a pathway in a protein remain to be established. The focus of this work is to estimate such benchmarks for the statistical significance of contiguous pathways for the null model of selecting residues at random. We found that when 20% of residues in proteins are randomly selected, contiguous pathways at the 6 Å cutoff level were found with success rates of 51% in PDZ, 30% in p53, and 3% in MutS. The results suggest that the significance of pathways may have system specific factors involved. Furthermore, the possible existence of false positives for contiguous pathways implies that signaling could be occurring via alternate routes including those consistent with the energetic landscape model.

New Advanced Technologies in Stem Cell Therapy

DTIC Science & Technology

2012-09-01

directions for this project include investigating modulation of the IKK/NF-kB pathway as a means to rejuvenate the phenotype of aged muscle stem and...Reference 1. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young...the influence that age plays on the regeneration capacity of the cells. Study Design: We will investigate the effects of cell survival, proliferation

Knockdown of TNFR1 Suppresses Expression of TLR2 in the Cellular Response to Staphylococcus aureus Infection.

PubMed

Chen, Qianbo; Hou, Tianyong; Wu, Xuehui; Luo, Fei; Xie, Zhao; Xu, Jianzhong

2016-04-01

Osteomyelitis is a common manifestation of invasive Staphylococcus aureus infection characterized by widespread bone loss and destruction. Phagocytes possess various receptors to detect pathogens, including the Toll-like receptors (TLRs). Previous studies have demonstrated that the S. aureus protein SpA binds directly to pre-osteoblastic cells via tumor necrosis factor receptor-1 (TNFR-1). In our present study, we investigated the relationship between TLR2 and TNFR-1 in S. aureus-infected osteoblasts. Our results showed that cell viability decreased, and apoptosis, expression of TLR2, and the secretion of inflammatory cytokines (TNF-α and IL-6) increased with increasing concentrations of S. aureus. The JNK pathway was also activated in response to S. aureus infection. Knockdown of TNFR1 not only inhibited the JNK pathway but also reduced TLR2 protein and RANKL levels in S. aureus-infected cells. Inhibition of the JNK pathway reduced the protein level of TLR2 and reduced TNF-α and IL-6 secretion in S. aureus-infected cells.

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish.

PubMed

Lovely, C Ben; Swartz, Mary E; McCarthy, Neil; Norrie, Jacqueline L; Eberhart, Johann K

2016-06-01

The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. © 2016. Published by The Company of Biologists Ltd.

Aqueous photodegradation of antibiotic florfenicol: kinetics and degradation pathway studies.

PubMed

Zhang, Ya; Li, Jianhua; Zhou, Lei; Wang, Guoqing; Feng, Yanhong; Wang, Zunyao; Yang, Xi

2016-04-01

The occurrence of antibacterial agents in natural environment was of scientific concern in recent years. As endocrine disrupting chemicals, they had potential risk on ecology system and human beings. In the present study, the photodegradation kinetics and pathways of florfenicol were investigated under solar and xenon lamp irradiation in aquatic systems. Direct photolysis half-lives of florfenicol were determined as 187.29 h under solar irradiation and 22.43 h under xenon lamp irradiation, respectively. Reactive oxygen species (ROS), such as hydroxyl radical (·OH) and singlet oxygen ((1)O2) were found to play an important role in indirect photolysis process. The presence of nitrate and dissolved organic matters (DOMs) could affect photolysis of florfenicol in solutions through light screening effect, quenching effect, and photoinduced oxidization process. Photoproducts of florfenicol in DOMs solutions were identified by solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC-MS) analysis techniques, and degradation pathways were proposed, including photoinduced hydrolysis, oxidation by (1)O2 and ·OH, dechlorination, and cleavage of the side chain.

Store-operated Ca2+ entry in muscle physiology and diseases

PubMed Central

Pan, Zui; Brotto, Marco; Ma, Jianjie

2014-01-01

Ca2+ release from intracellular stores and influx from extracellular reservoir regulate a wide range of physiological functions including muscle contraction and rhythmic heartbeat. One of the most ubiquitous pathways involved in controlled Ca2+ influx into cells is store-operated Ca2+ entry (SOCE), which is activated by the reduction of Ca2+ concentration in the lumen of endoplasmic or sarcoplasmic reticulum (ER/SR). Although SOCE is pronounced in non-excitable cells, accumulating evidences highlight its presence and important roles in skeletal muscle and heart. Recent discovery of STIM proteins as ER/SR Ca2+ sensors and Orai proteins as Ca2+ channel pore forming unit expedited the mechanistic understanding of this pathway. This review focuses on current advances of SOCE components, regulation and physiologic and pathophysiologic roles in muscles. The specific property and the dysfunction of this pathway in muscle diseases, and new directions for future research in this rapidly growing field are discussed. [BMB Reports 2014; 47(2): 69-79] PMID:24411466

Leveraging Electron Transfer Dissociation for Site Selective Radical Generation: Applications for Peptide Epimer Analysis

NASA Astrophysics Data System (ADS)

Lyon, Yana A.; Beran, Gregory; Julian, Ryan R.

2017-07-01

Traditional electron-transfer dissociation (ETD) experiments operate through a complex combination of hydrogen abundant and hydrogen deficient fragmentation pathways, yielding c and z ions, side-chain losses, and disulfide bond scission. Herein, a novel dissociation pathway is reported, yielding homolytic cleavage of carbon-iodine bonds via electronic excitation. This observation is very similar to photodissociation experiments where homolytic cleavage of carbon-iodine bonds has been utilized previously, but ETD activation can be performed without addition of a laser to the mass spectrometer. Both loss of iodine and loss of hydrogen iodide are observed, with the abundance of the latter product being greatly enhanced for some peptides after additional collisional activation. These observations suggest a novel ETD fragmentation pathway involving temporary storage of the electron in a charge-reduced arginine side chain. Subsequent collisional activation of the peptide radical produced by loss of HI yields spectra dominated by radical-directed dissociation, which can be usefully employed for identification of peptide isomers, including epimers.

Epidermal wound repair is regulated by the planar cell polarity signaling pathway.

PubMed

Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A; Murdoch, Jennifer N; Humbert, Patrick O; Parekh, Vishwas; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M; Jane, Stephen M

2010-07-20

The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects, and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3(-)(/-) mice, we identified RhoGEF19, a homolog of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerization, cellular polarity, and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling and broadly implicate this pathway in epidermal repair. (c) 2010 Elsevier Inc. All rights reserved.

Epidermal wound repair is regulated by the planar cell polarity signaling pathway

PubMed Central

Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B.; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A.; Murdoch, Jennifer N.; Humbert, Patrick O.; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M.; Jane, Stephen M.

2010-01-01

SUMMARY The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3−/− mice, we identified RhoGEF19, a homologue of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerisation, cellular polarity and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling, and broadly implicate this pathway in epidermal repair. PMID:20643356

Emerging engineering principles for yield improvement in microbial cell design.

PubMed

Comba, Santiago; Arabolaza, Ana; Gramajo, Hugo

2012-01-01

Metabolic Engineering has undertaken a rapid transformation in the last ten years making real progress towards the production of a wide range of molecules and fine chemicals using a designed cellular host. However, the maximization of product yields through pathway optimization is a constant and central challenge of this field. Traditional methods used to improve the production of target compounds from engineered biosynthetic pathways in non-native hosts include: codon usage optimization, elimination of the accumulation of toxic intermediates or byproducts, enhanced production of rate-limiting enzymes, selection of appropriate promoter and ribosome binding sites, application of directed evolution of enzymes, and chassis re-circuit. Overall, these approaches tend to be specific for each engineering project rather than a systematic practice based on a more generalizable strategy. In this mini-review, we highlight some novel and extensive approaches and tools intended to address the improvement of a target product formation, founded in sophisticated principles such as dynamic control, pathway genes modularization, and flux modeling.

Emerging engineering principles for yield improvement in microbial cell design

PubMed Central

Comba, Santiago; Arabolaza, Ana; Gramajo, Hugo

2012-01-01

Metabolic Engineering has undertaken a rapid transformation in the last ten years making real progress towards the production of a wide range of molecules and fine chemicals using a designed cellular host. However, the maximization of product yields through pathway optimization is a constant and central challenge of this field. Traditional methods used to improve the production of target compounds from engineered biosynthetic pathways in non-native hosts include: codon usage optimization, elimination of the accumulation of toxic intermediates or byproducts, enhanced production of rate-limiting enzymes, selection of appropriate promoter and ribosome binding sites, application of directed evolution of enzymes, and chassis re-circuit. Overall, these approaches tend to be specific for each engineering project rather than a systematic practice based on a more generalizable strategy. In this mini-review, we highlight some novel and extensive approaches and tools intended to address the improvement of a target product formation, founded in sophisticated principles such as dynamic control, pathway genes modularization, and flux modeling. PMID:24688676

Sonic hedgehog signaling regulates actin cytoskeleton via Tiam1-Rac1 cascade during spine formation.

PubMed

Sasaki, Nobunari; Kurisu, Junko; Kengaku, Mineko

2010-12-01

The sonic hedgehog (Shh) pathway has essential roles in several processes during development of the vertebrate central nervous system (CNS). Here, we report that Shh regulates dendritic spine formation in hippocampal pyramidal neurons via a novel pathway that directly regulates the actin cytoskeleton. Shh signaling molecules Patched (Ptc) and Smoothened (Smo) are expressed in several types of postmitotic neurons, including cerebellar Purkinje cells and hippocampal pyramidal neurons. Knockdown of Smo induces dendritic spine formation in cultured hippocampal neurons independently of Gli-mediated transcriptional activity. Smo interacts with Tiam1, a guanine nucleotide exchange factor for Rac1, via its cytoplasmic C-terminal region. Inhibition of Tiam1 or Rac1 activity suppresses spine induction by Smo knockdown. Shh induces remodeling of the actin cytoskeleton independently of transcriptional activation in mouse embryonic fibroblasts. These findings demonstrate a novel Shh pathway that regulates the actin cytoskeleton via Tiam1-Rac1 activation. Copyright © 2010 Elsevier Inc. All rights reserved.

Oxidative Pentose Phosphate Pathway Inhibition Is A Key Determinant of Antimalarial Induced Cancer Cell Death

PubMed Central

Salas, Eduardo; Roy, Srirupa; Marsh, Timothy; Rubin, Brian; Debnath, Jayanta

2015-01-01

Despite immense interest in employing antimalarials as autophagy inhibitors to treat cancer, it remains unclear if these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells. PMID:26434592

The Vitamin Nicotinamide: Translating Nutrition into Clinical Care

PubMed Central

Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen

2009-01-01

Nicotinamide, the amide form of vitamin B3 (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyl-transferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs. PMID:19783937

Sleep-Active Neurons: Conserved Motors of Sleep

PubMed Central

Bringmann, Henrik

2018-01-01

Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

Completion of biosynthetic pathways for bacteriochlorophyll g in Heliobacterium modesticaldum: The C8-ethylidene group formation.

PubMed

Tsukatani, Yusuke; Yamamoto, Haruki; Mizoguchi, Tadashi; Fujita, Yuichi; Tamiaki, Hitoshi

2013-10-01

Heliobacteria have the simplest photosynthetic apparatus, i.e., a type-I reaction center lacking a peripheral light-harvesting complex. Bacteriochlorophyll (BChl) g molecules are bound to the reaction center complex and work both as special-pair and antenna pigments. The C8-ethylidene group formation for BChl g is the last missing link in biosynthetic pathways for bacterial special-pair pigments, which include BChls a and b as well. Here, we report that chlorophyllide a oxidoreductase (COR) of Heliobacterium modesticaldum catalyzes the C8-ethylidene formation from 8-vinyl-chlorophyllide a, producing bacteriochlorophyllide g, the direct precursor for BChl g without the farnesyl tail. The finding led to plausible biosynthetic pathways for 8(1)-hydroxy-chlorophyll a, a primary electron acceptor from the special pair in heliobacterial reaction centers. Proposed catalytic mechanisms on hydrogenation reaction of the ethylidene synthase-type CORs are also discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

PubMed Central

Swartz, Mary E.; McCarthy, Neil; Norrie, Jacqueline L.; Eberhart, Johann K.

2016-01-01

The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. PMID:27122171

Divergent Human Cortical Regions for Processing Distinct Acoustic-Semantic Categories of Natural Sounds: Animal Action Sounds vs. Vocalizations

PubMed Central

Webster, Paula J.; Skipper-Kallal, Laura M.; Frum, Chris A.; Still, Hayley N.; Ward, B. Douglas; Lewis, James W.

2017-01-01

A major gap in our understanding of natural sound processing is knowledge of where or how in a cortical hierarchy differential processing leads to categorical perception at a semantic level. Here, using functional magnetic resonance imaging (fMRI) we sought to determine if and where cortical pathways in humans might diverge for processing action sounds vs. vocalizations as distinct acoustic-semantic categories of real-world sound when matched for duration and intensity. This was tested by using relatively less semantically complex natural sounds produced by non-conspecific animals rather than humans. Our results revealed a striking double-dissociation of activated networks bilaterally. This included a previously well described pathway preferential for processing vocalization signals directed laterally from functionally defined primary auditory cortices to the anterior superior temporal gyri, and a less well-described pathway preferential for processing animal action sounds directed medially to the posterior insulae. We additionally found that some of these regions and associated cortical networks showed parametric sensitivity to high-order quantifiable acoustic signal attributes and/or to perceptual features of the natural stimuli, such as the degree of perceived recognition or intentional understanding. Overall, these results supported a neurobiological theoretical framework for how the mammalian brain may be fundamentally organized to process acoustically and acoustic-semantically distinct categories of ethologically valid, real-world sounds. PMID:28111538

The PDZ protein tax-interacting protein-1 inhibits beta-catenin transcriptional activity and growth of colorectal cancer cells.

PubMed

Kanamori, Mutsumi; Sandy, Peter; Marzinotto, Stefania; Benetti, Roberta; Kai, Chikatoshi; Hayashizaki, Yoshihide; Schneider, Claudio; Suzuki, Harukazu

2003-10-03

Wnt signaling is essential during development while deregulation of this pathway frequently leads to the formation of various tumors including colorectal carcinomas. A key component of the pathway is beta-catenin that, in association with TCF-4, directly regulates the expression of Wnt-responsive genes. To identify novel binding partners of beta-catenin that may control its transcriptional activity, we performed a mammalian two-hybrid screen and isolated the Tax-interacting protein (TIP-1). The in vivo complex formation between beta-catenin and TIP-1 was verified by coimmunoprecipitation, and a direct physical association was revealed by glutathione S-transferase pull-down experiments in vitro. By using a panel of deletion mutants of both proteins, we demonstrate that the interaction is mediated by the PDZ (PSD-95/DLG/ZO-1 homology) domain of TIP-1 and requires primarily the last four amino acids of beta-catenin. TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of beta-catenin when tested on the TOP/FOPFLASH reporter system. Conversely, siRNA-mediated knock-down of endogenous TIP-1 slightly increased endogenous beta-catenin transactivation function. Moreover, we show that overexpression of TIP-1 reduced the proliferation and anchorage-independent growth of colorectal cancer cells. These data suggest that TIP-1 may represent a novel regulatory element in the Wnt/beta-catenin signaling pathway.

Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.

PubMed

Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W

2015-08-07

Perturbations in dynamic properties of mitochondria including fission, fusion, and movement lead to disruption of energy supply to synapses contributing to neuropathology and cognitive dysfunction in Alzheimer׳s disease (AD). The molecular mechanisms underlying these defects are still unclear. Previously, we have shown that ERβ is localized in the mitochondria and ERβ knock down disrupts mitochondrial functions. Because a selective ERβ modulator (DPN) can activate PKA, and localized PKA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ERβ signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble Aβ oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble Aβ-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, Aβ treatment reduced the respiratory reserve capacity of hippocampal neuron and inhibited phosphorylation of Drp1 at its PKA site, which induces excessive mitochondrial fission, and DPN treatment ameliorates these inhibitions. Finally, we discovered a direct interaction of ERβ with a mitochondrial resident protein AKAP1, which induces the PKA-mediated local signaling pathway involved in increased oxidative phosphorylation and inhibition of mitochondrial fission. Taken together, our findings highlight the possibility that ERβ signaling pathway may be a useful mitochondria-directed therapeutic target for AD. Copyright © 2015 Elsevier B.V. All rights reserved.

Estimation of Direct Melanoma-related Costs by Disease Stage and by Phase of Diagnosis and Treatment According to Clinical Guidelines.

PubMed

Buja, Alessandra; Sartor, Gino; Scioni, Manuela; Vecchiato, Antonella; Bolzan, Mario; Rebba, Vincenzo; Sileni, Vanna Chiarion; Palozzo, Angelo Claudio; Montesco, Maria; Del Fiore, Paolo; Baldo, Vincenzo; Rossi, Carlo Riccardo

2018-02-07

Cutaneous melanoma is a major concern in terms of healthcare systems and economics. The aim of this study was to estimate the direct costs of melanoma by disease stage, phase of diagnosis, and treatment according to the pre-set clinical guidelines drafted by the AIOM (Italian Medical Oncological Association). Based on the AIOM guidelines for malignant cutaneous melanoma, a highly detailed decision-making model was developed describing the patient's pathway from diagnosis through the subsequent phases of disease staging, surgical and medical treatment, and follow-up. The model associates each phase potentially involving medical procedures with a likelihood measure and a cost, thus enabling an estimation of the expected costs by disease stage and clinical phase of melanoma diagnosis and treatment according to the clinical guidelines. The mean per-patient cost of the whole melanoma pathway (including one year of follow-up) ranged from €149 for stage 0 disease to €66,950 for stage IV disease. The costs relating to each phase of the disease's diagnosis and treatment depended on disease stage. It is essential to calculate the direct costs of managing malignant cutaneous melanoma according to clinical guidelines in order to estimate the economic burden of this disease and to enable policy-makers to allocate appropriate resources.

On-line metabolic pathway analysis based on metabolic signal flow diagram.

PubMed

Shi, H; Shimizu, K

In this work, an integrated modeling approach based on a metabolic signal flow diagram and cellular energetics was used to model the metabolic pathway analysis for the cultivation of yeast on glucose. This approach enables us to make a clear analysis of the flow direction of the carbon fluxes in the metabolic pathways as well as of the degree of activation of a particular pathway for the synthesis of biomaterials for cell growth. The analyses demonstrate that the main metabolic pathways of Saccharomyces cerevisiae change significantly during batch culture. Carbon flow direction is toward glycolysis to satisfy the increase of requirement for precursors and energy. The enzymatic activation of TCA cycle seems to always be at normal level, which may result in the overflow of ethanol due to its limited capacity. The advantage of this approach is that it adopts both virtues of the metabolic signal flow diagram and the simple network analysis method, focusing on the investigation of the flow directions of carbon fluxes and the degree of activation of a particular pathway or reaction loop. All of the variables used in the model equations were determined on-line; the information obtained from the calculated metabolic coefficients may result in a better understanding of cell physiology and help to evaluate the state of the cell culture process. Copyright 1998 John Wiley & Sons, Inc.

Unique molecular signatures as a hallmark of patients with metastatic breast cancer: implications for current treatment paradigms.

PubMed

Wheler, Jennifer J; Parker, Barbara A; Lee, Jack J; Atkins, Johnique T; Janku, Filip; Tsimberidou, Apostolia M; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Schwab, Richard; Moulder, Stacy; Valero, Vicente; Schwaederle, Maria; Yelensky, Roman; Miller, Vincent A; Stephens, M Philip J; Meric-Bernstam, Funda; Kurzrock, Razelle

2014-05-15

Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.

Sedentary behavior and sleep: paradoxical effects in association with childhood obesity.

PubMed

Must, A; Parisi, S M

2009-04-01

Sedentary behavior and sleep may be working in concert to increase the likelihood of a child becoming overweight, but in paradoxical ways. Reduction of sedentary behavior (that is, media screen time) has been extensively researched and touted as an intervention target. Inadequate sleep as a putative risk factor for obesity is only beginning to be explored. In this paper, we review the current state of research regarding these factors, and describe the existing evidence and mechanisms proposed to explain these relationships. Whereas the association between weight and sedentary behavior has been consistently shown in observational studies, effect sizes are small, and multiple mechanisms appear to be operating. Recent cross-sectional and longitudinal evidence suggests a link between short sleep duration and weight. Possible mechanisms here include direct metabolic effects as well as indirect behavioral pathways, including the presence of electronic media in children's bedrooms. Measurement issues present a challenge to both areas of research. Prospective studies that include more accurate measures of both sedentary behavior and of sleep will be needed to clarify causal pathways.

Multi-domain models of risk factors for depression and anxiety symptoms in preschoolers: evidence for common and specific factors.

PubMed

Hopkins, Joyce; Lavigne, John V; Gouze, Karen R; LeBailly, Susan A; Bryant, Fred B

2013-07-01

Relatively few studies have examined multiple pathways by which risk factors from different domains are related to symptoms of anxiety and depression in young children; even fewer have assessed risks for these symptoms specifically, rather than for internalizing symptoms in general. We examined a theoretically- and empirically-based model of variables associated with these symptom types in a diverse community sample of 796 4-year-olds (391 boys, 405 girls) that included factors from the following domains: contextual (SES, stress and family conflict); parent characteristics (parental depression); parenting (support/engagement, hostility and scaffolding); and child characteristics including negative affect (NA) effortful control (EC) sensory regulation (SR), inhibitory control (IC) and attachment. We also compared the models to determine which variables contribute to a common correlates of symptoms of anxiety or depression, and which correlates differentiate between those symptom types. In the best-fitting model for these symptom types (a) SES, stress and conflict had indirect effects on both symptom types via long-chain paths; (b) caregiver depression had direct effects and indirect ones (mediated through parenting and child effortful control) on both symptom types; (c) parenting had direct and indirect effects (via temperament and SR); and temperament had direct effects on both symptom types. These data provide evidence of common risk factors, as well as indicate some specific pathways/mediators for the different symptom types. EC was related to anxiety, but not depression symptoms, suggesting that strategies to improve child EC may be particularly effective for treatment of anxiety symptoms in young children.

Education Direct: An Alternative Entry Pathway to Pre-Service Teacher Education

ERIC Educational Resources Information Center

Pilkington, Kevin; Lock, Graeme

2012-01-01

Universities in Australia are offering alternative entrance pathways to attract students from a range of backgrounds. These alternative pathways will undoubtedly be reviewed due to the recommendation in the Review of Australian Higher Education (Bradley, Noonan, Nugent & Scales, 2008) concerning increasing the diversity of university entrants.…

The Transcription Factor EB Links Cellular Stress to the Immune Response



PubMed Central

Nabar, Neel R.; Kehrl, John H.

2017-01-01

The transcription factor EB (TFEB) is the master transcriptional regulator of autophagy and lysosome biogenesis. Recent advances have led to a paradigm shift in our understanding of lysosomes from a housekeeping cellular waste bin to a dynamically regulated pathway that is efficiently turned up or down based on cellular needs. TFEB coordinates the cellular response to nutrient deprivation and other forms of cell stress through the lysosome system, and regulates a myriad of cellular processes associated with this system including endocytosis, phagocytosis, autophagy, and lysosomal exocytosis. Autophagy and the endolysosomal system are critical to both the innate and adaptive arms of the immune system, with functions in effector cell priming and direct pathogen clearance. Recent studies have linked TFEB to the regulation of the immune response through the endolysosmal pathway and by direct transcriptional activation of immune related genes. In this review, we discuss the current understanding of TFEB’s function and the molecular mechanisms behind TFEB activation. Finally, we discuss recent advances linking TFEB to the immune response that positions lysosomal signaling as a potential target for immune modulation. PMID:28656016

Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement

PubMed Central

Nobes, Catherine D.; Hall, Alan

1999-01-01

Cell movement is essential during embryogenesis to establish tissue patterns and to drive morphogenetic pathways and in the adult for tissue repair and to direct cells to sites of infection. Animal cells move by crawling and the driving force is derived primarily from the coordinated assembly and disassembly of actin filaments. The small GTPases, Rho, Rac, and Cdc42, regulate the organization of actin filaments and we have analyzed their contributions to the movement of primary embryo fibroblasts in an in vitro wound healing assay. Rac is essential for the protrusion of lamellipodia and for forward movement. Cdc42 is required to maintain cell polarity, which includes the localization of lamellipodial activity to the leading edge and the reorientation of the Golgi apparatus in the direction of movement. Rho is required to maintain cell adhesion during movement, but stress fibers and focal adhesions are not required. Finally, Ras regulates focal adhesion and stress fiber turnover and this is essential for cell movement. We conclude that the signal transduction pathways controlled by the four small GTPases, Rho, Rac, Cdc42, and Ras, cooperate to promote cell movement. PMID:10087266

Identifying and quantifying urban recharge: a review

NASA Astrophysics Data System (ADS)

Lerner, David N.

2002-02-01

The sources of and pathways for groundwater recharge in urban areas are more numerous and complex than in rural environments. Buildings, roads, and other surface infrastructure combine with man-made drainage networks to change the pathways for precipitation. Some direct recharge is lost, but additional recharge can occur from storm drainage systems. Large amounts of water are imported into most cities for supply, distributed through underground pipes, and collected again in sewers or septic tanks. The leaks from these pipe networks often provide substantial recharge. Sources of recharge in urban areas are identified through piezometry, chemical signatures, and water balances. All three approaches have problems. Recharge is quantified either by individual components (direct recharge, water-mains leakage, septic tanks, etc.) or holistically. Working with individual components requires large amounts of data, much of which is uncertain and is likely to lead to large uncertainties in the final result. Recommended holistic approaches include the use of groundwater modelling and solute balances, where various types of data are integrated. Urban recharge remains an under-researched topic, with few high-quality case studies reported in the literature.

Endoplasmic reticulum stress and proteasomal system in amyotrophic lateral sclerosis.

PubMed

Karademir, Betul; Corek, Ceyda; Ozer, Nesrin Kartal

2015-11-01

Protein processing including folding, unfolding and degradation is involved in the mechanisms of many diseases. Unfolded protein response and/or endoplasmic reticulum stress are accepted to be the first steps which should be completed via protein degradation. In this direction, proteasomal system and autophagy play important role as the degradation pathways and controlled via complex mechanisms. Amyotrophic lateral sclerosis is a multifactorial neurodegenerative disease which is also known as the most catastrophic one. Mutation of many different genes are involved in the pathogenesis such as superoxide dismutase 1, chromosome 9 open reading frame 72 and ubiquilin 2. These genes are mainly related to the antioxidant defense systems, endoplasmic reticulum stress related proteins and also protein aggregation, degradation pathways and therefore mutation of these genes cause related disorders.This review focused on the role of protein processing via endoplasmic reticulum and proteasomal system in amyotrophic lateral sclerosis which are the main players in the pathology. In this direction, dysfunction of endoplasmic reticulum associated degradation and related cell death mechanisms that are autophagy/apoptosis have been detailed. Copyright © 2015 Elsevier Inc. All rights reserved.

The Transcription Factor EB Links Cellular Stress to the Immune Response

.

PubMed

Nabar, Neel R; Kehrl, John H

2017-06-01

The transcription factor EB (TFEB) is the master transcriptional regulator of autophagy and lysosome biogenesis. Recent advances have led to a paradigm shift in our understanding of lysosomes from a housekeeping cellular waste bin to a dynamically regulated pathway that is efficiently turned up or down based on cellular needs. TFEB coordinates the cellular response to nutrient deprivation and other forms of cell stress through the lysosome system, and regulates a myriad of cellular processes associated with this system including endocytosis, phagocytosis, autophagy, and lysosomal exocytosis. Autophagy and the endolysosomal system are critical to both the innate and adaptive arms of the immune system, with functions in effector cell priming and direct pathogen clearance. Recent studies have linked TFEB to the regulation of the immune response through the endolysosmal pathway and by direct transcriptional activation of immune related genes. In this review, we discuss the current understanding of TFEB's function and the molecular mechanisms behind TFEB activation. Finally, we discuss recent advances linking TFEB to the immune response that positions lysosomal signaling as a potential target for immune modulation.

GPER (GPR30): A Nongenomic Receptor (GPCR) for Steroid Hormones with Implications for Cardiovascular Disease and Cancer.

PubMed

Feldman, Ross D; Limbird, Lee E

2017-01-06

Although the rapid effects of steroids, such as estrogen and aldosterone, were postulated originally to be nongenomic, it is now appreciated that activation of such signaling pathways via a steroid-acting G protein-coupled receptor, the G protein estrogen receptor (GPER), has important transcription-dependent outcomes in the regulation of cell growth and programmed cell death secondary to GPER-regulated second-messenger pathways. GPER is expressed ubiquitously and has diverse biological effects, including regulation of endocrine, immune, neuronal, and cardiovascular functions. Perhaps the most biologically important consequences of GPER activation are the regulation of cell growth, migration, and apoptotic cell death. These cell growth regulatory effects, important in cancer biology, are also relevant in the regulation of cardiac and vascular hypertrophy and in the response to ischemia. This review provides a summary of relevant findings of the impact of GPER regulation by either estradiol or aldosterone in in vitro model systems and extends those findings to in vivo studies of direct clinical relevance for development of GPER-directed agents for treatment of cancer and cardiovascular diseases associated with cellular proliferation.

Novel HDL-directed pharmacotherapeutic strategies

PubMed Central

deGoma, Emil M.; Rader, Daniel J.

2011-01-01

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin–cholesterol acyltransferase. PMID:21243009

The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling

PubMed Central

Chakraborty, Atanu; Diefenbacher, Markus E.; Mylona, Anastasia; Kassel, Olivier; Behrens, Axel

2015-01-01

The c-Jun/AP-1 transcription factor controls key cellular behaviours, including proliferation and apoptosis, in response to JNK and Ras/MAPK signalling. While the JNK pathway has been well characterised, the mechanism of activation by Ras was elusive. Here we identify the uncharacterised ubiquitin ligase Trim7 as a critical component of AP-1 activation via Ras. We found that MSK1 directly phosphorylates Trim7 in response to direct activation by the Ras–Raf–MEK–ERK pathway, and this modification stimulates Trim7 E3 ubiquitin ligase activity. Trim7 mediates Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilisation. Consequently, Trim7 depletion reduces RACO-1 levels and AP-1-dependent gene expression. Moreover, transgenic overexpression of Trim7 increases lung tumour burden in a Ras-driven cancer model, and knockdown of Trim7 in established xenografts reduces tumour growth. Thus, phosphorylation-ubiquitination crosstalk between MSK1, Trim7 and RACO-1 completes the long sought-after mechanism linking growth factor signalling and AP-1 activation. PMID:25851810

miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-{beta}

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

Song, Libing, E-mail: lb.song1@gmail.com; Huang, Quan; Chen, Kun

2010-11-05

Research highlights: {yields} miR-218 is markedly downregulated in glioma cell lines and in primary glioma tissues. {yields} Upregulation of miR-218 dramatically reduces the invasive ability of glioma cells. {yields} Ectopic expression of miR-218 inactivates IKK-{beta}/NF-{kappa}B signaling pathway. {yields} miR-218 directly targets the 3'-untranslated region (3'-UTR) of IKK-{beta}. -- Abstract: Aberrant activation of nuclear factor-kappa B (NF-{kappa}B) pathway has been proven to play important roles in the development and progression of cancers. Activation of NF-{kappa}B via the classical pathway is modulated by I{kappa}Bs kinase (IKK-{beta}). However, the mechanism underlying the epigenetic regulation of IKK-{beta}/NF-{kappa}B pathway remains largely unknown. In this study,more » we found that the expression level of miR-218 was markedly downregulated in glioma cell lines and in human primary glioma tissues. Upregulation of miR-218 dramatically reduced the migratory speed and invasive ability of glioma cells. Furthermore, we showed that ectopically expressing miR-218 in glioma cells resulted in downregulation of matrix metalloproteinase-9 (MMP-9) and reduction in NF-{kappa}B transactivity at a transcriptional level, but inhibition of miR-218 enhanced the expression of MMP-9 and transcriptional activity of NF-{kappa}B. Moreover, we showed that miR-218 inactivated the NF-{kappa}B pathway through downregulating IKK-{beta} expression by directly targeting the 3'-untranslated region (3'-UTR) of IKK-{beta}. Taken together, our results suggest that miR-218 plays an important role in preventing the invasiveness of glioma cells, and our results present a novel mechanism of miRNA-mediated direct suppression of IKK-{beta}/NF-{kappa}B pathway in gliomas.« less

Characterization of cell surface and extracellular matrix remodeling of Azospirillum brasilense chemotaxis-like 1 signal transduction pathway mutants by atomic force microscopy.

PubMed

Edwards, Amanda Nicole; Siuti, Piro; Bible, Amber N; Alexandre, Gladys; Retterer, Scott T; Doktycz, Mitchel J; Morrell-Falvey, Jennifer L

2011-01-01

To compete in complex microbial communities, bacteria must sense environmental changes and adjust cellular functions for optimal growth. Chemotaxis-like signal transduction pathways are implicated in the regulation of multiple behaviors in response to changes in the environment, including motility patterns, exopolysaccharide production, and cell-to-cell interactions. In Azospirillum brasilense, cell surface properties, including exopolysaccharide production, are thought to play a direct role in promoting flocculation. Recently, the Che1 chemotaxis-like pathway from A. brasilense was shown to modulate flocculation, suggesting an associated modulation of cell surface properties. Using atomic force microscopy, distinct changes in the surface morphology of flocculating A. brasilense Che1 mutant strains were detected. Whereas the wild-type strain produces a smooth mucosal extracellular matrix after 24 h, the flocculating Che1 mutant strains produce distinctive extracellular fibril structures. Further analyses using flocculation inhibition, lectin-binding assays, and comparison of lipopolysaccharides profiles suggest that the extracellular matrix differs between the cheA1 and the cheY1 mutants, despite an apparent similarity in the macroscopic floc structures. Collectively, these data indicate that disruption of the Che1 pathway is correlated with distinctive changes in the extracellular matrix, which likely result from changes in surface polysaccharides structure and/or composition. FEMS Microbiology Letters © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. No claim to original US government works.

Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies.

PubMed

Thellung, Stefano; Favoni, Roberto E; Würth, Roberto; Nizzari, Mario; Pattarozzi, Alessandra; Daga, Antonio; Florio, Tullio; Barbieri, Federica

2016-01-01

Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.

Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway.

PubMed

Liu, Yan-Qiu; Hong, Zhi-Lai; Zhan, Li-Bin; Chu, Hui-Ying; Zhang, Xiao-Zhe; Li, Guo-Hui

2016-08-25

Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis.

Drinking motives as mediators of the impulsivity-substance use relation: pathways for negative urgency, lack of premeditation, and sensation seeking.

PubMed

Adams, Zachary W; Kaiser, Alison J; Lynam, Donald R; Charnigo, Richard J; Milich, Richard

2012-07-01

Trait impulsivity is a reliable, robust predictor of risky, problematic alcohol use. Mounting evidence supports a multidimensional model of impulsivity, whereby several distinct traits serve as personality pathways to rash action. Different impulsivity-related traits may predispose individuals to drink for different reasons (e.g., to enhance pleasure, to cope with distress) and these different motives may, in turn, influence drinking behavior. Previous findings support such a mediational model for two well-studied traits: sensation seeking and lack of premeditation. This study addresses other impulsivity-related traits, including negative urgency. College students (N=432) completed questionnaires assessing personality, drinking motives, and multiple indicators of problematic drinking. Negative urgency, sensation seeking, and lack of premeditation were all significantly related to problematic drinking. When drinking motives were included in the model, direct effects for sensation seeking and lack of premeditation remained significant, and indirect effects of sensation seeking and lack of premeditation on problematic drinking were observed through enhancement motives. A distinct pathway was observed for negative urgency. Negative urgency bore a significant total effect on problematic drinking through both coping and enhancement motives. This study highlights unique motivational pathways through which different impulsive traits may operate, suggesting that interventions aimed at preventing or reducing problematic drinking should be tailored to individuals' personalities. For instance, individuals high in negative urgency may benefit from learning healthier strategies for coping with distress. Copyright © 2012 Elsevier Ltd. All rights reserved.

Drinking Motives as Mediators of the Impulsivity-Substance Use Relation: Pathways for Negative Urgency, Lack of Premeditation, and Sensation Seeking

PubMed Central

Adams, Zachary W.; Kaiser, Alison J.; Lynam, Donald R.; Charnigo, Richard J.; Milich, Richard

2012-01-01

Trait impulsivity is a reliable, robust predictor of risky, problematic alcohol use. Mounting evidence supports a multidimensional model of impulsivity, whereby several distinct traits serve as personality pathways to rash action. Different impulsivity-related traits may predispose individuals to drink for different reasons (e.g., to enhance pleasure, to cope with distress) and these different motives may, in turn, influence drinking behavior. Previous findings support such a mediational model for two well-studied traits: sensation seeking and lack of premeditation. This study addresses other impulsivity-related traits, including negative urgency. College students (N = 432) completed questionnaires assessing personality, drinking motives, and multiple indicators of problematic drinking. Negative urgency, sensation seeking, and lack of premeditation were all significantly related to problematic drinking. When drinking motives were included in the model, direct effects for sensation seeking and lack of premeditation remained significant, and indirect effects of sensation seeking and lack of premeditation on problematic drinking were observed through enhancement motives. A distinct pathway was observed for negative urgency. Negative urgency bore a significant total effect on problematic drinking through both coping and enhancement motives. This study highlights unique motivational pathways through which different impulsive traits may operate, suggesting that interventions aimed at preventing or reducing problematic drinking should be tailored to individuals' personalities. For instance, individuals high in negative urgency may benefit from learning healthier strategies for coping with distress. PMID:22472524

Apelin13/APJ promotes proliferation of colon carcinoma by activating Notch3 signaling pathway.

PubMed

Chen, Tong; Liu, Ning; Xu, Guang-Meng; Liu, Tong-Jun; Liu, Ying; Zhou, Yan; Huo, Si-Bo; Zhang, Kai

2017-11-24

The link between Apelin (APL)/APL receptor (APJ) and Jagged (JAG)/Notch signaling pathways in colorectal cancer (CRC) has been poorly investigated. APL/APJ system, a potent angiogenic factor, is up-regulated in a variety of cancers. It contributes to tumor angiogenesis, and correlates with progression of malignancy. JAG/Notch signaling also contributes to progression, proliferation and metastasis of multiple cancers, including CRC. Here we tested the hypothesis that APL/APJ system promotes CRC proliferation by up-regulating Notch3, thus allowing further binding of JAG1 to Notch3. We used a variety of methods including Western blot, RT-qPCR, gene silencing, ELISA, immunofluorescence staining, to investigate the interaction between APL/APJ system and Notch3 signaling pathway in both surgically-resected specimens and CRC cell line LS180. We show that the expression of APL13, APJ, and Notch3 is elevated in CRC. We further demonstrate that APL13 can be secreted into culture media of LS180 cells, suggesting the existence of autocrine loop in CRC. Moreover, we found that APL13 stimulated expression of Notch3. Finally, we found that inhibition of either APJ or Notch3 prevents proliferation of LS180 cells. Our results suggest that APL13/APJ and JAG1/Notch3 signaling pathways are linked in CRC. These findings provide a new direction to the efforts targeting effective therapeutic and management approaches in the treatment of CRC.

Cluster Analysis of Atmospheric Dynamics and Pollution Transport in a Coastal Area

NASA Astrophysics Data System (ADS)

Sokolov, Anton; Dmitriev, Egor; Maksimovich, Elena; Delbarre, Hervé; Augustin, Patrick; Gengembre, Cyril; Fourmentin, Marc; Locoge, Nadine

2016-11-01

Summertime atmospheric dynamics in the coastal zone of the industrialized Dunkerque agglomeration in northern France was characterized by a cluster analysis of back trajectories in the context of pollution transport. The MESO-NH atmospheric model was used to simulate the local dynamics at multiple scales with horizontal resolution down to 500 m, and for the online calculation of the Lagrangian backward trajectories with 30-min temporal resolution. Airmass transport was performed along six principal pathways obtained by the weighted k-means clustering technique. Four of these centroids corresponded to a range of wind speeds over the English Channel: two for wind directions from the north-east and two from the south-west. Another pathway corresponded to a south-westerly continental transport. The backward trajectories of the largest and most dispersed sixth cluster contained low wind speeds, including sea-breeze circulations. Based on analyses of meteorological data and pollution measurements, the principal atmospheric pathways were related to local air-contamination events. Continuous air quality and meteorological data were collected during the Benzene-Toluene-Ethylbenzene-Xylene 2006 campaign. The sites of the pollution measurements served as the endpoints for the backward trajectories. Pollutant transport pathways corresponding to the highest air contamination were defined.

Prickle1b mediates interpretation of migratory cues during zebrafish facial branchiomotor neuron migration

PubMed Central

Mapp, Oni M.; Wanner, Sarah J.; Rohrschneider, Monica R.; Prince, Victoria E.

2011-01-01

The facial branchiomotor neurons undergo a characteristic tangential migration in the vertebrate hindbrain. Several signaling mechanisms have been implicated in this process, including the non-canonical Wnt/planar cell polarity (PCP) pathway. However, the role of this signaling pathway in controlling the dynamics of these neurons is unclear. Here, we describe the cellular dynamics of the facial neurons as they migrate, focusing on the speed and direction of migration, extension of protrusions, cell shape and orientation. Furthermore, we show that the PET/LIM domain protein Prickle1b (Pk1b) is required for several aspects of these migratory behaviors, including cell orientation. However, we find that centrosome localization is not significantly affected by disruption of Pk1b function, suggesting that polarization of the neurons is not completely lost. Together, our data suggest that Pk1b function may be required to integrate the multiple migratory cues received by the neurons into polarization instructions for proper posterior movement. PMID:20503357

Metabolic Pathway Assignment of Plant Genes based on Phylogenetic Profiling–A Feasibility Study

PubMed Central

Weißenborn, Sandra; Walther, Dirk

2017-01-01

Despite many developed experimental and computational approaches, functional gene annotation remains challenging. With the rapidly growing number of sequenced genomes, the concept of phylogenetic profiling, which predicts functional links between genes that share a common co-occurrence pattern across different genomes, has gained renewed attention as it promises to annotate gene functions based on presence/absence calls alone. We applied phylogenetic profiling to the problem of metabolic pathway assignments of plant genes with a particular focus on secondary metabolism pathways. We determined phylogenetic profiles for 40,960 metabolic pathway enzyme genes with assigned EC numbers from 24 plant species based on sequence and pathway annotation data from KEGG and Ensembl Plants. For gene sequence family assignments, needed to determine the presence or absence of particular gene functions in the given plant species, we included data of all 39 species available at the Ensembl Plants database and established gene families based on pairwise sequence identities and annotation information. Aside from performing profiling comparisons, we used machine learning approaches to predict pathway associations from phylogenetic profiles alone. Selected metabolic pathways were indeed found to be composed of gene families of greater than expected phylogenetic profile similarity. This was particularly evident for primary metabolism pathways, whereas for secondary pathways, both the available annotation in different species as well as the abstraction of functional association via distinct pathways proved limiting. While phylogenetic profile similarity was generally not found to correlate with gene co-expression, direct physical interactions of proteins were reflected by a significantly increased profile similarity suggesting an application of phylogenetic profiling methods as a filtering step in the identification of protein-protein interactions. This feasibility study highlights the potential and challenges associated with phylogenetic profiling methods for the detection of functional relationships between genes as well as the need to enlarge the set of plant genes with proven secondary metabolism involvement as well as the limitations of distinct pathways as abstractions of relationships between genes. PMID:29163570

Genetically Expressed Transneuronal Tracer Reveals Direct and Indirect Serotonergic Descending Control Circuits

PubMed Central

BRAZ, JOÃO MANUEL; BASBAUM, ALLAN I.

2016-01-01

Despite the evidence for a significant contribution of brainstem serotonergic (5HT) systems to the control of spinal cord “pain” transmission neurons, attention has turned recently to the influence of nonserotonergic neurons, including the facilitatory and inhibitory controls that originate from so-called “on” and “off” cells of the rostroventral medulla (RVM). Unclear, however, is the extent to which these latter circuits interact with or are influenced by the serotonergic cell groups. To address this question we selectively targeted expression of a transneuronal tracer, wheat germ agglutinin (WGA), in the 5HT neurons so as to study the interplay between the 5HT and non-5HT systems. In addition to confirming the direct medullary 5HT projection to the spinal cord we also observed large numbers of non-5HT neurons, in the medullary nucleus reticularis gigantocellularis and magnocellularis, that were WGA-immunoreactive, i.e., were transneuronally labeled from 5HT neurons. Fluoro-Gold injections into the spinal cord established that these reticular neurons are not only postsynaptic to the 5HT neurons of the medulla, but that most are also at the origin of descending, bulbospinal pathways. By contrast, we found no evidence that neurons of the midbrain periaqueductal gray that project to the RVM are postsynaptic to midbrain or medullary 5HT neurons. Finally, we found very few examples of WGA-immunoreactive noradrenergic neurons, which suggests that there is considerable independence of the monoaminergic bulbospinal pathways. Our results indicate that 5HT neurons influence “pain” processing at the spinal cord level both directly and indirectly via feedforward connections with multiple non-5HT descending control pathways. PMID:18273889

Melatonin regulates somatotrope and lactotrope function through common and distinct signaling pathways in cultured primary pituitary cells from female primates.

PubMed

Ibáñez-Costa, Alejandro; Córdoba-Chacón, José; Gahete, Manuel D; Kineman, Rhonda D; Castaño, Justo P; Luque, Raúl M

2015-03-01

Melatonin (MT) is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied, some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between MT and pituitary function remains controversial, and studies focusing on the direct role of MT in normal pituitary cells are limited to nonprimate species. Here, adult normal primate (baboons) primary pituitary cell cultures were used to determine the direct impact of MT on the functioning of all pituitary cell types from the pars distalis. MT increased GH and prolactin (PRL) expression/release in a dose- and time-dependent fashion, a response that was blocked by somatostatin. However, MT did not significantly affect ACTH, FSH, LH, or TSH expression/release. MT did not alter GHRH- or ghrelin-induced GH and/or PRL secretions, suggesting that MT may activate similar signaling pathways as ghrelin/GHRH. The effects of MT on GH/PRL release, which are likely mediated through MT1 receptor, involve both common (adenylyl cyclase/protein kinase A/extracellular calcium-channels) and distinct (phospholipase C/intracellular calcium-channels) signaling pathways. Actions of MT on pituitary cells also included regulation of the expression of other key components for the control of somatotrope/lactotrope function (GHRH, ghrelin, and somatostatin receptors). These results show, for the first time in a primate model, that MT directly regulates somatotrope/lactotrope function, thereby lending support to the notion that the actions of MT on these cells might substantially contribute to the define daily patterns of GH and PRL observed in primates and perhaps in humans.

Childhood socioeconomic disadvantage and prediabetes and diabetes in later life: a study of biopsychosocial pathways.

PubMed

Tsenkova, Vera; Pudrovska, Tetyana; Karlamangla, Arun

2014-10-01

We examined the relationship between childhood socioeconomic status (SES) and glucoregulation in later life and used a life-course framework to examine critical periods and underlying pathways. Data came from the Midlife in the US (MIDUS) national study (n = 895). Childhood SES indicators retrospectively reported at MIDUS I were used to create a childhood SES disadvantage index. Adult SES disadvantage and potential pathways were measured at MIDUS I and included waist circumference, depressive symptoms, and physical activity. Glucose and hemoglobin A1c, measured approximately 9 to 10 years later at MIDUS II, were used to create the ordinal outcome measure (no diabetes/prediabetes/diabetes). Childhood SES disadvantage predicted increased odds of prediabetes and diabetes net of age, sex, race, and smoking (odds ratio = 1.11, 95% confidence interval = 1.01-1.22). Childhood SES disadvantage predicted adult SES disadvantage (β = .26, p = .001) and the three key mediators: waist circumference (β = 0.10, p = .002), physical activity (β = -0.11, p = .001), and depressive symptoms (β = 0.07, p = .072). When childhood and adult SES disadvantage were in the same model, only adult SES predicted glucoregulation (odds ratio = 1.07, 95% confidence interval = 1.01-1.13). The SES disadvantage measures were no longer significantly associated with glucoregulation after including waist circumference, physical activity, and depressive symptoms, all of which were significant predictors of glucoregulation. The consequences of childhood SES disadvantage are complex and include both critical period and pathway effects. The lack of a direct effect of childhood SES on glucoregulation does not negate the importance of early environment but suggests that early-life socioeconomic factors propel unequal life-course trajectories that ultimately influence health.

Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression.

PubMed

Lee, Jong Hun; Khor, Tin Oo; Shu, Limin; Su, Zheng-Yuan; Fuentes, Francisco; Kong, Ah-Ng Tony

2013-02-01

Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-κB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2-mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2-Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including NSAIDs. Copyright © 2012 Elsevier Inc. All rights reserved.

Childhood Socioeconomic Disadvantage and Pre-diabetes and Diabetes in Later Life: A Study of Biopsychosocial Pathways

PubMed Central

Tsenkova, Vera; Pudrovska, Tetyana; Karlamangla, Arun

2014-01-01

Objective We examined the relationship between childhood socioeconomic status (SES) and glucoregulation in later life and used a life-course framework to examine critical periods and underlying pathways. Methods Data came from the MIDUS (Midlife in the U.S.) national study (n=895). Childhood SES indicators retrospectively reported at MIDUS I were used to create a childhood SES disadvantage index. Adult SES disadvantage and potential pathways were measured at MIDUS I and included waist circumference, depressive symptoms, and physical activity. Glucose and HbA1c, measured approximately 9-10 years later at MIDUS II, were used to create the ordinal outcome measure (no diabetes/prediabetes/diabetes). Results Childhood SES disadvantage predicted increased odds of prediabetes and diabetes net of age, gender, race, and smoking (OR=1.11, 95% CI: 1.01-1.22). Childhood SES disadvantage predicted adult SES disadvantage (β=.26, p=.001) and the three key mediators: higher waist circumference (β=.10, p=.002), lower physical activity (β=−.11, p=.001), and marginally higher depressive symptoms (β=.07, p=.072). When childhood and adult SES disadvantage were in the same model, only adult SES predicted glucoregulation (OR=1.07, 95% CI: 1.01-1.13). The SES disadvantage measures were no longer significantly associated with glucoregulation after including waist circumference, physical activity, and depressive symptoms, all of which were significant predictors of glucoregulation. Conclusions The consequences of childhood SES disadvantage are complex and include both critical period and pathway effects. The lack of a direct effect of childhood SES on glucoregulation does not negate the importance of early environment but suggests that early-life socioeconomic factors propel unequal life-course trajectories that ultimately influence health. PMID:25272201

Early risk pathways to physical versus relational peer aggression: The interplay of externalizing behavior and corporal punishment varies by child sex.

PubMed

Zulauf, Courtney A; Sokolovsky, Alexander W; Grabell, Adam S; Olson, Sheryl L

2018-03-01

Children who aggress against their peers may use physical or relational forms, yet little research has looked at early childhood risk factors and characteristics that uniquely predict high levels of relational versus physical aggression in preadolescence. Accordingly, the main aim of our study was to link early corporal punishment and externalizing behavior to children's physical and relational peer aggression during preadolescence and to examine how these pathways differed by sex. Participants were 193, 3-year-old boys (39%) and girls who were reassessed following the transition to kindergarten (5.5 years) and preadolescence (10.5 years). A series of autoregressive, cross-lagged path analyses were conducted to examine the relationships between child externalizing problems and corporal punishment at ages 3 and 5.5 years, and their association with physical and relational aggression at age 10.5. Multiple group analysis was used to determine whether pathways differed by sex. Three developmental pathways were identified: (i) direct associations between stable childhood externalizing problems and later physical aggression; (ii) a direct pathway from early corporal punishment to preadolescent relational and physical peer aggression; and (iii) an indirect pathway from early corporal punishment to later physical aggression via continuing externalizing problems in middle childhood. Child sex moderated the nature of these pathways, as well as the direction of association between risk and outcome variables. These data advance our understanding of the etiology of distinct forms of peer aggression and highlight the potential for more efficacious prevention and intervention efforts in the early childhood years. © 2018 Wiley Periodicals, Inc.

A systematic review of transmission dynamic studies of methicillin-resistant Staphylococcus aureus in non-hospital residential facilities.

PubMed

Kwok, Kin On; Read, Jonathan M; Tang, Arthur; Chen, Hong; Riley, Steven; Kam, Kai Man

2018-04-18

Non-hospital residential facilities are important reservoirs for MRSA transmission. However, conclusions and public health implications drawn from the many mathematical models depicting nosocomial MRSA transmission may not be applicable to these settings. Therefore, we reviewed the MRSA transmission dynamics studies in defined non-hospital residential facilities to: (1) provide an overview of basic epidemiology which has been addressed; (2) identify future research direction; and (3) improve future model implementation. A review was conducted by searching related keywords in PUBMED without time restriction as well as internet searches via Google search engine. We included only articles describing the epidemiological transmission pathways of MRSA/community-associated MRSA within and between defined non-hospital residential settings. Among the 10 included articles, nursing homes (NHs) and correctional facilities (CFs) were two settings considered most frequently. Importation of colonized residents was a plausible reason for MRSA outbreaks in NHs, where MRSA was endemic without strict infection control interventions. The importance of NHs over hospitals in increasing nosocomial MRSA prevalence was highlighted. Suggested interventions in NHs included: appropriate staffing level, screening and decolonizing, and hand hygiene. On the other hand, the small population amongst inmates in CFs has no effect on MRSA community transmission. Included models ranged from system-level compartmental models to agent-based models. There was no consensus over the course of disease progression in these models, which were mainly featured with NH residents /CF inmates/ hospital patients as transmission pathways. Some parameters used by these models were outdated or unfit. Importance of NHs has been highlighted from these current studies addressing scattered aspects of MRSA epidemiology. However, the wide variety of non-hospital residential settings suggest that more work is needed before robust conclusions can be drawn. Learning from existing work for hospitals, we identified critical future research direction in this area from infection control, ecological and economic perspectives. From current model deficiencies, we suggest more transmission pathways be specified to depict MRSA transmission, and further empirical studies be stressed to support evidence-based mathematical models of MRSA in non-hospital facilities. Future models should be ready to cope with the aging population structure.

Quorum Sensing Regulation of Competence and Bacteriocins in Streptococcus pneumoniae and mutans

PubMed Central

Shanker, Erin; Federle, Michael J.

2017-01-01

The human pathogens Streptococcus pneumoniae and Streptococcus mutans have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural transformation. Natural transformation provides bacteria with a mechanism to repair damaged genes or as a source of new advantageous traits. In S. pneumoniae, the competence pathway is controlled by the two-component signal transduction pathway ComCDE, which directly regulates SigX, the alternative sigma factor required for the initiation into competence. Over the past two decades, effectors of cellular killing (i.e., fratricides) have been recognized as important targets of the pneumococcal competence QS pathway. Recently, direct interactions between the ComCDE and the paralogous BlpRH pathway, regulating bacteriocin production, were identified, further strengthening the interconnections between these two QS systems. Interestingly, a similar theme is being revealed in S. mutans, the primary etiological agent of dental caries. This review compares the relationship between the bacteriocin and the competence QS pathways in both S. pneumoniae and S. mutans, and hopes to provide clues to regulatory pathways across the genus Streptococcus as a potential tool to efficiently investigate putative competence pathways in nontransformable streptococci. PMID:28067778

46,XX sex reversal.

PubMed

Zenteno-Ruiz, J C; Kofman-Alfaro, S; Méndez, J P

2001-01-01

In humans, sexual differentiation is directed by SRY, a master regulatory gene located at the Y chromosome. This gene initiates the male pathway or represses the female pathway by regulating the transcription of downstream genes; however, the precise mechanisms by which SRY acts are largely unknown. Moreover, several genes have recently been implicated in the development of the bipotential gonad even before SRY is expressed. In some individuals, the normal process of sexual differentiation is altered and a sex reversal disorder is observed. These subjects present the chromosomes of one sex but the physical attributes of the other. Over the past years, considerable progress has been achieved in the molecular characterization of these disorders by using a combination of strategies including cell biology, animal models, and by studying patients with these pathologic entities.

The OH-initiated atmospheric oxidation of divinyl sulfoxide: A theoretical investigation on the reaction mechanism

NASA Astrophysics Data System (ADS)

Zhang, Weichao; Zhang, Dongju

2012-08-01

The potential energy surfaces for the OH + divinyl sulfoxide reaction in the presence of O2/NO are theoretically characterized at the CCSD(T)/6-311+G(d,p)//BH&HLYP/6-311++G(d,p)+ZPE level of theory. Various possible pathways including the direct hydrogen abstraction channels and the addition-elimination channels are considered. The calculations show that the exclusive feasible entrance channel is the formation of adduct CH2(OH)CHS(O)CHdbnd CH2 (IM1) in the initial reaction pathways. In the atmosphere, the newly formed adduct IM1 can further react with O2/NO to form the dominant products HCHO + C(O)HS(O)CHdbnd CH2 (P9). The calculated results confirm the experimental studies.

Lifecycle assessment of microalgae to biofuel: Comparison of thermochemical processing pathways

DOE PAGES

Bennion, Edward P.; Ginosar, Daniel M.; Moses, John; ...

2015-01-16

Microalgae are currently being investigated as a renewable transportation fuel feedstock based on various advantages that include high annual yields, utilization of poor quality land, does not compete with food, and can be integrated with various waste streams. This study focuses on directly assessing the impact of two different thermochemical conversion technologies on the microalgae to biofuel process through life cycle assessment. A system boundary of a “well to pump” (WTP) is defined and includes sub-process models of the growth, dewatering, thermochemical bio-oil recovery, bio-oil stabilization, conversion to renewable diesel, and transport to the pump. Models were validated with experimentalmore » and literature data and are representative of an industrial-scale microalgae to biofuel process. Two different thermochemical bio-oil conversion systems are modeled and compared on a systems level, hydrothermal liquefaction (HTL) and pyrolysis. The environmental impact of the two pathways were quantified on the metrics of net energy ratio (NER), defined here as energy consumed over energy produced, and greenhouse gas (GHG) emissions. Results for WTP biofuel production through the HTL pathway were determined to be 1.23 for the NER and GHG emissions of -11.4 g CO 2-eq (MJ renewable diesel) -1. WTP biofuel production through the pyrolysis pathway results in a NER of 2.27 and GHG emissions of 210 g CO2 eq (MJ renewable diesel)-1. The large environmental impact associated with the pyrolysis pathway is attributed to feedstock drying requirements and combustion of co-products to improve system energetics. Discussion focuses on a detailed breakdown of the overall process energetics and GHGs, impact of modeling at laboratory- scale compared to industrial-scale, environmental impact sensitivity to engineering systems input parameters for future focused research and development and a comparison of results to literature.« less

Developmental Pathways to Conduct Disorder: Implications for Future Directions in Research, Assessment, and Treatment

ERIC Educational Resources Information Center

Frick, Paul J.

2012-01-01

Research has indicated that there are several common pathways through which children and adolescents develop conduct disorder, each with different risk factors and each with different underlying developmental mechanisms leading to the child's aggressive and antisocial behavior. The current article briefly summarizes research on these pathways,…

Principles for circadian orchestration of metabolic pathways.

PubMed

Thurley, Kevin; Herbst, Christopher; Wesener, Felix; Koller, Barbara; Wallach, Thomas; Maier, Bert; Kramer, Achim; Westermark, Pål O

2017-02-14

Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.

Principles for circadian orchestration of metabolic pathways

PubMed Central

Thurley, Kevin; Herbst, Christopher; Wesener, Felix; Koller, Barbara; Wallach, Thomas; Maier, Bert; Kramer, Achim

2017-01-01

Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo. PMID:28159888

Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway

PubMed Central

Reizis, Boris; Leder, Philip

2002-01-01

The Notch signaling pathway regulates the commitment and early development of T lymphocytes. We studied Notch-mediated induction of the pre-T cell receptor α (pTa) gene, a T-cell-specific transcriptional target of Notch. The pTa enhancer was activated by Notch signaling and contained binding sites for its nuclear effector, CSL. Mutation of the CSL-binding sites abolished enhancer induction by Notch and delayed the up-regulation of pTa transgene expression during T cell lineage commitment. These results show a direct mechanism of stage- and tissue-specific gene induction by the mammalian Notch/CSL signaling pathway. PMID:11825871

Turning over renal osteodystrophy dogma: direct actions of FGF23 on osteoblast β-catenin pathway.

PubMed

Schiavi, Susan C; Moysés, Rosa M A

2016-07-01

Although recognized as a major complication of chronic kidney disease (CKD), the pathophysiology of the CKD-related mineral and bone disorder (CKD-MBD) is not completely understood. Recently, the inhibition of Wnt/β-catenin pathway in osteocytes by sclerostin has been shown to play a role in CKD-MBD. The study by Carrilo-Lopez et al. confirms this inhibition in an experimental model of CKD. Moreover, they describe direct actions of FGF23-Klotho on osteoblasts, increasing the expression of DKK1, another Wnt/β-catenin pathway inhibitor. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

High resolution Chromatin Immunoprecipitation (ChIP) sequencing reveals novel bindings targets and prognostic role for SOX11 in Mantle cell lymphoma

PubMed Central

Kuo, Pei-Yu; Leshchenko, Violetta V.; Fazzari, Melissa J.; Perumal, Deepak; Gellen, Tobias; He, Tianfang; Iqbal, Javeed; Baumgartner-Wennerholm, Stefanie; Nygren, Lina; Zhang, Fan; Zhang, Weijia; Suh, K. Stephen; Goy, Andre; Yang, David T.; Chan, Wing-Chung; Kahl, Brad S.; Verma, Amit K.; Gascoyne, Randy D.; Kimby, Eva; Sander, Birgitta; Ye, B. Hilda; Melnick, Ari M.; Parekh, Samir

2015-01-01

SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-Hodgkin's lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes. PMID:24681958

Combinatorial pathway optimization in Escherichia coli by directed co-evolution of rate-limiting enzymes and modular pathway engineering.

PubMed

Lv, Xiaomei; Gu, Jiali; Wang, Fan; Xie, Wenping; Liu, Min; Ye, Lidan; Yu, Hongwei

2016-12-01

Metabolic engineering of microorganisms for heterologous biosynthesis is a promising route to sustainable chemical production which attracts increasing research and industrial interest. However, the efficiency of microbial biosynthesis is often restricted by insufficient activity of pathway enzymes and unbalanced utilization of metabolic intermediates. This work presents a combinatorial strategy integrating modification of multiple rate-limiting enzymes and modular pathway engineering to simultaneously improve intra- and inter-pathway balance, which might be applicable for a range of products, using isoprene as an example product. For intra-module engineering within the methylerythritol-phosphate (MEP) pathway, directed co-evolution of DXS/DXR/IDI was performed adopting a lycopene-indicated high-throughput screening method developed herein, leading to 60% improvement of isoprene production. In addition, inter-module engineering between the upstream MEP pathway and the downstream isoprene-forming pathway was conducted via promoter manipulation, which further increased isoprene production by 2.94-fold compared to the recombinant strain with solely protein engineering and 4.7-fold compared to the control strain containing wild-type enzymes. These results demonstrated the potential of pathway optimization in isoprene overproduction as well as the effectiveness of combining metabolic regulation and protein engineering in improvement of microbial biosynthesis. Biotechnol. Bioeng. 2016;113: 2661-2669. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Integrated lipidomics and transcriptomic analysis of peripheral blood reveals significantly enriched pathways in type 2 diabetes mellitus.

PubMed

Zhao, Chen; Mao, Jinghe; Ai, Junmei; Shenwu, Ming; Shi, Tieliu; Zhang, Daqing; Wang, Xiaonan; Wang, Yunliang; Deng, Youping

2013-01-01

Insulin resistance is a key element in the pathogenesis of type 2 diabetes mellitus. Plasma free fatty acids were assumed to mediate the insulin resistance, while the relationship between lipid and glucose disposal remains to be demonstrated across liver, skeletal muscle and blood. We profiled both lipidomics and gene expression of 144 total peripheral blood samples, 84 from patients with T2D and 60 from healthy controls. Then, factor and partial least squares models were used to perform a combined analysis of lipidomics and gene expression profiles to uncover the bioprocesses that are associated with lipidomic profiles in type 2 diabetes. According to factor analysis of the lipidomic profile, several species of lipids were found to be correlated with different phenotypes, including diabetes-related C23:2CE, C23:3CE, C23:4CE, ePE36:4, ePE36:5, ePE36:6; race-related (African-American) PI36:1; and sex-related PE34:1 and LPC18:2. The major variance of gene expression profile was not caused by known factors and no significant difference can be directly derived from differential gene expression profile. However, the combination of lipidomic and gene expression analyses allows us to reveal the correlation between the altered lipid profile with significantly enriched pathways, such as one carbon pool by folate, arachidonic acid metabolism, insulin signaling pathway, amino sugar and nucleotide sugar metabolism, propanoate metabolism, and starch and sucrose metabolism. The genes in these pathways showed a good capability to classify diabetes samples. Combined analysis of gene expression and lipidomic profiling reveals type 2 diabetes-associated lipid species and enriched biological pathways in peripheral blood, while gene expression profile does not show direct correlation. Our findings provide a new clue to better understand the mechanism of disordered lipid metabolism in association with type 2 diabetes.

The DAF-16 FOXO Transcription Factor Regulates natc-1 to Modulate Stress Resistance in Caenorhabditis elegans, Linking Insulin/IGF-1 Signaling to Protein N-Terminal Acetylation

PubMed Central

Warnhoff, Kurt; Murphy, John T.; Kumar, Sandeep; Schneider, Daniel L.; Peterson, Michelle; Hsu, Simon; Guthrie, James; Robertson, J. David; Kornfeld, Kerry

2014-01-01

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance. PMID:25330323

Novel Directions for Diabetes Mellitus Drug Discovery

PubMed Central

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan Chen; Wang, Shaohui

2012-01-01

Introduction Diabetes mellitus impacts almost 200 million individuals worldwide and leads to debilitating complications. New avenues of drug discovery must target the underlying cellular processes of oxidative stress, apoptosis, autophagy, and inflammation that can mediate multi-system pathology during diabetes mellitus. Areas Covered We examine novel directions for drug discovery that involve the β-nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide, the cytokine erythropoietin, the NAD+-dependent protein histone deacetylase SIRT1, the serine/threonine-protein kinase mammalian target of rapamycin (mTOR), and the wingless pathway. Implications for the targeting of these pathways that oversee gluconeogenic genes, insulin signaling and resistance, fatty acid beta-oxidation, inflammation, and cellular survival are presented. Expert Opinion Nicotinamide, erythropoietin, and the downstram pathways of SIRT1, mTOR, forkhead transcription factors, and wingless signaling offer exciting prospects for novel directions of drug discovery for the treatment of metabolic disorders. Future investigations must dissect the complex relationship and fine modulation of these pathways for the successful translation of robust reparative and regenerative strategies against diabetes mellitus and the complications of this disorder. PMID:23092114

Genetic moderation of multiple pathways linking early cumulative socioeconomic adversity and young adults' cardiometabolic disease risk.

PubMed

Wickrama, Kandauda A S; Lee, Tae Kyoung; O'Neal, Catherine Walker

2018-02-01

Recent research suggests that psychosocial resources and life stressors are mediating pathways explaining socioeconomic variation in young adults' health risks. However, less research has examined both these pathways simultaneously and their genetic moderation. A nationally representative sample of 11,030 respondents with prospective data collected over 13 years from the National Study of Adolescent to Adult Health was examined. First, the association between early cumulative socioeconomic adversity and young adults' (ages 25-34) cardiometabolic disease risk, as measured by 10 biomarkers, through psychosocial resources (educational attainment) and life stressors (accelerated transition to adulthood) was examined. Second, moderation of these pathways by the serotonin transporter linked polymorphic region gene (5-HTTLPR) was examined. There was evidence for the association between early socioeconomic adversity and young adults' cardiometabolic disease risk directly and indirectly through educational attainment and accelerated transitions. These direct and mediating pathways were amplified by the 5-HTTLPR polymorphism. These findings elucidate how early adversity can have an enduring influence on young adults' cardiometabolic disease risk directly and indirectly through psychosocial resources and life stressors and their genetic moderation. This information suggests that effective intervention and prevention programs should focus on early adversity, youth educational attainment, and their transition to young adulthood.

Chronic stress inhibits growth and induces proteolytic mechanisms through two different nonoverlapping pathways in the skeletal muscle of a teleost fish.

PubMed

Valenzuela, Cristián A; Zuloaga, Rodrigo; Mercado, Luis; Einarsdottir, Ingibjörg Eir; Björnsson, Björn Thrandur; Valdés, Juan Antonio; Molina, Alfredo

2018-01-01

Chronic stress detrimentally affects animal health and homeostasis, with somatic growth, and thus skeletal muscle, being particularly affected. A detailed understanding of the underlying endocrine and molecular mechanisms of how chronic stress affects skeletal muscle growth remains lacking. To address this issue, the present study assessed primary (plasma cortisol), secondary (key components of the GH/IGF system, muscular proteolytic pathways, and apoptosis), and tertiary (growth performance) stress responses in fine flounder ( Paralichthys adspersus) exposed to crowding chronic stress. Levels of plasma cortisol, glucocorticoid receptor 2 ( gr2), and its target genes ( klf15 and redd1) mRNA increased significantly only at 4 wk of crowding ( P < 0.05). The components of the GH/IGF system, including ligands, receptors, and their signaling pathways, were significantly downregulated at 7 wk of crowding ( P < 0.05). Interestingly, chronic stress upregulated the ubiquitin-proteasome pathway and the intrinsic apoptosis pathways at 4wk ( P < 0.01), whereas autophagy was only significantly activated at 7 wk ( P < 0.05), and meanwhile the ubiquitin-proteasome and the apoptosis pathways returned to control levels. Overall growth was inhibited in fish in the 7-wk chronic stress trial ( P < 0.05). In conclusion, chronic stress directly affects muscle growth and downregulates the GH/IGF system, an action through which muscular catabolic mechanisms are promoted by two different and nonoverlapping proteolytic pathways. These findings provide new information on molecular mechanisms involved in the negative effects that chronic stress has on muscle anabolic/catabolic signaling balance.

Activation of the miR-34a/SIRT1/p53 Signaling Pathway Contributes to the Progress of Liver Fibrosis via Inducing Apoptosis in Hepatocytes but Not in HSCs.

PubMed

Tian, Xiao-Feng; Ji, Fu-Jian; Zang, Hong-Liang; Cao, Hong

2016-01-01

Liver fibrosis results from a sustained wound healing response to chronic liver injury, and the activation of nonparenchymal hepatic stellate cells (HSCs) is the pivotal process. MicroRNA-34a (miR-34a) is the direct target gene of p53 and activates p53 through sirtuin 1 (SIRT1) simultaneously. The miR-34a/SIRT1/p53 signaling pathway thus forms a positive feedback loop wherein p53 induces miR-34a and miR-34a activates p53 by inhibiting SIRT1, playing an important role in cell proliferation and apoptosis. miR-34a expression has been found to be increased in animal models or in human patients with different liver diseases, including liver fibrosis. However, the exact role of this classical miR-34a/SIRT1/p53 signaling pathway in liver fibrosis remains unclear. In the present study, using a CCl4-induced rat liver fibrosis model, we found that the miR-34a/SIRT1/p53 signaling pathway was activated and could be inhibited by SIRT1 activator SRT1720. Further studies showed that the miR-34a/SIRT1/p53 signaling pathway was activated in hepatocytes but not in HSCs. The activation of this pathway in hepatocytes resulted in the apoptosis of hepatocytes and thus activated HSCs. Our data indicate that the miR-34a/SIRT1/p53 signaling pathway might be a promising therapeutic target for liver fibrosis.

A Corticocortical Circuit Directly Links Retrosplenial Cortex to M2 in the Mouse

PubMed Central

Radulovic, Jelena

2016-01-01

Retrosplenial cortex (RSC) is a dorsomedial parietal area involved in a range of cognitive functions, including episodic memory, navigation, and spatial memory. Anatomically, the RSC receives inputs from dorsal hippocampal networks and in turn projects to medial neocortical areas. A particularly prominent projection extends rostrally to the posterior secondary motor cortex (M2), suggesting a functional corticocortical link from the RSC to M2 and thus a bridge between hippocampal and neocortical networks involved in mnemonic and sensorimotor aspects of navigation. We investigated the cellular connectivity in this RSC→M2 projection in the mouse using optogenetic photostimulation, retrograde labeling, and electrophysiology. Axons from RSC formed monosynaptic excitatory connections onto M2 pyramidal neurons across layers and projection classes, including corticocortical/intratelencephalic neurons (reciprocally and callosally projecting) in layers 2–6, pyramidal tract neurons (corticocollicular, corticopontine) in layer 5B, and, to a lesser extent, corticothalamic neurons in layer 6. In addition to these direct connections, disynaptic connections were made via posterior parietal cortex (RSC→PPC→M2) and anteromedial thalamus (RSC→AM→M2). In the reverse direction, axons from M2 monosynaptically excited M2-projecting corticocortical neurons in the RSC, especially in the superficial layers of the dysgranular region. These findings establish an excitatory RSC→M2 corticocortical circuit that engages diverse types of excitatory projection neurons in the downstream area, suggesting a basis for direct communication from dorsal hippocampal networks involved in spatial memory and navigation to neocortical networks involved in diverse aspects of sensorimotor integration and motor control. SIGNIFICANCE STATEMENT Corticocortical pathways interconnect cortical areas extensively, but the cellular connectivity in these pathways remains largely uncharacterized. Here, we show that a posterior part of secondary motor cortex receives corticocortical axons from the rostral retrosplenial cortex (RSC) and these form monosynaptic excitatory connections onto a wide spectrum of excitatory projection neurons in this area. Our results define a cellular basis for direct communication from RSC to this medial frontal area, suggesting a direct link from dorsal hippocampal networks involved in spatial cognition and navigation (the “map”) to sensorimotor networks involved the control of movement (the “motor”). PMID:27605612

How extractive industries affect health: Political economy underpinnings and pathways.

PubMed

Schrecker, Ted; Birn, Anne-Emanuelle; Aguilera, Mariajosé

2018-06-07

A systematic and theoretically informed analysis of how extractive industries affect health outcomes and health inequities is overdue. Informed by the work of Saskia Sassen on "logics of extraction," we adopt an expansive definition of extractive industries to include (for example) large-scale foreign acquisitions of agricultural land for export production. To ground our analysis in concrete place-based evidence, we begin with a brief review of four case examples of major extractive activities. We then analyze the political economy of extractivism, focusing on the societal structures, processes, and relationships of power that drive and enable extraction. Next, we examine how this global order shapes and interacts with politics, institutions, and policies at the state/national level contextualizing extractive activity. Having provided necessary context, we posit a set of pathways that link the global political economy and national politics and institutional practices surrounding extraction to health outcomes and their distribution. These pathways involve both direct health effects, such as toxic work and environmental exposures and assassination of activists, and indirect effects, including sustained impoverishment, water insecurity, and stress-related ailments. We conclude with some reflections on the need for future research on the health and health equity implications of the global extractive order. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Food Perceptions and Dietary Behavior of American-Indian Children, Their Caregivers, and Educators: Formative Assessment Findings from Pathways.

PubMed

Gittelsohn, Joel; Toporoff, Elanah Greer; Story, Mary; Evans, Marguerite; Anliker, Jean; Davis, Sally; Sharma, Anjali; White, Jean

2000-01-01

Dietary findings from a school-based obesity prevention project (Pathways) are reported for children from six different American-Indian nations. A formative assessment was undertaken with teachers, caregivers, and children from nine schools to design a culturally appropriate intervention, including classroom curriculum, food service, physical education, and family components. This assessment employed a combination of qualitative and quantitative methods (including direct observations, paired-child in-depth interviews, focus groups with child caregivers and teachers, and semistructured interviews with caregivers and foodservice personnel) to query local perceptions and beliefs about foods commonly eaten and risk behaviors associated with childhood obesity at home, at school, and in the community. An abundance of high-fat, high-sugar foods was detected in children's diets described by caregivers, school food-service workers, and the children themselves. Although children and caregivers identified fruits and vegetables as healthy food choices, this knowledge does not appear to influence actual food choices. Frequent high-fat/high-sugar food sales in the schools, high-fat entrees in school meals, the use of food rewards in the classroom, rules about finishing all of one's food, and limited family resources are some of the competing factors that need to be addressed in the Pathways intervention.

New insights into the environmental photochemistry of 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan): reconsidering the importance of indirect photoreactions.

PubMed

Bianco, Angelica; Fabbri, Debora; Minella, Marco; Brigante, Marcello; Mailhot, Gilles; Maurino, Valter; Minero, Claudio; Vione, Davide

2015-04-01

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a widely used antimicrobial agent that undergoes fairly slow biodegradation. It is often found in surface waters in both the acidic (HTric) and basic (Tric(-)) forms (pKa ∼8), and it can undergo direct photodegradation to produce several intermediates including a dioxin congener (2,8-dichlorodibenzodioxin, hereafter 28DCDD). The latter is formed from Tric(-) and causes non-negligible environmental concern. Differently from current literature reports, in this paper we show that the direct photolysis would not be the only important transformation pathway of triclosan in surface waters. This is particularly true for HTric, which could undergo very significant reactions with (•)OH and, if the laser-derived quenching rate constants of this work are comparable to the actual reaction rate constants, with the triplet states of chromophoric dissolved organic matter ((3)CDOM*). Model calculations suggest that reaction with (3)CDOM* could be the main HTric phototransformation pathway in deep waters with high dissolved organic carbon (DOC), while reaction with (•)OH could prevail in low-DOC waters. In the case of Tric(-) the direct photolysis is much more important than for HTric, but triplet-sensitised transformation could produce 28DCDD + 27DCDD with higher yield compared to the direct photolysis, and it could play some role as dioxin source in deep waters with elevated DOC. Copyright © 2014 Elsevier Ltd. All rights reserved.

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT

PubMed Central

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-01-01

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway. PMID:26177797

Steering liquid metal flow in microchannels using low voltages.

PubMed

Tang, Shi-Yang; Lin, Yiliang; Joshipura, Ishan D; Khoshmanesh, Khashayar; Dickey, Michael D

2015-10-07

Liquid metals based on gallium, such as eutectic gallium indium (EGaIn) and Galinstan, have been integrated as static components in microfluidic systems for a wide range of applications including soft electrodes, pumps, and stretchable electronics. However, there is also a possibility to continuously pump liquid metal into microchannels to create shape reconfigurable metallic structures. Enabling this concept necessitates a simple method to control dynamically the path the metal takes through branched microchannels with multiple outlets. This paper demonstrates a novel method for controlling the directional flow of EGaIn liquid metal in complex microfluidic networks by simply applying a low voltage to the metal. According to the polarity of the voltage applied between the inlet and an outlet, two distinct mechanisms can occur. The voltage can lower the interfacial tension of the metal via electrocapillarity to facilitate the flow of the metal towards outlets containing counter electrodes. Alternatively, the voltage can drive surface oxidation of the metal to form a mechanical impediment that redirects the movement of the metal towards alternative pathways. Thus, the method can be employed like a 'valve' to direct the pathway chosen by the metal without mechanical moving parts. The paper elucidates the operating mechanisms of this valving system and demonstrates proof-of-concept control over the flow of liquid metal towards single or multiple directions simultaneously. This method provides a simple route to direct the flow of liquid metal for applications in microfluidics, optics, electronics, and microelectromechanical systems.

Characteristics of hearing and echolocation in under-studied odontocete species

NASA Astrophysics Data System (ADS)

Smith, Adam B.

All odontoctes (toothed whales and dolphins) studied to date have been shown to echolocate. They use sound as their primary means for foraging, navigation, and communication with conspecifics and are thus considered acoustic specialists. However, the vast majority of what is known about odontocete acoustic systems comes from only a handful of the 76 recognized extant species. The research presented in this dissertation investigated basic characteristics of odontocete hearing and echolocation, including auditory temporal resolution, auditory pathways, directional hearing, and transmission beam characteristics, in individuals of five different odontocete species that are understudied. Modulation rate transfer functions were measured from formerly stranded individuals of four different species (Stenella longirostris, Feresa attenuata, Globicephala melas, Mesoplodon densirostris) using non-invasive auditory evoked potential methods. All individuals showed acute auditory temporal resolution that was comparable to other studied odontocete species. Using the same electrophysiological methods, auditory pathways and directional hearing were investigated in a Risso's dolphin (Grampus griseus) using both localized and far-field acoustic stimuli. The dolphin's hearing showed significant, frequency dependent asymmetry to localized sound presented on the right and left sides of its head. The dolphin also showed acute, but mostly symmetrical, directional auditory sensitivity to sounds presented in the far-field. Furthermore, characteristics of the echolocation transmission beam of this same individual Risso's dolphin were measured using a 16 element hydrophone array. The dolphin exhibited both single and dual lobed beam shapes that were more directional than similar measurements from a bottlenose dolphin, harbor porpoise, and false killer whale.

40 CFR 270.10 - General application requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... associated with transportation to or from the unit; (ii) The potential pathways of human exposure to... resulting from both direct and indirect exposure pathways. The Director may also require a permittee or...

MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2.

PubMed

He, Yu; Ge, Yugang; Jiang, Mingkun; Zhou, Jundong; Luo, Dakui; Fan, Hao; Shi, Liang; Lin, Linling; Yang, Li

2018-06-21

Gastric cancer (GC) is one of the most prevalent digestive malignancies. MicroRNAs (miRNAs) are involved in multiple cellular processes, including oncogenesis, and miR-592 itself participates in many malignancies; however, its role in GC remains unknown. In this study, we investigated the expression and molecular mechanisms of miR-592 in GC. Quantitative real-time PCR and immunohistochemistry were performed to determine the expression of miR-592 and its putative targets in human tissues and cell lines. Proliferation, migration, and invasion were evaluated by Cell Counting Kit-8, population doubling time, colony formation, Transwell, and wound-healing assays in transfected GC cells in vitro. A dual-luciferase reporter assay was used to determine whether miR-592 could directly bind its target. A tumorigenesis assay was used to study whether miR-592 affected GC growth in vivo. Proteins involved in signaling pathways and the epithelial-mesenchymal transition (EMT) were detected with western blot. The ectopic expression of miR-592 promoted GC proliferation, migration, and invasion in vitro and facilitated tumorigenesis in vivo. Spry2 was a direct target of miR-592 and Spry2 overexpression partially counteracted the effects of miR-592. miR-592 induced the EMT and promoted its progression in GC via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2. Overexpression of miR-592 promotes GC proliferation, migration, and invasion and induces the EMT via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2, suggesting a potential therapeutic target for GC. © 2018 The Author(s). Published by S. Karger AG, Basel.

Revealing mechanisms of selective, concentration-dependent potentials of 4-hydroxy-2-nonenal to induce apoptosis in cancer cells through inactivation of membrane-associated catalase.

PubMed

Bauer, Georg; Zarkovic, Neven

2015-04-01

Tumor cells generate extracellular superoxide anions and are protected against superoxide anion-mediated intercellular apoptosis-inducing signaling by the expression of membrane-associated catalase. 4-Hydroxy-2-nonenal (4-HNE), a versatile second messenger generated during lipid peroxidation, has been shown to induce apoptosis selectively in malignant cells. The findings described in this paper reveal the strong, concentration-dependent potential of 4-HNE to specifically inactivate extracellular catalase of tumor cells both indirectly and directly and to consequently trigger apoptosis in malignant cells through superoxide anion-mediated intercellular apoptosis-inducing signaling. Namely, 4-HNE caused apoptosis selectively in NOX1-expressing tumor cells through inactivation of their membrane-associated catalase, thus reactivating subsequent intercellular signaling through the NO/peroxynitrite and HOCl pathways, followed by the mitochondrial pathway of apoptosis. Concentrations of 4-HNE of 1.2 µM and higher directly inactivated membrane-associated catalase of tumor cells, whereas at lower concentrations, 4-HNE triggered a complex amplificatory pathway based on initial singlet oxygen formation through H2O2 and peroxynitrite interaction. Singlet-oxygen-dependent activation of the FAS receptor and caspase-8 increased superoxide anion generation by NOX1 and amplification of singlet oxygen generation, which allowed singlet-oxygen-dependent inactivation of catalase. 4-HNE and singlet oxygen cooperate in complex autoamplificatory loops during this process. The finding of these novel anticancer pathways may be useful for understanding the role of 4-HNE in the control of malignant cells and for the optimization of ROS-dependent therapeutic approaches including antioxidant treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Transcriptome profiling in engrailed-2 mutant mice reveals common molecular pathways associated with autism spectrum disorders.

PubMed

Sgadò, Paola; Provenzano, Giovanni; Dassi, Erik; Adami, Valentina; Zunino, Giulia; Genovesi, Sacha; Casarosa, Simona; Bozzi, Yuri

2013-12-19

Transcriptome analysis has been used in autism spectrum disorder (ASD) to unravel common pathogenic pathways based on the assumption that distinct rare genetic variants or epigenetic modifications affect common biological pathways. To unravel recurrent ASD-related neuropathological mechanisms, we took advantage of the En2-/- mouse model and performed transcriptome profiling on cerebellar and hippocampal adult tissues. Cerebellar and hippocampal tissue samples from three En2-/- and wild type (WT) littermate mice were assessed for differential gene expression using microarray hybridization followed by RankProd analysis. To identify functional categories overrepresented in the differentially expressed genes, we used integrated gene-network analysis, gene ontology enrichment and mouse phenotype ontology analysis. Furthermore, we performed direct enrichment analysis of ASD-associated genes from the SFARI repository in our differentially expressed genes. Given the limited number of animals used in the study, we used permissive criteria and identified 842 differentially expressed genes in En2-/- cerebellum and 862 in the En2-/- hippocampus. Our functional analysis revealed that the molecular signature of En2-/- cerebellum and hippocampus shares convergent pathological pathways with ASD, including abnormal synaptic transmission, altered developmental processes and increased immune response. Furthermore, when directly compared to the repository of the SFARI database, our differentially expressed genes in the hippocampus showed enrichment of ASD-associated genes significantly higher than previously reported. qPCR was performed for representative genes to confirm relative transcript levels compared to those detected in microarrays. Despite the limited number of animals used in the study, our bioinformatic analysis indicates the En2-/- mouse is a valuable tool for investigating molecular alterations related to ASD.

Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review

PubMed Central

Rosenblat, Christian; McIntyre, Roger S.; Alves, Gilberto S.; Fountoulakis, Konstantinos N.; Carvalho, André F.

2015-01-01

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown. PMID:26467412

Induction of Cytoprotective Pathways Is Central to the Extension of Lifespan Conferred by Multiple Longevity Pathways

PubMed Central

Shore, David E.; Carr, Christopher E.; Ruvkun, Gary

2012-01-01

Many genetic and physiological treatments that extend lifespan also confer resistance to a variety of stressors, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of cytoprotective pathways is essential for lifespan extension or merely correlated. Using a panel of GFP-fused stress response genes, we identified the suites of cytoprotective pathways upregulated by 160 gene inactivations known to increase Caenorhabditis elegans longevity, including the mitochondrial UPR (hsp-6, hsp-60), the ER UPR (hsp-4), ROS response (sod-3, gst-4), and xenobiotic detoxification (gst-4). We then screened for other gene inactivations that disrupt the induction of these responses by xenobiotic or genetic triggers, identifying 29 gene inactivations required for cytoprotective gene expression. If cytoprotective responses contribute directly to lifespan extension, inactivation of these genes would be expected to compromise the extension of lifespan conferred by decreased insulin/IGF-1 signaling, caloric restriction, or the inhibition of mitochondrial function. We find that inactivation of 25 of 29 cytoprotection-regulatory genes shortens the extension of longevity normally induced by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, without disrupting normal longevity nearly as dramatically. These data demonstrate that induction of cytoprotective pathways is central to longevity extension and identify a large set of new genetic components of the pathways that detect cellular damage and couple that detection to downstream cytoprotective effectors. PMID:22829775

Differential miRNA expression in B cells is associated with inter-individual differences in humoral immune response to measles vaccination

PubMed Central

Haralambieva, Iana H.; Kennedy, Richard B.; Simon, Whitney L.; Goergen, Krista M.; Grill, Diane E.; Ovsyannikova, Inna G.

2018-01-01

Background MicroRNAs are important mediators of post-transcriptional regulation of gene expression through RNA degradation and translational repression, and are emerging biomarkers of immune system activation/response after vaccination. Methods We performed Next Generation Sequencing (mRNA-Seq) of intracellular miRNAs in measles virus-stimulated B and CD4+ T cells from high and low antibody responders to measles vaccine. Negative binomial generalized estimating equation (GEE) models were used for miRNA assessment and the DIANA tool was used for gene/target prediction and pathway enrichment analysis. Results We identified a set of B cell-specific miRNAs (e.g., miR-151a-5p, miR-223, miR-29, miR-15a-5p, miR-199a-3p, miR-103a, and miR-15a/16 cluster) and biological processes/pathways, including regulation of adherens junction proteins, Fc-receptor signaling pathway, phosphatidylinositol-mediated signaling pathway, growth factor signaling pathway/pathways, transcriptional regulation, apoptosis and virus-related processes, significantly associated with neutralizing antibody titers after measles vaccination. No CD4+ T cell-specific miRNA expression differences between high and low antibody responders were found. Conclusion Our study demonstrates that miRNA expression directly or indirectly influences humoral immunity to measles vaccination and suggests that B cell-specific miRNAs may serve as useful predictive biomarkers of vaccine humoral immune response. PMID:29381765

Microarray analysis of peripheral blood lymphocytes from ALS patients and the SAFE detection of the KEGG ALS pathway

PubMed Central

2011-01-01

Background Sporadic amyotrophic lateral sclerosis (sALS) is a motor neuron disease with poorly understood etiology. Results of gene expression profiling studies of whole blood from ALS patients have not been validated and are difficult to relate to ALS pathogenesis because gene expression profiles depend on the relative abundance of the different cell types present in whole blood. We conducted microarray analyses using Agilent Human Whole Genome 4 × 44k Arrays on a more homogeneous cell population, namely purified peripheral blood lymphocytes (PBLs), from ALS patients and healthy controls to identify molecular signatures possibly relevant to ALS pathogenesis. Methods Differentially expressed genes were determined by LIMMA (Linear Models for MicroArray) and SAM (Significance Analysis of Microarrays) analyses. The SAFE (Significance Analysis of Function and Expression) procedure was used to identify molecular pathway perturbations. Proteasome inhibition assays were conducted on cultured peripheral blood mononuclear cells (PBMCs) from ALS patients to confirm alteration of the Ubiquitin/Proteasome System (UPS). Results For the first time, using SAFE in a global gene ontology analysis (gene set size 5-100), we show significant perturbation of the KEGG (Kyoto Encyclopedia of Genes and Genomes) ALS pathway of motor neuron degeneration in PBLs from ALS patients. This was the only KEGG disease pathway significantly upregulated among 25, and contributing genes, including SOD1, represented 54% of the encoded proteins or protein complexes of the KEGG ALS pathway. Further SAFE analysis, including gene set sizes >100, showed that only neurodegenerative diseases (4 out of 34 disease pathways) including ALS were significantly upregulated. Changes in UBR2 expression correlated inversely with time since onset of disease and directly with ALSFRS-R, implying that UBR2 was increased early in the course of ALS. Cultured PBMCs from ALS patients accumulated more ubiquitinated proteins than PBMCs from healthy controls in a serum-dependent manner confirming changes in this pathway. Conclusions Our study indicates that PBLs from sALS patients are strong responders to systemic signals or local signals acquired by cell trafficking, representing changes in gene expression similar to those present in brain and spinal cord of sALS patients. PBLs may provide a useful means to study ALS pathogenesis. PMID:22027401

The comprehensive profile of fermentation products during in situ CO2 recycling by Rubisco-based engineered Escherichia coli.

PubMed

Yang, Cheng-Han; Liu, En-Jung; Chen, Yi-Ling; Ou-Yang, Fan-Yu; Li, Si-Yu

2016-08-02

In our previous study, the feasibility of Rubisco-based engineered E. coli (that contains heterologous phosphoribulokinase (PrkA) and Rubisco) for in situ CO2 recycling during the fermentation of pentoses or hexoses was demonstrated. Nevertheless, it is perplexing to see that only roughly 70 % of the carbon fed to the bacterial culture could be accounted for in the standard metabolic products. This low carbon recovery during fermentation occurred even though CO2 emission was effectively reduced by Rubisco-based engineered pathway. In this study, the heterologous expression of form I Rubisco was found to enhance the accumulation of pyruvate in Escherichia coli MZLF [E. coli BL21(DE3) Δzwf, Δldh, Δfrd]. This may be attributed to the enhanced glycolytic reaction supported by the increased biomass and the ethanol/acetate ratio. Besides, it was found that the transcription of arcA (encodes the redox-dependent transcriptional activators ArcA that positively regulates the transcription of pyruvate formate-lyase) was down-regulated in the presence of Rubisco. The enhanced accumulation of pyruvate also occurs when PrkA is co-expressed with Rubisco in E. coli MZLF. Furthermore, E. coli containing Rubisco-based engineered pathway has a distinct profile of the fermentation products, indicating CO2 was converted into fermentation products. By analyzing the ratio of total C-2 (2-carbon fermentation products) to total C-1 (1-carbon fermentation product) of MZLFB (MZLF containing Rubisco-based engineered pathway), it is estimated that 9 % of carbon is directed into Rubisco-based engineered pathway. Here, we report for the first time the complete profile of fermentation products using E. coli MZLF and its derived strains. It has been shown that the expression of Rubisco alone in MZLF enhances the accumulation of pyruvate. By including the contribution of pyruvate accumulation, the perplexing problem of low carbon recovery during fermentation by E. coli containing Rubisco-based engineered pathway has been solved. 9 % of glucose consumption is directed from glycolysis to Rubisco-based engineered pathway in MZLFB. The principle characteristics of mixotroph MZLFB are the high bacterial growth and the low CO2 emission.

Search for the Evolution of Steroid Biosynthesis in the Geological Record

NASA Astrophysics Data System (ADS)

Brocks, J. J.

2004-12-01

To study the evolution of the structure of organisms we can directly examine fossilized shells, skeletons and petrified cells. In contrast, for the tentative reconstruction of the phylogeny of biosynthetic pathways, such as steroid anabolism, we rely entirely on the comparative molecular biology of living organisms. Thus, without fossil evidence, the times in geological history when successive steps of a metabolic pathway evolved remain particularly elusive. Molecular clocks of genes coding for the enzymes involved in a biosynthetic pathway might provide a rough guess when a natural product first appeared in geological time, but they are intrinsically unreliable without calibration points in the distant past. However, it might be possible to trace the evolutionary history of some biosynthetic pathways directly in the geological record by searching for hydrocarbon biomarkers of anabolic intermediates. Biomarkers are molecular fossils of natural products. They often retain the diagnostic carbon skeleton of their biological precursor and remain stable over hundreds of millions of years enclosed in organic-rich sedimentary rocks. Sterane hydrocarbons are particularly abundant biomarkers and potentially suitable for the search of biosynthetic intermediates. Steranes are the fossil equivalents of functionalized steroids found in eukaryotes and certain bacteria. The biosynthesis of typical eukaryotic steroids such as cholesterol (C27), ergosterol (C28) and sitosterol (C29) from the acyclic precursor squalene (C30) involves more than 20 enzymatic steps. The most crucial steps include modification of the carbon skeleton by removal of several methyl groups from the ring system and addition of alkyl groups to the steroid side chain. The evolution of this complex pathway must have occurred over geologically significant periods of time and likely involved several preadaptive intermediates that represented structurally less derived but fully functional lipids. Thus, if a molecular corollary of `ontogeny recapitulates phylogeny' applies, it might be possible to detect a sequence of increasingly modified fossil steroids in the geological record and to create a time frame for the evolution of this fundamental biosynthetic pathway. Here we present first results of an extensive search for the fossil remains of evolutionary intermediate steroids in sedimentary successions of Precambrian age.

Metabolome searcher: a high throughput tool for metabolite identification and metabolic pathway mapping directly from mass spectrometry and using genome restriction.

PubMed

Dhanasekaran, A Ranjitha; Pearson, Jon L; Ganesan, Balasubramanian; Weimer, Bart C

2015-02-25

Mass spectrometric analysis of microbial metabolism provides a long list of possible compounds. Restricting the identification of the possible compounds to those produced by the specific organism would benefit the identification process. Currently, identification of mass spectrometry (MS) data is commonly done using empirically derived compound databases. Unfortunately, most databases contain relatively few compounds, leaving long lists of unidentified molecules. Incorporating genome-encoded metabolism enables MS output identification that may not be included in databases. Using an organism's genome as a database restricts metabolite identification to only those compounds that the organism can produce. To address the challenge of metabolomic analysis from MS data, a web-based application to directly search genome-constructed metabolic databases was developed. The user query returns a genome-restricted list of possible compound identifications along with the putative metabolic pathways based on the name, formula, SMILES structure, and the compound mass as defined by the user. Multiple queries can be done simultaneously by submitting a text file created by the user or obtained from the MS analysis software. The user can also provide parameters specific to the experiment's MS analysis conditions, such as mass deviation, adducts, and detection mode during the query so as to provide additional levels of evidence to produce the tentative identification. The query results are provided as an HTML page and downloadable text file of possible compounds that are restricted to a specific genome. Hyperlinks provided in the HTML file connect the user to the curated metabolic databases housed in ProCyc, a Pathway Tools platform, as well as the KEGG Pathway database for visualization and metabolic pathway analysis. Metabolome Searcher, a web-based tool, facilitates putative compound identification of MS output based on genome-restricted metabolic capability. This enables researchers to rapidly extend the possible identifications of large data sets for metabolites that are not in compound databases. Putative compound names with their associated metabolic pathways from metabolomics data sets are returned to the user for additional biological interpretation and visualization. This novel approach enables compound identification by restricting the possible masses to those encoded in the genome.

Direct labeling of serum proteins by fluorescent dye for antibody microarray.

PubMed

Klimushina, M V; Gumanova, N G; Metelskaya, V A

2017-05-06

Analysis of serum proteome by antibody microarray is used to identify novel biomarkers and to study signaling pathways including protein phosphorylation and protein-protein interactions. Labeling of serum proteins is important for optimal performance of the antibody microarray. Proper choice of fluorescent label and optimal concentration of protein loaded on the microarray ensure good quality of imaging that can be reliably scanned and processed by the software. We have optimized direct serum protein labeling using fluorescent dye Arrayit Green 540 (Arrayit Corporation, USA) for antibody microarray. Optimized procedure produces high quality images that can be readily scanned and used for statistical analysis of protein composition of the serum. Copyright © 2017 Elsevier Inc. All rights reserved.

Advancing Suicide Prevention Research With Rural American Indian and Alaska Native Populations

PubMed Central

Chandler, Michael; Gone, Joseph P.; Cwik, Mary; Kirmayer, Laurence J.; LaFromboise, Teresa; Brockie, Teresa; O’Keefe, Victoria; Walkup, John; Allen, James

2015-01-01

As part of the National Action Alliance for Suicide Prevention’s American Indian and Alaska Native (AI/AN) Task Force, a multidisciplinary group of AI/AN suicide research experts convened to outline pressing issues related to this subfield of suicidology. Suicide disproportionately affects Indigenous peoples, and remote Indigenous communities can offer vital and unique insights with relevance to other rural and marginalized groups. Outcomes from this meeting include identifying the central challenges impeding progress in this subfield and a description of promising research directions to yield practical results. These proposed directions expand the alliance’s prioritized research agenda and offer pathways to advance the field of suicide research in Indigenous communities and beyond. PMID:25790403

Heterogeneity in multiple transmission pathways: modelling the spread of cholera and other waterborne disease in networks with a common water source.

PubMed

Robertson, Suzanne L; Eisenberg, Marisa C; Tien, Joseph H

2013-01-01

Many factors influencing disease transmission vary throughout and across populations. For diseases spread through multiple transmission pathways, sources of variation may affect each transmission pathway differently. In this paper we consider a disease that can be spread via direct and indirect transmission, such as the waterborne disease cholera. Specifically, we consider a system of multiple patches with direct transmission occurring entirely within patch and indirect transmission via a single shared water source. We investigate the effect of heterogeneity in dual transmission pathways on the spread of the disease. We first present a 2-patch model for which we examine the effect of variation in each pathway separately and propose a measure of heterogeneity that incorporates both transmission mechanisms and is predictive of R(0). We also explore how heterogeneity affects the final outbreak size and the efficacy of intervention measures. We conclude by extending several results to a more general n-patch setting.

Wolff-Parkinson-White Syndrome and Accessory Pathways

MedlinePlus

... is generated by the SA node, and that electricity spreads through the right and left atria, directing ... in that it is the only pathway for electricity that communicates from the upper chambers (atria) to ...

Goal-Directed Visual Processing Differentially Impacts Human Ventral and Dorsal Visual Representations

PubMed Central

2017-01-01

Recent studies have challenged the ventral/“what” and dorsal/“where” two-visual-processing-pathway view by showing the existence of “what” and “where” information in both pathways. Is the two-pathway distinction still valid? Here, we examined how goal-directed visual information processing may differentially impact visual representations in these two pathways. Using fMRI and multivariate pattern analysis, in three experiments on human participants (57% females), by manipulating whether color or shape was task-relevant and how they were conjoined, we examined shape-based object category decoding in occipitotemporal and parietal regions. We found that object category representations in all the regions examined were influenced by whether or not object shape was task-relevant. This task effect, however, tended to decrease as task-relevant and irrelevant features were more integrated, reflecting the well-known object-based feature encoding. Interestingly, task relevance played a relatively minor role in driving the representational structures of early visual and ventral object regions. They were driven predominantly by variations in object shapes. In contrast, the effect of task was much greater in dorsal than ventral regions, with object category and task relevance both contributing significantly to the representational structures of the dorsal regions. These results showed that, whereas visual representations in the ventral pathway are more invariant and reflect “what an object is,” those in the dorsal pathway are more adaptive and reflect “what we do with it.” Thus, despite the existence of “what” and “where” information in both visual processing pathways, the two pathways may still differ fundamentally in their roles in visual information representation. SIGNIFICANCE STATEMENT Visual information is thought to be processed in two distinctive pathways: the ventral pathway that processes “what” an object is and the dorsal pathway that processes “where” it is located. This view has been challenged by recent studies revealing the existence of “what” and “where” information in both pathways. Here, we found that goal-directed visual information processing differentially modulates shape-based object category representations in the two pathways. Whereas ventral representations are more invariant to the demand of the task, reflecting what an object is, dorsal representations are more adaptive, reflecting what we do with the object. Thus, despite the existence of “what” and “where” information in both pathways, visual representations may still differ fundamentally in the two pathways. PMID:28821655

Analysis of Borderline Substitution/Electron Transfer Pathways from Direct ab initio MD Simulations

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

Yamataka, H; Aida, M A.; Dupuis, Michel

Ab initio molecular dynamics simulations were carried out for the borderline reaction pathways in the reaction of CH2O?- with CH3Cl. The simulations reveal distinctive features of three types of mechanisms passing through the SN2-like transition state (TS): (i) a direct formation of SN2 products, (ii) a direct formation of ET products, and (iii) a 2-step formation of ET products via the SN2 valley. The direct formation of the ET product through the SN2-like TS appears to be more favorable at higher temperatures. The 2-step process depends on the amount of energy that goes into the C-C stretching mode.

Cyanidin attenuates Aβ25-35-induced neuroinflammation by suppressing NF-κB activity downstream of TLR4/NOX4 in human neuroblastoma cells.

PubMed

Thummayot, Sarinthorn; Tocharus, Chainarong; Jumnongprakhon, Pichaya; Suksamrarn, Apichart; Tocharus, Jiraporn

2018-04-19

Cyanidin is polyphenolic pigment found in plants. We have previously demonstrated that cyanidin protects nerve cells against Aβ 25-35 -induced toxicity by decreasing oxidative stress and attenuating apoptosis mediated by both the mitochondrial apoptotic pathway and the ER stress pathway. To further elucidate the molecular mechanisms underlying the neuroprotective effects of cyanidin, we investigated the effects of cyanidin on neuroinflammation mediated by the TLR4/NOX4 pathway in Aβ 25-35 -treated human neuroblastoma cell line (SK-N-SH). SK-N-SH cells were exposed to Aβ 25-35 (10 μmol/L) for 24 h. Pretreatment with cyanidin (20 μmol/L) or NAC (20 μmol/L) strongly inhibited the NF-κB signaling pathway in the cells evidenced by suppressing the degradation of IκBα, translocation of the p65 subunit of NF-κB from the cytoplasm to the nucleus, and thereby reducing the expression of iNOS protein and the production of NO. Furthermore, pretreatment with cyanidin greatly promoted the translocation of the Nrf2 protein from the cytoplasm to the nucleus; upregulating cytoprotective enzymes, including HO-1, NQO-1 and GCLC; and increased the activity of SOD enzymes. Pretreatment with cyanidin also decreased the expression of TLR4, directly improved intracellular ROS levels and regulated the activity of inflammation-related downstream pathways including NO production and SOD activity through TLR4/NOX4 signaling. These results demonstrate that TLR4 is a primary receptor in SK-N-SH cells, by which Aβ 25-35 triggers neuroinflammation, and cyanidin attenuates Aβ-induced inflammation and ROS production mediated by the TLR4/NOX4 pathway, suggesting that inhibition of TLR4 by cyanidin could be beneficial in preventing neuronal cell death in the process of Alzheimer's disease.

Evaluating the role of large jellyfish and forage fishes as energy pathways, and their interplay with fisheries, in the Northern Humboldt Current System

NASA Astrophysics Data System (ADS)

Chiaverano, Luciano M.; Robinson, Kelly L.; Tam, Jorge; Ruzicka, James J.; Quiñones, Javier; Aleksa, Katrina T.; Hernandez, Frank J.; Brodeur, Richard D.; Leaf, Robert; Uye, Shin-ichi; Decker, Mary Beth; Acha, Marcelo; Mianzan, Hermes W.; Graham, William M.

2018-05-01

Large jellyfish are important consumers of plankton, fish eggs and fish larvae in heavily fished ecosystems worldwide; yet they are seldom included in fisheries production models. Here we developed a trophic network model with 41 functional groups using ECOPATH re-expressed in a donor-driven, end-to-end format to directly evaluate the efficiency of large jellyfish and forage fish at transferring energy to higher trophic levels, as well as the ecosystem-wide effects of varying jellyfish and forage fish consumption rates and fishing rates, in the Northern Humboldt Current system (NHCS) off of Peru. Large jellyfish were an energy-loss pathway for high trophic-level consumers, while forage fish channelized the production of lower trophic levels directly into production of top-level consumers. A simulated jellyfish bloom resulted in a decline in productivity of all functional groups, including forage fish (12%), with the exception of sea turtles. A modeled increase in forage fish consumption rate by 50% resulted in a decrease in large jellyfish productivity (29%). A simulated increase of 40% in forage fish harvest enhanced jellyfish productivity (24%), while closure of all fisheries caused a decline in large jellyfish productivity (26%) and productivity increases in upper level consumers. These outcomes not only suggest that jellyfish blooms and fisheries have important effects on the structure of the NHCS, but they also support the hypothesis that forage fishing provides a competitive release for large jellyfish. We recommend including jellyfish as a functional group in future ecosystem modeling efforts, including ecosystem-based approaches to fishery management of coastal ecosystems worldwide.

Pathways from College to University: A Social Science Example from Ontario

ERIC Educational Resources Information Center

LeSage, Ann; Samis, John; Hinch, Ron; Longo, Fabiola; DiGiuseppe, Maurice; Goodman, William; Percival, Jennifer; De La Rocha, Arlene; Rodrigues, Anna; Raby, Phil; Sanchez, Otto

2014-01-01

This study evaluates the impact of a College to University Pathway Program in the Faculty of Social Science and Humanities at The University of Ontario Institute of Technology. The findings support the assertion that Pathway students perform as well as or better than students who enter university directly from secondary school. This finding is…

Contrast Sensitivity for Motion Detection and Direction Discrimination in Adolescents with Autism Spectrum Disorders and Their Siblings

ERIC Educational Resources Information Center

Koh, Hwan Cui; Milne, Elizabeth; Dobkins, Karen

2010-01-01

The magnocellular (M) pathway hypothesis proposes that impaired visual motion perception observed in individuals with Autism Spectrum Disorders (ASD) might be mediated by atypical functioning of the subcortical M pathway, as this pathway provides the bulk of visual input to cortical motion detectors. To test this hypothesis, we measured luminance…

The Role of the Ventral and Dorsal Pathways in Reading Chinese Characters and English Words

ERIC Educational Resources Information Center

Sun, Yafeng; Yang, Yanhui; Desroches, Amy S.; Liu, Li; Peng, Danling

2011-01-01

Previous literature in alphabetic languages suggests that the occipital-temporal region (the ventral pathway) is specialized for automatic parallel word recognition, whereas the parietal region (the dorsal pathway) is specialized for serial letter-by-letter reading (and). However, few studies have directly examined the role of the ventral and…

T7 replisome directly overcomes DNA damage

NASA Astrophysics Data System (ADS)

Sun, Bo; Pandey, Manjula; Inman, James T.; Yang, Yi; Kashlev, Mikhail; Patel, Smita S.; Wang, Michelle D.

2015-12-01

Cells and viruses possess several known `restart' pathways to overcome lesions during DNA replication. However, these `bypass' pathways leave a gap in replicated DNA or require recruitment of accessory proteins, resulting in significant delays to fork movement or even cell division arrest. Using single-molecule and ensemble methods, we demonstrate that the bacteriophage T7 replisome is able to directly replicate through a leading-strand cyclobutane pyrimidine dimer (CPD) lesion. We show that when a replisome encounters the lesion, a substantial fraction of DNA polymerase (DNAP) and helicase stay together at the lesion, the replisome does not dissociate and the helicase does not move forward on its own. The DNAP is able to directly replicate through the lesion by working in conjunction with helicase through specific helicase-DNAP interactions. These observations suggest that the T7 replisome is fundamentally permissive of DNA lesions via pathways that do not require fork adjustment or replisome reassembly.

Melatonin: A Multifunctional Factor in Plants

PubMed Central

Fan, Jibiao; Zhang, Zaichao; Chen, Liang

2018-01-01

Melatonin (N-acetyl-5-methoxy-tryptamine) is a universal molecule that is present in animals and plants. It has been detected in different kinds of plants and organs in different levels. Melatonin in plants shares the same initial biosynthesis compound with auxin, and therefore functions as indole-3-acetic acid like hormones. Moreover, melatonin is involved in regulating plant growth and development, protecting plants against biotic and abiotic stresses, such as salt, drought, cold, heat and heavy metal stresses. Melatonin improves the stress tolerance of plants via a direct pathway, which scavenges reactive oxygen species directly, and indirect pathways, such as increasing antioxidate enzymes activity, photosynthetic efficiency and metabolites content. In addition, melatonin plays a role in regulating gene expression, and hence affects performance of plants. In this review, the biosynthesis pathway, growth and development regulation, and the environment stress response of melatonin in plants are summarized and future research directions and priorities of melatonin in plants are speculated. PMID:29883400

Aggressive Marital Conflict, Maternal Harsh Punishment, and Child Aggressive-Disruptive Behavior: Evidence for Direct and Mediated Relations

PubMed Central

Erath, Stephen A.; Bierman, Karen L.

2009-01-01

Direct associations between aggressive marital conflict and child aggressive-disruptive behavior at home and school were explored in this cross-sectional study of 360 kindergarten children. In addition, mediated pathways linking aggressive marital conflict to maternal harsh punishment to child aggressive-disruptive behavior were examined. Moderation analyses explored how the overall frequency of marital disagreement might buffer or exacerbate the impact of aggressive marital conflict on maternal harsh punishment and child aggressive-disruptive behavior. Hierarchical regressions revealed direct pathways linking aggressive marital conflict to child aggressive-disruptive behavior at home and school and a partially mediated pathway linking aggressive marital conflict to child aggressive-disruptive behavior at home. Further analyses revealed that rates of marital disagreement moderated the association between aggressive marital conflict and child aggressive-disruptive behavior at home, with an attenuated association at high rates of marital disagreement as compared with low rates of marital disagreement. PMID:16756397

Engineering Heteromaterials to Control Lithium Ion Transport Pathways

DOE PAGES

Liu, Yang; Vishniakou, Siarhei; Yoo, Jinkyoung; ...

2015-12-21

Safe and efficient operation of lithium ion batteries requires precisely directed flow of lithium ions and electrons to control the first directional volume changes in anode and cathode materials. Understanding and controlling the lithium ion transport in battery electrodes becomes crucial to the design of high performance and durable batteries. Some recent work revealed that the chemical potential barriers encountered at the surfaces of heteromaterials play an important role in directing lithium ion transport at nanoscale. We utilize in situ transmission electron microscopy to demonstrate that we can switch lithiation pathways from radial to axial to grain-by-grain lithiation through themore » systematic creation of heteromaterial combinations in the Si-Ge nanowire system. Furthermore, our systematic studies show that engineered materials at nanoscale can overcome the intrinsic orientation-dependent lithiation, and open new pathways to aid in the development of compact, safe, and efficient batteries.« less

Engineering Heteromaterials to Control Lithium Ion Transport Pathways

PubMed Central

Liu, Yang; Vishniakou, Siarhei; Yoo, Jinkyoung; Dayeh, Shadi A.

2015-01-01

Safe and efficient operation of lithium ion batteries requires precisely directed flow of lithium ions and electrons to control the first directional volume changes in anode and cathode materials. Understanding and controlling the lithium ion transport in battery electrodes becomes crucial to the design of high performance and durable batteries. Recent work revealed that the chemical potential barriers encountered at the surfaces of heteromaterials play an important role in directing lithium ion transport at nanoscale. Here, we utilize in situ transmission electron microscopy to demonstrate that we can switch lithiation pathways from radial to axial to grain-by-grain lithiation through the systematic creation of heteromaterial combinations in the Si-Ge nanowire system. Our systematic studies show that engineered materials at nanoscale can overcome the intrinsic orientation-dependent lithiation, and open new pathways to aid in the development of compact, safe, and efficient batteries. PMID:26686655

Melatonin: A Multifunctional Factor in Plants.

PubMed

Fan, Jibiao; Xie, Yan; Zhang, Zaichao; Chen, Liang

2018-05-21

Melatonin ( N -acetyl-5-methoxy-tryptamine) is a universal molecule that is present in animals and plants. It has been detected in different kinds of plants and organs in different levels. Melatonin in plants shares the same initial biosynthesis compound with auxin, and therefore functions as indole-3-acetic acid like hormones. Moreover, melatonin is involved in regulating plant growth and development, protecting plants against biotic and abiotic stresses, such as salt, drought, cold, heat and heavy metal stresses. Melatonin improves the stress tolerance of plants via a direct pathway, which scavenges reactive oxygen species directly, and indirect pathways, such as increasing antioxidate enzymes activity, photosynthetic efficiency and metabolites content. In addition, melatonin plays a role in regulating gene expression, and hence affects performance of plants. In this review, the biosynthesis pathway, growth and development regulation, and the environment stress response of melatonin in plants are summarized and future research directions and priorities of melatonin in plants are speculated.

Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function

PubMed Central

May, Rebecca M.; Okumura, Mariko; Hsu, Chin-Jung; Bassiri, Hamid; Yang, Enjun; Rak, Gregory; Mace, Emily M.; Philip, Naomi H.; Zhang, Weiguo; Baumgart, Tobias; Orange, Jordan S.; Nichols, Kim E.

2013-01-01

Signaling pathways leading to natural killer (NK)–cell effector function are complex and incompletely understood. Here, we investigated the proximal signaling pathways downstream of the immunotyrosine-based activation motif (ITAM) bearing activating receptors. We found that the adaptor molecule SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is recruited to microclusters at the plasma membrane in activated NK cells and that this is required for initiation of downstream signaling and multiple NK-cell effector functions in vitro and in vivo. Surprisingly, we found that 2 types of proximal signaling complexes involving SLP-76 were formed. In addition to the canonical membrane complex formed between SLP-76 and linker for activation of T cells (LAT) family members, a novel LAT family–independent SLP-76–dependent signaling pathway was identified. The LAT family–independent pathway involved the SH2 domain of SLP-76 and adhesion and degranulation-promoting adaptor protein (ADAP). Both the LAT family–dependent and ADAP-dependent pathway contributed to interferon-gamma production and cytotoxicity; however, they were not essential for other SLP-76–dependent events, including phosphorylation of AKT and extracellular signal–related kinase and cellular proliferation. These results demonstrate that NK cells possess an unexpected bifurcation of proximal ITAM-mediated signaling, each involving SLP-76 and contributing to optimal NK-cell function. PMID:23407547

The Hippo pathway in normal development and cancer.

PubMed

Maugeri-Saccà, Marcello; De Maria, Ruggero

2018-06-01

The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption. Copyright © 2018 Elsevier Inc. All rights reserved.

Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan.

PubMed

Liu, Ruifeng; Printz, Richard L; Jenkins, Erin C; O'Brien, Tracy P; Te, Jerez A; Shiota, Masakazu; Wallqvist, Anders

2018-04-01

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Not Available].

PubMed

Yanashima, Ryoji; Kitagawa, Noriyuki; Matsubara, Yoshiya; Weatheritt, Robert; Oka, Kotaro; Kikuchi, Shinichi; Tomita, Masaru; Ishizaki, Shun

2009-01-01

The scale-free and small-world network models reflect the functional units of networks. However, when we investigated the network properties of a signaling pathway using these models, no significant differences were found between the original undirected graphs and the graphs in which inactive proteins were eliminated from the gene expression data. We analyzed signaling networks by focusing on those pathways that best reflected cellular function. Therefore, our analysis of pathways started from the ligands and progressed to transcription factors and cytoskeletal proteins. We employed the Python module to assess the target network. This involved comparing the original and restricted signaling cascades as a directed graph using microarray gene expression profiles of late onset Alzheimer's disease. The most commonly used method of shortest-path analysis neglects to consider the influences of alternative pathways that can affect the activation of transcription factors or cytoskeletal proteins. We therefore introduced included k-shortest paths and k-cycles in our network analysis using the Python modules, which allowed us to attain a reasonable computational time and identify k-shortest paths. This technique reflected results found in vivo and identified pathways not found when shortest path or degree analysis was applied. Our module enabled us to comprehensively analyse the characteristics of biomolecular networks and also enabled analysis of the effects of diseases considering the feedback loop and feedforward loop control structures as an alternative path.

Intersection of autophagy with pathways of antigen presentation.

PubMed

Patterson, Natalie L; Mintern, Justine D

2012-12-01

Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

IBM1, a JmjC domain-containing histone demethylase, is involved in the regulation of RNA-directed DNA methylation through the epigenetic control of RDR2 and DCL3 expression in Arabidopsis

PubMed Central

Fan, Di; Dai, Yan; Wang, Xuncheng; Wang, Zhenjie; He, Hang; Yang, Hongchun; Cao, Ying; Deng, Xing Wang; Ma, Ligeng

2012-01-01

Small RNA-directed DNA methylation (RdDM) is an important epigenetic pathway in Arabidopsis that controls the expression of multiple genes and several developmental processes. RNA-DEPENDENT RNA POLYMERASE 2 (RDR2) and DICER-LIKE 3 (DCL3) are necessary factors in 24-nt small interfering RNA (siRNA) biogenesis, which is part of the RdDM pathway. Here, we found that Increase in BONSAI Methylation 1 (IBM1), a conserved JmjC family histone demethylase, is directly associated with RDR2 and DCL3 chromatin. The mutation of IBM1 induced the hypermethylation of H3K9 and DNA non-CG sites within RDR2 and DCL3, which repressed their expression. A genome-wide analysis suggested that the reduction in RDR2 and DCL3 expression affected siRNA biogenesis in a locus-specific manner and disrupted RdDM-directed gene repression. Together, our results suggest that IBM1 regulates gene expression through two distinct pathways: direct association to protect genes from silencing by preventing the coupling of histone and DNA methylation, and indirect silencing of gene expression through RdDM-directed repression. PMID:22772985

Beliefs in the Future as a Positive Youth Development Construct: A Conceptual Review

PubMed Central

Sun, Rachel C. F.; Shek, Daniel T. L.

2012-01-01

Beliefs in the future are an internalization of hope and optimism about future outcomes. This paper reviews and compares several theories of hope and optimism and highlights the features constituting beliefs in the future. This paper points out that beliefs in the future include a series of goal-directed thoughts and motivation, such as setting up valued and attainable goals, planning pathways, and maintaining self-confidence and mastery, so as to keep adolescents engaged in the pursuit of goals. This kind of personal mastery, together with sociocultural values, family, school, and peers are the antecedents leading to beliefs in the future, which is related to adolescents' well-being and positive development. In order to cultivate adolescents' beliefs in the future, enabling their ability to manipulate goal-directed thoughts and motivation and providing a supportive environment including their family, school, peers, and the society are recommended. PMID:22654623

PATTERNS OF PHYSICAL ACTIVITY AMONG AMERICAN INDIAN CHILDREN: AN ASSESSMENT OF BARRIERS AND SUPPORT

PubMed Central

Thompson, Janice L.; Davis, Sally M.; Gittelsohn, Joel; Going, Scott; Becenti, Alberta; Metcalfe, Lauve; Stone, Elaine; Harnack, Lisa; Ring, Kim

2016-01-01

Estimates indicate that 10% to 50% of American Indian and non-Indian children in the U.S. are obese, defined as a body mass index ≥ 95th percentile of the NHANES II reference data. Pathways is a two-phase, multi-site study to develop and test a school-based obesity prevention program in American Indian schoolchildren in grades three through five. During Phase I feasibility prior to initiation of the Pathways trial, data were collected related to physical activity patterns, and the supports of, and barriers to, physical activity. Nine schools from communities representing six different tribal groups participated in this study. Multiple measures were used for data collection including direct observation, paired child interviews, and in-depth interviews and focus groups with adults. Students completed the self-administered Knowledge, Attitudes, and Behaviors (KAB) survey, and a Physical Activity Questionnaire (PAQ). Barriers to physical activity at schools included a lack of facilities, equipment, and trained staff persons for PE. Adults were not consistently active with their children, but they were highly supportive of their children’s activity level. Children reported a strong enjoyment of physical activity and strong peer support to be physically active. Weather conditions, safety concerns, and homework/chores were common barriers to physical activity reported by children and adult caregivers. The information was used to design culturally and age-appropriate, practical interventions including the five physical activity programs for schoolchildren in the Pathways study. PMID:11759094

Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types.

PubMed Central

Satoh, T; Fantl, W J; Escobedo, J A; Williams, L T; Kaziro, Y

1993-01-01

A series of pieces of evidence have shown that Ras protein acts as a transducer of the platelet-derived growth factor (PDGF) receptor-mediated signaling pathway: (i) formation of Ras.GTP is detected immediately on PDGF stimulation, and (ii) a dominant inhibitory mutant Ras, as well as a neutralizing anti-Ras antibody, can interfere with PDGF-induced responses. On the other hand, several signal transducing molecules including phosphatidylinositol 3-kinase (PI3-K), GTPase-activating protein (GAP), and phospholipase C gamma (PLC gamma) bind directly to the PDGF receptor and become tyrosine phosphorylated. Recently, it was shown that specific phosphorylated tyrosines of the PDGF receptor are responsible for interaction between the receptor and each signaling molecule. However, the roles of these signaling molecules have not been elucidated, and it remains unclear which molecules are implicated in the Ras pathway. In this study, we measured Ras activation in cell lines expressing mutant PDGF receptors that are deficient in coupling with specific molecules. In fibroblast CHO cells, a mutant receptor (Y708F/Y719F [PI3-K-binding sites]) was unable to stimulate Ras, whereas another mutant (Y739F [the GAP-binding site]) could do so, suggesting an indispensable role of PI3-K or a protein that binds to the same sites as PI3-K for PDGF-stimulated Ras activation. By contrast, both of the above mutants were capable of stimulating Ras protein in a pro-B-cell line, BaF3. Furthermore, a mutant receptor (Y977F/Y989F [PLC gamma-binding sites]) could fully activate Ras, and the direct activation of protein kinase C and calcium mobilization had almost no effect on the GDP/GTP state of Ras in this cell line. These results suggest that, in the pro-B-cell transfectants, each of the above pathways (PI3-K, GAP, and PLC gamma) can be eliminated without a loss of Ras activation. It remains unclear whether another unknown essential pathway which regulates Ras protein exists within BaF3 cells. Therefore, it is likely that several different PDGF receptor-mediated signaling pathways function upstream of Ras, and the extent of the contribution of each pathway for the regulation of Ras may differ among different cell types. Images PMID:8388543

Transcriptome Profiling of Khat (Catha edulis) and Ephedra sinica Reveals Gene Candidates Potentially Involved in Amphetamine-Type Alkaloid Biosynthesis

PubMed Central

Groves, Ryan A.; Hagel, Jillian M.; Zhang, Ye; Kilpatrick, Korey; Levy, Asaf; Marsolais, Frédéric; Lewinsohn, Efraim; Sensen, Christoph W.; Facchini, Peter J.

2015-01-01

Amphetamine analogues are produced by plants in the genus Ephedra and by khat (Catha edulis), and include the widely used decongestants and appetite suppressants (1S,2S)-pseudoephedrine and (1R,2S)-ephedrine. The production of these metabolites, which derive from L-phenylalanine, involves a multi-step pathway partially mapped out at the biochemical level using knowledge of benzoic acid metabolism established in other plants, and direct evidence using khat and Ephedra species as model systems. Despite the commercial importance of amphetamine-type alkaloids, only a single step in their biosynthesis has been elucidated at the molecular level. We have employed Illumina next-generation sequencing technology, paired with Trinity and Velvet-Oases assembly platforms, to establish data-mining frameworks for Ephedra sinica and khat plants. Sequence libraries representing a combined 200,000 unigenes were subjected to an annotation pipeline involving direct searches against public databases. Annotations included the assignment of Gene Ontology (GO) terms used to allocate unigenes to functional categories. As part of our functional genomics program aimed at novel gene discovery, the databases were mined for enzyme candidates putatively involved in alkaloid biosynthesis. Queries used for mining included enzymes with established roles in benzoic acid metabolism, as well as enzymes catalyzing reactions similar to those predicted for amphetamine alkaloid metabolism. Gene candidates were evaluated based on phylogenetic relationships, FPKM-based expression data, and mechanistic considerations. Establishment of expansive sequence resources is a critical step toward pathway characterization, a goal with both academic and industrial implications. PMID:25806807

Site Environmental Report for Calendar Year 2001. DOE Operations at The Boeing Company, Rocketdyne Propulsion & Power

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

Rutherford, Phil; Samuels, Sandy; Leee, Majelle

2002-09-01

This Annual Site Environmental Report (ASER) for 2001 describes the environmental conditions related to work performed for the Department of Energy (DOE) at Area IV of the Boeing Rocketdyne Santa Susana Field Laboratory (SSFL). In the past, these operations included development, fabrication, and disassembly of nuclear reactors, reactor fuel, and other radioactive materials under the former Atomics International (AI) Division. Other activities included the operation of large-scale liquid metal facilities for testing of liquid metal fast breeder components at the Energy Technology Engineering Center (ETEC), a government-owned, company-operated test facility within Area IV. All nuclear work was terminated in 1988,more » and subsequently, all radiological work has been directed toward decontamination and decommissioning (D&D) of the previously used nuclear facilities and associated site areas. Closure of the sodium test facilities began in 1996. Results of the radiological monitoring program for the calendar year of 2001 continue to indicate that there are no significant releases of radioactive material from Area IV of SSFL. All potential exposure pathways are sampled and/or monitored, including air, soil, surface water, groundwater, direct radiation, transfer of property (land, structures, waste), and recycling. All radioactive wastes are processed for disposal at DOE disposal sites and other sites approved by DOE and licensed for radioactive waste. Liquid radioactive wastes are not released into the environment and do not constitute an exposure pathway. No structural debris from buildings, released for unrestricted use, was transferred to municipal landfills or recycled in 2001.« less

Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses

PubMed Central

MacLullich, Alasdair MJ; Ferguson, Karen J; Miller, Thomas; de Rooij, Sophia EJA; Cunningham, Colm

2015-01-01

Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep-wake cycle, and other changes in mental status. The main risk factors are old age, cognitive impairment, and other comorbidities. Though delirium has consistent core clinical features, it has a very wide range of precipitating factors, including acute illness, surgery, trauma, and drugs. The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article we attempt to narrow down some specific causal pathways. We propose a basic classification for the aetiological factors: (a) direct brain insults, and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (eg. hypoxia, hypoglycaemia, stroke), metabolic abnormalities (eg. hyponatraemia, hypercalcaemia), and the effects of drugs. Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress-response pathways which, in health, are adaptive. Ageing and central nervous system disease, two major predisposing factors for delirium, are associated with alterations in the magnitude or duration of stress and sickness behaviour responses, and increased vulnerability to the effects of these responses. We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behaviour response, and activity of the limbic-hypothalamic-pituitary-adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium. PMID:18707945

Increased mortality risk among the visually impaired: the roles of mental well-being and preventive care practices.

PubMed

Zheng, D Diane; Christ, Sharon L; Lam, Byron L; Arheart, Kristopher L; Galor, Anat; Lee, David J

2012-05-14

Mechanisms by which visual impairment (VI) increases mortality risk are poorly understood. We estimated the direct and indirect effects of self-rated VI on risk of mortality through mental well-being and preventive care practice mechanisms. Using complete data from 12,987 adult participants of the 2000 Medical Expenditure Panel Survey with mortality linkage through 2006, we undertook structural equation modeling using two latent variables representing mental well-being and poor preventive care to examine multiple effect pathways of self-rated VI on all-cause mortality. Generalized linear structural equation modeling was used to simultaneously estimate pathways including the latent variables and Cox regression model, with adjustment for controls and the complex sample survey design. VI increased the risk of mortality directly after adjusting for mental well-being and other covariates (hazard ratio [HR] = 1.25 [95% confidence interval: 1.01, 1.55]). Poor preventive care practices were unrelated to VI and to mortality. Mental well-being decreased mortality risk (HR = 0.68 [0.64, 0.74], P < 0.001). VI adversely affected mental well-being (β = -0.54 [-0.65, -0.43]; P < 0.001). VI also increased mortality risk indirectly through mental well-being (HR = 1.23 [1.16, 1.30]). The total effect of VI on mortality including its influence through mental well-being was HR 1.53 [1.24, 1.90]. Similar but slightly stronger patterns of association were found when examining cardiovascular disease-related mortality, but not cancer-related mortality. VI increases the risk of mortality directly and indirectly through its adverse impact on mental well-being. Prevention of disabling ocular conditions remains a public health priority along with more aggressive diagnosis and treatment of depression and other mental health conditions in those living with VI.

The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation.

PubMed

Li, Min; Tang, Yuxiao; Wu, Lusha; Mo, Fengfeng; Wang, Xin; Li, Hongxia; Qi, Ruirui; Zhang, Hongwei; Srivastava, Arun; Ling, Chen

2017-08-24

Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe -/- ) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy. © 2017 by The American Society of Hematology.

Repression of cell proliferation by miR319-regulated TCP4.

PubMed

Schommer, Carla; Debernardi, Juan M; Bresso, Edgardo G; Rodriguez, Ramiro E; Palatnik, Javier F

2014-10-01

Leaf development has been extensively studied on a genetic level. However, little is known about the interplay between the developmental regulators and the cell cycle machinery--a link that ultimately affects leaf form and size. miR319 is a conserved microRNA that regulates TCP transcription factors involved in multiple developmental pathways, including leaf development and senescence, organ curvature, and hormone biosynthesis and signaling. Here, we analyze the participation of TCP4 in the control of cell proliferation. A small increase in TCP4 activity has an immediate impact on leaf cell number, by significantly reducing cell proliferation. Plants with high TCP4 levels have a strong reduction in the expression of genes known to be active in G2-M phase of the cell cycle. Part of these effects is mediated by induction of miR396, which represses Growth-Regulating Factor (GRF) transcription factors. Detailed analysis revealed TCP4 to be a direct regulator of MIR396b. However, we found that TCP4 can control cell proliferation through additional pathways, and we identified a direct connection between TCP4 and ICK1/KRP1, a gene involved in the progression of the cell cycle. Our results show that TCP4 can activate different pathways that repress cell proliferation. © The Author 2014. Published by the Molecular Plant Shanghai Editorial Office in association with Oxford University Press on behalf of CSPB and IPPE, SIBS, CAS.

Direct Leukocyte Migration across Pulmonary Arterioles and Venules into the Perivascular Interstitium of Murine Lungs during Bleomycin Injury and Repair

PubMed Central

Wang, Ping M.; Kachel, Diane L.; Cesta, Mark F.; Martin, William J.

2011-01-01

During acute lung injury and repair, leukocytes are thought to enter the lung primarily across alveolar capillaries and postcapillary venules. We hypothesized that leukocytes also migrate across pulmonary arterioles and venules, which serve as alternative sites for leukocyte influx into the lung during acute lung injury and repair. Lung sections from C57BL/6J mice up to 14 days after intratracheal bleomycin (3.33 U/kg) or saline instillation were assessed by light, fluorescence, confocal, and transmission electron microscopy for evidence of inflammatory cell sequestration and transmigration at these sites. After bleomycin treatment, large numbers of leukocytes (including neutrophils, eosinophils, and monocytes) were present in the vascular lumina and in perivascular interstitia of pulmonary arterioles and venules, as well as within the vascular walls. Leukocytes were observed within well-defined pathways in arteriolar walls and much less structured pathways in venular walls, apparently in the process of transmigration. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were expressed at sites of leukocyte interaction with the luminal surface, especially in arterioles. Leukocytes appeared to exit from the vessels near collagen fibers into the perivascular interstitium. Results indicate that leukocytes can directly migrate across arteriolar and venular walls into the perivascular interstitium, which may represent an important but under-recognized pathway for leukocyte influx into the lung during injury and repair. PMID:21641381

CWF-145, a novel synthetic quinolone derivative exerts potent antimitotic activity against human prostate cancer: Rapamycin enhances antimitotic drug-induced apoptosis through the inhibition of Akt/mTOR pathway.

PubMed

Hung, Chao-Ming; Lin, Ying-Chao; Liu, Liang-Chih; Kuo, Sheng-Chu; Ho, Chi-Tang; Way, Tzong-Der

2016-12-25

CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU-145 and LNCap. It had a very low IC 50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin at the colchicine-binding site then disrupted microtubule polymerization. Furthermore, the damaged microtubule affected the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our data showed that CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. The increased cyclin B1 and securin arrested cell cycle at G2/M phase. Moreover, we showed that Akt activation markedly increased resistance to microtubule-directed agents, including CWF-145, colchicine, and paclitaxel. Interestingly, rapamycin inhibited Akt-mediated therapeutic resistance, indicating that these effects were dependent on mTOR. Taken together, these observations suggest that activation of the Akt/mTOR signaling pathway can promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data may provide insight into potentially synergistic combinations of anticancer therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Regulation of extracellular matrix vesicles via rapid responses to steroid hormones during endochondral bone formation.

PubMed

Asmussen, Niels; Lin, Zhao; McClure, Michael J; Schwartz, Zvi; Boyan, Barbara D

2017-12-09

Endochondral bone formation is a precise and highly ordered process whose exact regulatory framework is still being elucidated. Multiple regulatory pathways are known to be involved. In some cases, regulation impacts gene expression, resulting in changes in chondrocyte phenotypic expression and extracellular matrix synthesis. Rapid regulatory mechanisms are also involved, resulting in release of enzymes, factors and micro RNAs stored in extracellular matrisomes called matrix vesicles. Vitamin D metabolites modulate endochondral development via both genomic and rapid membrane-associated signaling pathways. 1α,25-dihydroxyvitamin D3 [1α,25(OH) 2 D 3 ] acts through the vitamin D receptor (VDR) and a membrane associated receptor, protein disulfide isomerase A3 (PDIA3). 24R,25-dihydroxyvitamin D3 [24R,25(OH) 2 D 3 ] affects primarily chondrocytes in the resting zone (RC) of the growth plate, whereas 1α,25(OH) 2 D 3 affects cells in the prehypertrophic and upper hypertrophic cell zones (GC). This includes genomically directing the cells to produce matrix vesicles with zone specific characteristics. In addition, vitamin D metabolites produced by the cells interact directly with the matrix vesicle membrane via rapid signal transduction pathways, modulating their activity in the matrix. The matrix vesicle payload is able to rapidly impact the extracellular matrix via matrix processing enzymes as well as providing a feedback mechanism to the cells themselves via the contained micro RNAs. Copyright © 2017. Published by Elsevier Inc.

Two Components of the RNA-Directed DNA Methylation Pathway Associate with MORC6 and Silence Loci Targeted by MORC6 in Arabidopsis

PubMed Central

Liu, Zhang-Wei; Zhou, Jin-Xing; Huang, Huan-Wei; Li, Yong-Qiang; Shao, Chang-Rong; Li, Lin; Cai, Tao; Chen, She

2016-01-01

The SU(VAR)3-9 homolog SUVH9 and the double-stranded RNA-binding protein IDN2 were thought to be components of an RNA-directed DNA methylation (RdDM) pathway in Arabidopsis. We previously found that SUVH9 interacts with MORC6 but how the interaction contributes to transcriptional silencing remains elusive. Here, our genetic analysis indicates that SUVH2 and SUVH9 can either act in the same pathway as MORC6 or act synergistically with MORC6 to mediate transcriptional silencing. Moreover, we demonstrate that IDN2 interacts with MORC6 and mediates the silencing of a subset of MORC6 target loci. Like SUVH2, SUVH9, and IDN2, other RdDM components including Pol IV, Pol V, RDR2, and DRM2 are also required for transcriptional silencing at a subset of MORC6 target loci. MORC6 was previously shown to mediate transcriptional silencing through heterochromatin condensation. We demonstrate that the SWI/SNF chromatin-remodeling complex components SWI3B, SWI3C, and SWI3D interact with MORC6 as well as with SUVH9 and then mediate transcriptional silencing. These results suggest that the RdDM components are involved not only in DNA methylation but also in MORC6-mediated heterochromatin condensation. This study illustrates how DNA methylation is linked to heterochromatin condensation and thereby enhances transcriptional silencing at methylated genomic regions. PMID:27171427

A structural equation modeling approach to understanding pathways that connect socioeconomic status and smoking.

PubMed

Martinez, Sydney A; Beebe, Laura A; Thompson, David M; Wagener, Theodore L; Terrell, Deirdra R; Campbell, Janis E

2018-01-01

The inverse association between socioeconomic status and smoking is well established, yet the mechanisms that drive this relationship are unclear. We developed and tested four theoretical models of the pathways that link socioeconomic status to current smoking prevalence using a structural equation modeling (SEM) approach. Using data from the 2013 National Health Interview Survey, we selected four indicator variables (poverty ratio, personal earnings, educational attainment, and employment status) that we hypothesize underlie a latent variable, socioeconomic status. We measured direct, indirect, and total effects of socioeconomic status on smoking on four pathways through four latent variables representing social cohesion, financial strain, sleep disturbance, and psychological distress. Results of the model indicated that the probability of being a smoker decreased by 26% of a standard deviation for every one standard deviation increase in socioeconomic status. The direct effects of socioeconomic status on smoking accounted for the majority of the total effects, but the overall model also included significant indirect effects. Of the four mediators, sleep disturbance and psychological distress had the largest total effects on current smoking. We explored the use of structural equation modeling in epidemiology to quantify effects of socioeconomic status on smoking through four social and psychological factors to identify potential targets for interventions. A better understanding of the complex relationship between socioeconomic status and smoking is critical as we continue to reduce the burden of tobacco and eliminate health disparities related to smoking.

A structural equation modeling approach to understanding pathways that connect socioeconomic status and smoking

PubMed Central

Beebe, Laura A.; Thompson, David M.; Wagener, Theodore L.; Terrell, Deirdra R.; Campbell, Janis E.

2018-01-01

The inverse association between socioeconomic status and smoking is well established, yet the mechanisms that drive this relationship are unclear. We developed and tested four theoretical models of the pathways that link socioeconomic status to current smoking prevalence using a structural equation modeling (SEM) approach. Using data from the 2013 National Health Interview Survey, we selected four indicator variables (poverty ratio, personal earnings, educational attainment, and employment status) that we hypothesize underlie a latent variable, socioeconomic status. We measured direct, indirect, and total effects of socioeconomic status on smoking on four pathways through four latent variables representing social cohesion, financial strain, sleep disturbance, and psychological distress. Results of the model indicated that the probability of being a smoker decreased by 26% of a standard deviation for every one standard deviation increase in socioeconomic status. The direct effects of socioeconomic status on smoking accounted for the majority of the total effects, but the overall model also included significant indirect effects. Of the four mediators, sleep disturbance and psychological distress had the largest total effects on current smoking. We explored the use of structural equation modeling in epidemiology to quantify effects of socioeconomic status on smoking through four social and psychological factors to identify potential targets for interventions. A better understanding of the complex relationship between socioeconomic status and smoking is critical as we continue to reduce the burden of tobacco and eliminate health disparities related to smoking. PMID:29408939

Evaluation of Yersinia pestis Transmission Pathways for Sylvatic Plague in Prairie Dog Populations in the Western U.S.

PubMed

Richgels, Katherine L D; Russell, Robin E; Bron, Gebbiena M; Rocke, Tonie E

2016-06-01

Sylvatic plague, caused by the bacterium Yersinia pestis, is periodically responsible for large die-offs in rodent populations that can spillover and cause human mortalities. In the western US, prairie dog populations experience nearly 100% mortality during plague outbreaks, suggesting that multiple transmission pathways combine to amplify plague dynamics. Several alternate pathways in addition to flea vectors have been proposed, such as transmission via direct contact with bodily fluids or inhalation of infectious droplets, consumption of carcasses, and environmental sources of plague bacteria, such as contaminated soil. However, evidence supporting the ability of these proposed alternate pathways to trigger large-scale epizootics remains elusive. Here we present a short review of potential plague transmission pathways and use an ordinary differential equation model to assess the contribution of each pathway to resulting plague dynamics in black-tailed prairie dogs (Cynomys ludovicianus) and their fleas (Oropsylla hirsuta). Using our model, we found little evidence to suggest that soil contamination was capable of producing plague epizootics in prairie dogs. However, in the absence of flea transmission, direct transmission, i.e., contact with bodily fluids or inhalation of infectious droplets, could produce enzootic dynamics, and transmission via contact with or consumption of carcasses could produce epizootics. This suggests that these pathways warrant further investigation.

Evaluation of Yersinia pestis transmission pathways for sylvatic plague in prairie dog populations in the western U.S.

USGS Publications Warehouse

Richgels, Katherine L. D.; Russell, Robin E.; Bron, Gebbiena; Rocke, Tonie E.

2016-01-01

Sylvatic plague, caused by the bacterium Yersinia pestis, is periodically responsible for large die-offs in rodent populations that can spillover and cause human mortalities. In the western US, prairie dog populations experience nearly 100% mortality during plague outbreaks, suggesting that multiple transmission pathways combine to amplify plague dynamics. Several alternate pathways in addition to flea vectors have been proposed, such as transmission via direct contact with bodily fluids or inhalation of infectious droplets, consumption of carcasses, and environmental sources of plague bacteria, such as contaminated soil. However, evidence supporting the ability of these proposed alternate pathways to trigger large-scale epizootics remains elusive. Here we present a short review of potential plague transmission pathways and use an ordinary differential equation model to assess the contribution of each pathway to resulting plague dynamics in black-tailed prairie dogs (Cynomys ludovicianus) and their fleas (Oropsylla hirsuta). Using our model, we found little evidence to suggest that soil contamination was capable of producing plague epizootics in prairie dogs. However, in the absence of flea transmission, direct transmission, i.e., contact with bodily fluids or inhalation of infectious droplets, could produce enzootic dynamics, and transmission via contact with or consumption of carcasses could produce epizootics. This suggests that these pathways warrant further investigation.

Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

PubMed Central

Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

2015-01-01

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

Elucidating Direct Photolysis Mechanisms of Different Dissociation Species of Norfloxacin in Water and Mg2+ Effects by Quantum Chemical Calculations.

PubMed

Wang, Se; Wang, Zhuang

2017-11-11

The study of pollution due to combined antibiotics and metals is urgently needed. Photochemical processes are an important transformation pathway for antibiotics in the environment. The mechanisms underlying the effects of metal-ion complexation on the aquatic photochemical transformation of antibiotics in different dissociation forms are crucial problems in science, and beg solutions. Herein, we investigated the mechanisms of direct photolysis of norfloxacin (NOR) in different dissociation forms in water and metal ion Mg 2+ effects using quantum chemical calculations. Results show that different dissociation forms of NOR had different maximum electronic absorbance wavelengths (NOR 2+ < NOR⁰ < NOR⁺) and showed different photolysis reactivity. Analysis of transition states (TS) and reaction activation energies ( E a ) indicated NOR⁺ generally underwent loss of the piperazine ring (C10-N13 bond cleavage) and damage to piperazine ring (N13-C14 bond cleavage). For NOR 2+ , the main direct photolysis pathways were de-ethylation (N7-C8 bond cleavage) and decarboxylation (C2-C5 bond cleavage). Furthermore, the presence of Mg 2+ changed the order of the wavelength at maximum electronic absorbance (NOR⁺-Mg 2+ < NOR⁰-Mg 2+ < NOR 2+ -Mg 2+ ) and increased the intensities of absorbance peaks of all three dissociation species of NOR, implying that Mg 2+ played an important role in the direct photolysis of NOR⁰, NOR⁺, and NOR 2+ . The calculated TS results indicated that the presence of Mg 2+ increased E a for most direct photolysis pathways of NOR, while it decreased E a for some direct photolysis pathways such as the loss of the piperazine ring and the damage of the piperazine ring of NOR⁰ and the defluorination of NOR⁺.

Coincidence and covariance data acquisition in photoelectron and -ion spectroscopy. I. Formal theory

NASA Astrophysics Data System (ADS)

Mikosch, Jochen; Patchkovskii, Serguei

2013-10-01

We derive a formal theory of noisy Poisson processes with multiple outcomes. We obtain simple, compact expressions for the probability distribution function of arbitrarily complex composite events and its moments. We illustrate the utility of the theory by analyzing properties of coincidence and covariance photoelectron-photoion detection involving single-ionization events. The results and techniques introduced in this work are directly applicable to more general coincidence and covariance experiments, including multiple ionization and multiple-ion fragmentation pathways.

The Preliminary Pollutant Limit Value Approach: Manual for Users

DTIC Science & Technology

1988-07-01

48 5.2.3 Plant Consumption by Dairy Cows (Upd) ............. 48 5.2.4 Water Consumption by Dairy Cows (Uwd) ............. 48 5.2.5 Soil...other equations include the effect of concurrent consumption of soil by grazing cows (equation 19), and for contaminated water intake, such as from a...ingestion of soil by dairy cow , kg/day. A default value of 0.87 kg/day is suggested (see Section 5.2.5) 4.2.6 Direct Soil Intake Two pathway equations are

Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis.

PubMed

Jayaraj, Richard L; Rodriguez, Eric A; Wang, Yi; Block, Michelle L

2017-06-01

Accumulating research indicates that ambient outdoor air pollution impacts the brain and may affect neurodegenerative diseases, yet the potential underlying mechanisms are poorly understood. The neuroinflammation hypothesis holds that elevation of cytokines and reactive oxygen species in the brain mediates the deleterious effects of urban air pollution on the central nervous system (CNS). Studies in human and animal research document that neuroinflammation occurs in response to several inhaled pollutants. Microglia are a prominent source of cytokines and reactive oxygen species in the brain, implicated in the progressive neuron damage in diverse neurodegenerative diseases, and activated by inhaled components of urban air pollution through both direct and indirect pathways. The MAC1-NOX2 pathway has been identified as a mechanism through which microglia respond to different forms of air pollution, suggesting a potential common deleterious pathway. Multiple direct and indirect pathways in response to air pollution exposure likely interact in concert to exert CNS effects.

A novel use of structural equation models to examine factors associated with prediabetes among adults aged 50 years and older: National Health and Nutrition Examination Survey 2001-2006.

PubMed

Bardenheier, Barbara H; Bullard, Kai McKeever; Caspersen, Carl J; Cheng, Yiling J; Gregg, Edward W; Geiss, Linda S

2013-09-01

To use structural modeling to test a hypothesized model of causal pathways related with prediabetes among older adults in the U.S. Cross-sectional study of 2,230 older adults (≥ 50 years) without diabetes included in the morning fasting sample of the 2001-2006 National Health and Nutrition Examination Surveys. Demographic data included age, income, marital status, race/ethnicity, and education. Behavioral data included physical activity (metabolic equivalent hours per week for vigorous or moderate muscle strengthening, walking/biking, and house/yard work), and poor diet (refined grains, red meat, added sugars, solid fats, and high-fat dairy). Structural-equation modeling was performed to examine the interrelationships among these variables with family history of diabetes, high blood pressure, BMI, large waist (waist circumference: women, ≥ 35 inches; men, ≥ 40 inches), triglycerides ≥ 200 mg/dL, and total and HDL (≥ 60 mg/dL) cholesterol. After dropping BMI and total cholesterol, our best-fit model included three single factors: socioeconomic position (SEP), physical activity, and poor diet. Large waist had the strongest direct effect on prediabetes (0.279), followed by male sex (0.270), SEP (-0.157), high blood pressure (0.122), family history of diabetes (0.070), and age (0.033). Physical activity had direct effects on HDL (0.137), triglycerides (-0.136), high blood pressure (-0.132), and large waist (-0.067); poor diet had direct effects on large waist (0.146) and triglycerides (0.148). Our results confirmed that, while including factors known to be associated with high risk of developing prediabetes, large waist circumference had the strongest direct effect. The direct effect of SEP on prediabetes suggests mediation by some unmeasured factor(s).

Hanford Site National Environmental Policy Act (NEPA) Characterization. Revision 5

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

Cushing, C.E.

1992-12-01

This fifth revision of the Hanford Site National Environmental Policy (NEPA) Characterization presents current environmental data regarding the Hanford Site and its immediate environs. This information is intended for use in preparing Site-related NEPA documentation. Information is presented on climate and meteorology, geology and hydrology, ecology, history and archaeology, socioeconomics, land use, and noise levels, prepared by Pacific Northwest Laboratory (PNL) staff. Models are described that are to be used in simulating realized or potential impacts from nuclear materials at the Hanford Site. Included are models of radionuclide transport in groundwater and atmospheric pathways, and of radiation dose to populationsmore » via all known pathways from known initial conditions. Federal and state regulations, DOE orders and permits, and environmental standards directly applicable for the NEPA documents at the Hanford Site, are provided.« less

Hanford Site National Environmental Policy Act (NEPA) Characterization

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

Cushing, C.E.

1992-12-01

This fifth revision of the Hanford Site National Environmental Policy (NEPA) Characterization presents current environmental data regarding the Hanford Site and its immediate environs. This information is intended for use in preparing Site-related NEPA documentation. Information is presented on climate and meteorology, geology and hydrology, ecology, history and archaeology, socioeconomics, land use, and noise levels, prepared by Pacific Northwest Laboratory (PNL) staff. Models are described that are to be used in simulating realized or potential impacts from nuclear materials at the Hanford Site. Included are models of radionuclide transport in groundwater and atmospheric pathways, and of radiation dose to populationsmore » via all known pathways from known initial conditions. Federal and state regulations, DOE orders and permits, and environmental standards directly applicable for the NEPA documents at the Hanford Site, are provided.« less

Marriage and health: his and hers.

PubMed

Kiecolt-Glaser, J K; Newton, T L

2001-07-01

This review focuses on the pathway leading from the marital relationship to physical health. Evidence from 64 articles published in the past decade, particularly marital interaction studies, suggests that marital functioning is consequential for health; negative dimensions of marital functioning have indirect influences on health outcomes through depression and health habits, and direct influences on cardiovascular, endocrine, immune, neurosensory, and other physiological mechanisms. Moreover, individual difference variables such as trait hostility augment the impact of marital processes on biological systems. Emerging themes in the past decade include the importance of differentiating positive and negative dimensions of marital functioning, the explanatory power of behavioral data, and gender differences in the pathways from the marital relationship to physiological functioning. Contemporary models of gender that emphasize self-processes, traits, and roles furnish alternative perspectives on the differential costs and benefits of marriage for men's and women's health.

Swimming behavior of zebrafish is accurately classified by direct modeling and behavioral space analysis

NASA Astrophysics Data System (ADS)

Feng, Ruopei; Chemla, Yann; Gruebele, Martin

Larval zebrafish is a popular organism in the search for the correlation between locomotion behavior and neural pathways because of their highly stereotyped and temporally episodic swimming motion. This correlation is usually investigated using electrophysiological recordings of neural activities in partially immobilized fish. Seeking for a way to study animal behavior without constraints or intruding electrodes, which can in turn modify their behavior, our lab has introduced a parameter-free approach which allows automated classification of the locomotion behaviors of freely swimming fish. We looked into several types of swimming bouts including free swimming and two modes of escape responses and established a new classification of these behaviors. Combined with a neurokinematic model, our analysis showed the capability to probe intrinsic properties of the underlying neural pathways of freely swimming larval zebrafish by inspecting swimming movies only.

Theorizing a model information pathway to mitigate the menstrual taboo.

PubMed

Yagnik, Arpan

2017-12-13

The impact of menstruation on the society is directly seen in the educational opportunities, quality of life and professional endeavors of females. However, lack of menstrual hygiene management has indirect implication on the balance and development of the society and nation. This study is set in the Indian context. The researcher identifies actors with a potential of mitigating menstrual taboo and then theorizes an optimal information pathway to mitigate menstrual taboo. Diffusion of innovation, framing and agenda setting theories contribute as frameworks in the creation of an optimal pathway to dissolve the menstrual taboo. The actors identified in this model are scholars, health activists, students, NGOs, media, government, corporations and villages or communities. The determinants for the direction and the order of the pathway to diffuse knowledge and confidence among these actors are the ultimate goal and sustainability of the model, strengths and weaknesses of actors, and actors' extent of influence. Considering the absence of an existing alternate, this model pathway provides a solid framework purely from a theoretical perspective. Theoretically, this model pathway is possible, practical and optimal. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A multitasking Argonaute: exploring the many facets of C. elegans CSR-1.

PubMed

Wedeles, Christopher J; Wu, Monica Z; Claycomb, Julie M

2013-12-01

While initial studies of small RNA-mediated gene regulatory pathways focused on the cytoplasmic functions of such pathways, identifying roles for Argonaute/small RNA pathways in modulating chromatin and organizing the genome has become a topic of intense research in recent years. Nuclear regulatory mechanisms for Argonaute/small RNA pathways appear to be widespread, in organisms ranging from plants to fission yeast, Caenorhabditis elegans to humans. As the effectors of small RNA-mediated gene regulatory pathways, Argonaute proteins guide the chromatin-directed activities of these pathways. Of particular interest is the C. elegans Argonaute, chromosome segregation and RNAi deficient (CSR-1), which has been implicated in such diverse functions as organizing the holocentromeres of worm chromosomes, modulating germline chromatin, protecting the genome from foreign nucleic acid, regulating histone levels, executing RNAi, and inhibiting translation in conjunction with Pumilio proteins. CSR-1 interacts with small RNAs known as 22G-RNAs, which have complementarity to 25 % of the protein coding genes. This peculiar Argonaute is the only essential C. elegans Argonaute out of 24 family members in total. Here, we summarize the current understanding of CSR-1 functions in the worm, with emphasis on the chromatin-directed activities of this ever-intriguing Argonaute.

Analysis of borderline substitution/electron transfer pathways from direct ab initio MD simulations

NASA Astrophysics Data System (ADS)

Yamataka, Hiroshi; Aida, Misako; Dupuis, Michel

2002-02-01

Ab initio molecular dynamics simulations were carried out for the borderline reaction pathways in the reaction of CH 2O rad - with CH 3Cl. The simulations reveal distinctive features of three types of mechanisms passing through the S N2-like transition state (TS): (i) a direct formation of S N2 products, (ii) a direct formation of ET products, and (iii) a two-step formation of ET products via the S N2 valley. The direct formation of the ET product through the S N2-like TS appears to be more favorable at higher temperatures. The two-step process depends on the amount of energy that goes into the C-C stretching mode.

Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance

PubMed Central

Lee, Samuel; Kim, Soo Min

2013-01-01

Abstract The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes. Antioxid. Redox Signal. 18, 1165–1207. PMID:22607099

CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration.

PubMed

Décaillot, Fabien M; Kazmi, Manija A; Lin, Ying; Ray-Saha, Sarmistha; Sakmar, Thomas P; Sachdev, Pallavi

2011-09-16

G protein-coupled receptor hetero-oligomerization is emerging as an important regulator of ligand-dependent transmembrane signaling, but precisely how receptor heteromers affect receptor pharmacology remains largely unknown. In this study, we have attempted to identify the functional significance of the heteromeric complex between CXCR4 and CXCR7 chemokine receptors. We demonstrate that co-expression of CXCR7 with CXCR4 results in constitutive recruitment of β-arrestin to the CXCR4·CXCR7 complex and simultaneous impairment of G(i)-mediated signaling. CXCR7/CXCR4 co-expression also results in potentiation of CXCL12 (SDF-1)-mediated downstream β-arrestin-dependent cell signaling pathways, including ERK1/2, p38 MAPK, and SAPK as judged from the results of experiments using siRNA knockdown to deplete β-arrestin. Interestingly, CXCR7/CXCR4 co-expression enhances cell migration in response to CXCL12 stimulation. Again, inhibition of β-arrestin using either siRNA knockdown or a dominant negative mutant abrogates the enhanced CXCL12-dependent migration of CXCR4/CXCR7-expressing cells. These results show how CXCR7, which cannot signal directly through G protein-linked pathways, can nevertheless affect cellular signaling networks by forming a heteromeric complex with CXCR4. The CXCR4·CXCR7 heterodimer complex recruits β-arrestin, resulting in preferential activation of β-arrestin-linked signaling pathways over canonical G protein pathways. CXCL12-dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7.

CXCR7/CXCR4 Heterodimer Constitutively Recruits β-Arrestin to Enhance Cell Migration*

PubMed Central

Décaillot, Fabien M.; Kazmi, Manija A.; Lin, Ying; Ray-Saha, Sarmistha; Sakmar, Thomas P.; Sachdev, Pallavi

2011-01-01

G protein-coupled receptor hetero-oligomerization is emerging as an important regulator of ligand-dependent transmembrane signaling, but precisely how receptor heteromers affect receptor pharmacology remains largely unknown. In this study, we have attempted to identify the functional significance of the heteromeric complex between CXCR4 and CXCR7 chemokine receptors. We demonstrate that co-expression of CXCR7 with CXCR4 results in constitutive recruitment of β-arrestin to the CXCR4·CXCR7 complex and simultaneous impairment of Gi-mediated signaling. CXCR7/CXCR4 co-expression also results in potentiation of CXCL12 (SDF-1)-mediated downstream β-arrestin-dependent cell signaling pathways, including ERK1/2, p38 MAPK, and SAPK as judged from the results of experiments using siRNA knockdown to deplete β-arrestin. Interestingly, CXCR7/CXCR4 co-expression enhances cell migration in response to CXCL12 stimulation. Again, inhibition of β-arrestin using either siRNA knockdown or a dominant negative mutant abrogates the enhanced CXCL12-dependent migration of CXCR4/CXCR7-expressing cells. These results show how CXCR7, which cannot signal directly through G protein-linked pathways, can nevertheless affect cellular signaling networks by forming a heteromeric complex with CXCR4. The CXCR4·CXCR7 heterodimer complex recruits β-arrestin, resulting in preferential activation of β-arrestin-linked signaling pathways over canonical G protein pathways. CXCL12-dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7. PMID:21730065

Methylation and microRNA-mediated epigenetic regulation of SOCS3

PubMed Central

Boosani, Chandra S.; Agrawal, Devendra K.

2017-01-01

Epigenetic gene silencing of several genes causes different pathological conditions in humans, and DNA methylation has been identified as one of the key mechanisms that underlie this evolutionarily conserved phenomenon associated with developmental and pathological gene regulation. Recent advances in the miRNA technology with high throughput analysis of gene regulation further increased our understanding on the role of miRNAs regulating multiple gene expression. There is increasing evidence supporting that the miRNAs not only regulate gene expression but they also are involved in the hypermethylation of promoter sequences, which cumulatively contributes to the epigenetic gene silencing. Here, we critically evaluated the recent progress on the transcriptional regulation of an important suppressor protein that inhibits cytokine-mediated signaling, SOCS3, whose expression is directly regulated both by promoter methylation and also by microRNAs, affecting its vital cell regulating functions. SOCS3 was identified as a potent inhibitor of Jak/STAT signaling pathway which is frequently upregulated in several pathologies, including cardiovascular disease, cancer, diabetes, viral infections, and the expression of SOCS3 was inhibited or greatly reduced due to hypermethylation of the CpG islands in its promoter region or suppression of its expression by different microRNAs. Additionally, we discuss key intracellular signaling pathways regulated by SOCS3 involving cellular events, including cell proliferation, cell growth, cell migration and apoptosis. Identification of the pathway intermediates as specific targets would not only aid in the development of novel therapeutic drugs, but, would also assist in developing new treatment strategies that could successfully be employed in combination therapy to target multiple signaling pathways. PMID:25682267

The regulatory mechanism of fruit ripening revealed by analyses of direct targets of the tomato MADS-box transcription factor RIPENING INHIBITOR

PubMed Central

Fujisawa, Masaki; Ito, Yasuhiro

2013-01-01

The developmental process of ripening is unique to fleshy fruits and a key factor in fruit quality. The tomato (Solanum lycopersicum) MADS-box transcription factor RIPENING INHIBITOR (RIN), one of the earliest-acting ripening regulators, is required for broad aspects of ripening, including ethylene-dependent and -independent pathways. However, our knowledge of direct RIN target genes has been limited, considering the broad effects of RIN on ripening. In a recent work published in The Plant Cell, we identified 241 direct RIN target genes by chromatin immunoprecipitation coupled with DNA microarray (ChIP-chip) and transcriptome analysis. Functional classification of the targets revealed that RIN participates in the regulation of many biological processes including well-known ripening processes such as climacteric ethylene production and lycopene accumulation. In addition, we found that ethylene is required for the full expression of RIN and several RIN-targeting transcription factor genes at the ripening stage. Here, based on our recently published findings and additional data, we discuss the ripening processes regulated by RIN and the interplay between RIN and ethylene. PMID:23518588

Pathways of proton transfer in the light-driven pump bacteriorhodopsin

NASA Technical Reports Server (NTRS)

Lanyi, J. K.

1993-01-01

The mechanism of proton transport in the light-driven pump bacteriorhodopsin is beginning to be understood. Light causes the all-trans to 13-cis isomerization of the retinal chromophore. This sets off a sequential and directed series of transient decreases in the pKa's of a) the retinal Schiff base, b) an extracellular proton release complex which includes asp-85, and c) a cytoplasmic proton uptake complex which includes asp-96. The timing of these pKa changes during the photoreaction cycle causes sequential proton transfers which result in the net movement of a proton across the protein, from the cytoplasmic to the extracellular surface.

The stress-buffering effects of hope on adjustment to multiple sclerosis.

PubMed

Madan, Sindia; Pakenham, Kenneth I

2014-12-01

Hope is an important resource for coping with chronic illness; however, the role of hope in adjusting to multiple sclerosis (MS) has been neglected, and the mechanisms by which hope exerts beneficial impacts are not well understood. This study aims to examine the direct and stress-moderating effects of dispositional hope and its components (agency and pathways) on adjustment to MS. A total of 296 people with MS completed questionnaires at time 1 at 12 months later and time 2. Focal predictors were stress, hope, agency and pathways, and the adjustment outcomes were anxiety, depression, positive affect, positive states of mind and life satisfaction. Results of regression analyses showed that as predicted, greater hope was associated with better adjustment after controlling for the effects of time 1 adjustment and relevant demographics and illness variables. However, these direct effects of hope were subsumed by stress-buffering effects. Regarding the hope components, the beneficial impacts of agency emerged via a direct effects mechanism, whereas the effects of pathways were evidenced via a moderating mechanism. Findings highlight hope as an important protective coping resource for coping with MS and accentuate the roles of both agency and pathways thinking and their different modes of influence in this process.

Proceedings from the 2009 Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back

PubMed Central

Rauen, Katherine A.; Schoyer, Lisa; McCormick, Frank; Lin, Angela E.; Allanson, Judith E.; Stevenson, David A.; Gripp, Karen W.; Neri, Giovanni; Carey, John C.; Legius, Eric; Tartaglia, Marco; Schubbert, Suzanne; Roberts, Amy E.; Gelb, Bruce D.; Shannon, Kevin; Gutmann, David H.; McMahon, Martin; Guerra, Carmen; Fagin, James A.; Yu, Benjamin; Aoki, Yoko; Neel, Ben G.; Balmain, Allan; Drake, Richard R.; Nolan, Garry P.; Zenker, Martin; Bollag, Gideon; Sebolt-Leopold, Judith; Gibbs, Jackson B.; Silva, Alcino J.; Patton, E. Elizabeth; Viskochil, David H.; Kieran, Mark W.; Korf, Bruce R.; Hagerman, Randi J.; Packer, Roger J.; Melese, Teri

2012-01-01

The RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Some of these syndromes are neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, LEOPARD syndrome and Legius syndrome. Their common underlying pathogenetic mechanism brings about significant overlap in phenotypic features and includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium “Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back” chronicle the timely and typical research symposium which brought together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras syndromes and their families. The goals, to discuss basic science and clinical issues, to set forth a solid framework for future research, to direct translational applications towards therapy and to set forth best practices for individuals with RASopathies was successfully meet with a commitment to begin to move towards clinical trials. PMID:20014119

Plasma Sheet Circulation Pathways

NASA Technical Reports Server (NTRS)

Moore, Thomas E.; Delcourt, D. C.; Slinker, S. P.; Fedder, J. A.; Damiano, P.; Lotko, W.

2008-01-01

Global simulations of Earth's magnetosphere in the solar wind compute the pathways of plasma circulation through the plasma sheet. We address the pathways that supply and drain the plasma sheet, by coupling single fluid simulations with Global Ion Kinetic simulations of the outer magnetosphere and the Comprehensive Ring Current Model of the inner magnetosphere, including plasmaspheric plasmas. We find that the plasma sheet is supplied with solar wind plasmas via the magnetospheric flanks, and that this supply is most effective for northward IMF. For southward IMF, the innermost plasma sheet and ring current region are directly supplied from the flanks, with an asymmetry of single particle entry favoring the dawn flank. The central plasma sheet (near midnight) is supplied, as expected, from the lobes and polar cusps, but the near-Earth supply consists mainly of slowly moving ionospheric outflows for typical conditions. Work with the recently developed multi-fluid LFM simulation shows transport via plasma "fingers" extending Earthward from the flanks, suggestive of an interchange instability. We investigate this with solar wind ion trajectories, seeking to understand the fingering mechanisms and effects on transport rates.

Applications of Optical Coherence Tomography in Pediatric Clinical Neuroscience

PubMed Central

Avery, Robert A.; Rajjoub, Raneem D.; Trimboli-Heidler, Carmelina; Waldman, Amy T.

2015-01-01

For nearly two centuries, the ophthalmoscope has permitted examination of the retina and optic nerve—the only axons directly visualized by the physician. The retinal ganglion cells project their axons, which travel along the innermost retina to form the optic nerve, marking the beginning of the anterior visual pathway. Both the structure and function of the visual pathway are essential components of the neurologic examination as it can be involved in numerous acquired, congenital and genetic central nervous system conditions. The development of optical coherence tomography now permits the pediatric neuroscientist to visualize and quantify the optic nerve and retinal layers with unprecedented resolution. As optical coherence tomography becomes more accessible and integrated into research and clinical care, the pediatric neuroscientist may have the opportunity to utilize and/or interpret results from this device. This review describes the basic technical features of optical coherence tomography and highlights its potential clinical and research applications in pediatric clinical neuroscience including optic nerve swelling, optic neuritis, tumors of the visual pathway, vigabatrin toxicity, nystagmus, and neurodegenerative conditions. PMID:25803824

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature.

PubMed

Parikh, Jigarkumar; Coleman, Teresa; Messias, Nidia; Brown, James

2009-12-28

Xp11.2 translocation renal cell carcinomas (TRCCs) are a rare family of tumors newly recognized by the World Health Organization (WHO) in 2004. These tumors result in the fusion of partner genes to the TFE3 gene located on Xp11.2. They are most common in the pediatric population, but have been recently implicated in adult renal cell carcinoma (RCC) presenting at an early age. TFE3-mediated direct transcriptional upregulation of the Met tyrosine kinase receptor triggers dramatic activation of downstream signaling pathways including the protein kinase B (Akt)/phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of malignant cells. Here we present a case of a 22-year old female who has been treated with temsirolimus for her Xp11.2/TFE3 gene fusion RCC.

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature

PubMed Central

Parikh, Jigarkumar; Coleman, Teresa; Messias, Nidia; Brown, James

2009-01-01

Xp11.2 translocation renal cell carcinomas (TRCCs) are a rare family of tumors newly recognized by the World Health Organization (WHO) in 2004. These tumors result in the fusion of partner genes to the TFE3 gene located on Xp11.2. They are most common in the pediatric population, but have been recently implicated in adult renal cell carcinoma (RCC) presenting at an early age. TFE3-mediated direct transcriptional upregulation of the Met tyrosine kinase receptor triggers dramatic activation of downstream signaling pathways including the protein kinase B (Akt)/phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of malignant cells. Here we present a case of a 22-year old female who has been treated with temsirolimus for her Xp11.2/TFE3 gene fusion RCC. PMID:21139932

Developmental pathways to autism: A review of prospective studies of infants at risk☆

PubMed Central

Jones, Emily J.H.; Gliga, Teodora; Bedford, Rachael; Charman, Tony; Johnson, Mark H.

2014-01-01

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them. PMID:24361967

CalFitter: a web server for analysis of protein thermal denaturation data.

PubMed

Mazurenko, Stanislav; Stourac, Jan; Kunka, Antonin; Nedeljkovic, Sava; Bednar, David; Prokop, Zbynek; Damborsky, Jiri

2018-05-14

Despite significant advances in the understanding of protein structure-function relationships, revealing protein folding pathways still poses a challenge due to a limited number of relevant experimental tools. Widely-used experimental techniques, such as calorimetry or spectroscopy, critically depend on a proper data analysis. Currently, there are only separate data analysis tools available for each type of experiment with a limited model selection. To address this problem, we have developed the CalFitter web server to be a unified platform for comprehensive data fitting and analysis of protein thermal denaturation data. The server allows simultaneous global data fitting using any combination of input data types and offers 12 protein unfolding pathway models for selection, including irreversible transitions often missing from other tools. The data fitting produces optimal parameter values, their confidence intervals, and statistical information to define unfolding pathways. The server provides an interactive and easy-to-use interface that allows users to directly analyse input datasets and simulate modelled output based on the model parameters. CalFitter web server is available free at https://loschmidt.chemi.muni.cz/calfitter/.

Applications of optical coherence tomography in pediatric clinical neuroscience.

PubMed

Avery, Robert A; Rajjoub, Raneem D; Trimboli-Heidler, Carmelina; Waldman, Amy T

2015-04-01

For nearly two centuries, the ophthalmoscope has permitted examination of the retina and optic nerve-the only axons directly visualized by the physician. The retinal ganglion cells project their axons, which travel along the innermost retina to form the optic nerve, marking the beginning of the anterior visual pathway. Both the structure and function of the visual pathway are essential components of the neurologic examination as it can be involved in numerous acquired, congenital and genetic central nervous system conditions. The development of optical coherence tomography now permits the pediatric neuroscientist to visualize and quantify the optic nerve and retinal layers with unprecedented resolution. As optical coherence tomography becomes more accessible and integrated into research and clinical care, the pediatric neuroscientist may have the opportunity to utilize and/or interpret results from this device. This review describes the basic technical features of optical coherence tomography and highlights its potential clinical and research applications in pediatric clinical neuroscience including optic nerve swelling, optic neuritis, tumors of the visual pathway, vigabatrin toxicity, nystagmus, and neurodegenerative conditions. Georg Thieme Verlag KG Stuttgart · New York.

Understanding bistability in yeast glycolysis using general properties of metabolic pathways.

PubMed

Planqué, Robert; Bruggeman, Frank J; Teusink, Bas; Hulshof, Josephus

2014-09-01

Glycolysis is the central pathway in energy metabolism in the majority of organisms. In a recent paper, van Heerden et al. showed experimentally and computationally that glycolysis can exist in two states, a global steady state and a so-called imbalanced state. In the imbalanced state, intermediary metabolites accumulate at low levels of ATP and inorganic phosphate. It was shown that Baker's yeast uses a peculiar regulatory mechanism--via trehalose metabolism--to ensure that most yeast cells reach the steady state and not the imbalanced state. Here we explore the apparent bistable behaviour in a core model of glycolysis that is based on a well-established detailed model, and study in great detail the bifurcation behaviour of solutions, without using any numerical information on parameter values. We uncover a rich suite of solutions, including so-called imbalanced states, bistability, and oscillatory behaviour. The techniques employed are generic, directly suitable for a wide class of biochemical pathways, and could lead to better analytical treatments of more detailed models. Copyright © 2014 Elsevier Inc. All rights reserved.

The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.

PubMed

Sessa, Alessandro; Ciabatti, Ernesto; Drechsel, Daniela; Massimino, Luca; Colasante, Gaia; Giannelli, Serena; Satoh, Takashi; Akira, Shizuo; Guillemot, Francois; Broccoli, Vania

2017-06-01

The T-box containing Tbr2 gene encodes for a transcription factor essential for the specification of the intermediate neural progenitors (INPs) originating the excitatory neurons of the cerebral cortex. However, its overall mechanism of action, direct target genes and cofactors remain unknown. Herein, we carried out global gene expression profiling combined with genome-wide binding site identification to determine the molecular pathways regulated by TBR2 in INPs. This analysis led to the identification of novel protein-protein interactions that control multiple features of INPs including cell-type identity, morphology, proliferation and migration dynamics. In particular, NEUROG2 and JMJD3 were found to associate with TBR2 revealing unexplored TBR2-dependent mechanisms. These interactions can explain, at least in part, the role of this transcription factor in the implementation of the molecular program controlling developmental milestones during corticogenesis. These data identify TBR2 as a major determinant of the INP-specific traits by regulating both genetic and epigenetic pathways. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A contemporary view of atrioventricular nodal physiology.

PubMed

Markowitz, Steven M; Lerman, Bruce B

2018-06-16

In delaying transmission of the cardiac impulse from the atria to the ventricles, the atrioventricular (AV) node serves a critical function in augmenting ventricular filling during diastole and limiting the ventricular response during atrial tachyarrhythmias. The complex structure of the nodal region, however, also provides the substrate for reentrant rhythms. Recent discoveries have elucidated the cellular basis and anatomical determinants of slow conduction in the node. Based on analysis of gap junction proteins, distinct structural components of the AV node have been defined, including the compact node, right and left inferior nodal extensions, the lower nodal bundle, and transitional tissue. Emerging evidence supports the role of the inferior nodal extensions in mediating slow pathway conduction. The most common form of reentry involving the node, slow-fast AV nodal reentrant tachycardia (AVNRT), utilizes the inferior nodal extensions for anterograde slow pathway conduction; the structures responsible for retrograde fast pathway activation in the superior septum are less well defined and likely heterogeneous. Atypical forms of AVNRT arise from circuits that activate at least one of the inferior extensions in the retrograde direction.

Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives

PubMed Central

Ghosh, Arnab

2017-01-01

Abstract Significance: Soluble guanylate cyclase (sGC) is an intracellular enzyme that plays a primary role in sensing nitric oxide (NO) and transducing its multiple signaling effects in mammals. Recent Advances: The chaperone heat shock protein 90 (hsp90) associates with signaling proteins in cells, including sGC, where it helps to drive heme insertion into the sGC-β1 subunit. This allows sGC-β1 to associate with a partner sGC-α1 subunit and mature into an NO-responsive active form. Critical Issues: In this article, we review evidence to date regarding the mechanisms that modulate sGC activity by a pathway where binding of hsp90 or sGC agonist to heme-free sGC dictates the assembly and fate of an active sGC heterodimer, both by NO and heme-dependent or heme-independent pathways. Future Directions: We discuss some therapeutic implications of the NO-sGC-hsp90 nexus and its potential as a marker of inflammatory disease. Antioxid. Redox Signal. 26, 182–190. PMID:26983679

Neurodegenerative disease and iron storage in the brain.

PubMed

Thomas, Madhavi; Jankovic, Joseph

2004-08-01

Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration. Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area. In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease.

Impact of excipient interactions on solid dosage form stability.

PubMed

Narang, Ajit S; Desai, Divyakant; Badawy, Sherif

2012-10-01

Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.

THE LONG REACH OF EDUCATION: EARLY RETIREMENT.

PubMed

Venti, Steven; Wise, David A

2015-12-01

The goal of this paper is to draw attention to the long lasting effect of education on economic outcomes. We use the relationship between education and two routes to early retirement - the receipt of Social Security Disability Insurance (DI) and the early claiming of Social Security retirement benefits - to illustrate the long-lasting influence of education. We find that for both men and women with less than a high school degree the median DI participation rate is 6.6 times the participation rate for those with a college degree or more. Similarly, men and women with less than a high school education are over 25 percentage points more likely to claim Social Security benefits early than those with a college degree or more. We focus on four critical "pathways" through which education may indirectly influence early retirement - health, employment, earnings, and the accumulation of assets. We find that for women health is the dominant pathway through which education influences DI participation. For men, the health, earnings, and wealth pathways are of roughly equal magnitude. For both men and women the principal channel through which education influences early Social Security claiming decisions is the earnings pathway. We also consider the direct effect of education that does not operate through these pathways. The direct effect of education is much greater for early claiming of Social Security benefits than for DI participation, accounting for 72 percent of the effect of education for men and 67 percent for women. For women the direct effect of education on DI participation is not statistically significant, suggesting that the total effect may be through the four pathways.

Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors

PubMed Central

Zhu, Yun; Kawaguchi, Kayoko; Kiyama, Ryoiti

2017-01-01

Mammalian lignans or enterolignans are metabolites of plant lignans, an important category of phytochemicals. Although they are known to be associated with estrogenic activity, cell signaling pathways leading to specific cell functions, and especially the differences among lignans, have not been explored. We examined the estrogenic activity of enterolignans and their precursor plant lignans and cell signaling pathways for some cell functions, cell cycle and chemokine secretion. We used DNA microarray-based gene expression profiling in human breast cancer MCF-7 cells to examine the similarities, as well as the differences, among enterolignans, enterolactone and enterodiol, and their precursors, matairesinol, pinoresinol and sesamin. The profiles showed moderate to high levels of correlation (R values: 0.44 to 0.81) with that of estrogen (17β-estradiol or E2). Significant correlations were observed among lignans (R values: 0.77 to 0.97), and the correlations were higher for cell functions related to enzymes, signaling, proliferation and transport. All the enterolignans/precursors examined showed activation of the Erk1/2 and PI3K/Akt pathways, indicating the involvement of rapid signaling through the non-genomic estrogen signaling pathway. However, when their effects on specific cell functions, cell cycle progression and chemokine (MCP-1) secretion were examined, positive effects were observed only for enterolactone, suggesting that signals are given in certain directions at a position closer to cell functions. We hypothesized that, while estrogen signaling is initiated by the enterolignans/precursors examined, their signals are differentially and directionally modulated later in the pathways, resulting in the differences at the cell function level. PMID:28152041

The non-canonical BMP and Wnt/β-catenin signaling pathways orchestrate early tooth development

PubMed Central

Yuan, Guohua; Yang, Guobin; Zheng, Yuqian; Zhu, Xiaojing; Chen, Zhi; Zhang, Zunyi; Chen, YiPing

2015-01-01

BMP and Wnt signaling pathways play a crucial role in organogenesis, including tooth development. Despite extensive studies, the exact functions, as well as if and how these two pathways act coordinately in regulating early tooth development, remain elusive. In this study, we dissected regulatory functions of BMP and Wnt pathways in early tooth development using a transgenic noggin (Nog) overexpression model (K14Cre;pNog). It exhibits early arrested tooth development, accompanied by reduced cell proliferation and loss of odontogenic fate marker Pitx2 expression in the dental epithelium. We demonstrated that overexpression of Nog disrupted BMP non-canonical activity, which led to a dramatic reduction of cell proliferation rate but did not affect Pitx2 expression. We further identified a novel function of Nog by inhibiting Wnt/β-catenin signaling, causing loss of Pitx2 expression. Co-immunoprecipitation and TOPflash assays revealed direct binding of Nog to Wnts to functionally prevent Wnt/β-catenin signaling. In situ PLA and immunohistochemistry on Nog mutants confirmed in vivo interaction between endogenous Nog and Wnts and modulation of Wnt signaling by Nog in tooth germs. Genetic rescue experiments presented evidence that both BMP and Wnt signaling pathways contribute to cell proliferation regulation in the dental epithelium, with Wnt signaling also controlling the odontogenic fate. Reactivation of both BMP and Wnt signaling pathways, but not of only one of them, rescued tooth developmental defects in K14Cre;pNog mice, in which Wnt signaling can be substituted by transgenic activation of Pitx2. Our results reveal the orchestration of non-canonical BMP and Wnt/β-catenin signaling pathways in the regulation of early tooth development. PMID:25428587

Divergent Isoprenoid Biosynthesis Pathways in Staphylococcus Species Constitute a Drug Target for Treating Infections in Companion Animals

PubMed Central

Cain, Christine L.; Morris, Daniel O.; Rankin, Shelley C.

2016-01-01

ABSTRACT Staphylococcus species are a leading cause of skin and soft tissue infections in humans and animals, and the antibiotics used to treat these infections are often the same. Methicillin- and multidrug-resistant staphylococcal infections are becoming more common in human and veterinary medicine. From a “One Health” perspective, this overlap in antibiotic use and resistance raises concerns over the potential spread of antibiotic resistance genes. Whole-genome sequencing and comparative genomics analysis revealed that Staphylococcus species use divergent pathways to synthesize isoprenoids. Species frequently associated with skin and soft tissue infections in companion animals, including S. schleiferi and S. pseudintermedius, use the nonmevalonate pathway. In contrast, S. aureus, S. epidermidis, and S. lugdunensis use the mevalonate pathway. The antibiotic fosmidomycin, an inhibitor of the nonmevalonate pathway, was effective in killing canine clinical staphylococcal isolates but had no effect on the growth or survival of S. aureus and S. epidermidis. These data identify an essential metabolic pathway in Staphylococcus that differs among members of this genus and suggest that drugs such as fosmidomycin, which targets enzymes in the nonmevalonate pathway, may be an effective treatment for certain staphylococcal infections. IMPORTANCE Drug-resistant Staphylococcus species are a major concern in human and veterinary medicine. There is a need for new antibiotics that exhibit a selective effect in treating infections in companion and livestock animals and that would not be used to treat human bacterial infections. We have identified fosmidomycin as an antibiotic that selectively targets certain Staphylococcus species that are often encountered in skin infections in cats and dogs. These findings expand our understanding of Staphylococcus evolution and may have direct implications for treating staphylococcal infections in veterinary medicine. PMID:27704053

Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.

PubMed

Ponts, Nadia; Yang, Jianfeng; Chung, Duk-Won Doug; Prudhomme, Jacques; Girke, Thomas; Horrocks, Paul; Le Roch, Karine G

2008-06-11

Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders. Here we describe the use of an HMM search of functional Pfam domains found in the key components of the ubiquitin-mediated pathway necessary to activate and reversibly modify target proteins in eight apicomplexan parasitic protozoa for which complete or late-stage genome projects exist. In parallel, the same search was conducted on five model organisms, single-celled and metazoans, to generate data to validate both the search parameters employed and aid paralog classification in Apicomplexa. For each of the 13 species investigated, a set of proteins predicted to be involved in the ubiquitylation pathway has been identified and demonstrates increasing component members of the ubiquitylation pathway correlating with organism and genome complexity. Sequence homology and domain architecture analyses facilitated prediction of apicomplexan-specific protein function, particularly those involved in regulating cell division during these parasite's complex life cycles. This study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathway in a wide variety of cellular processes, our data is a key step in elucidating the biological networks that, in part, direct the pathogenicity of these parasites resulting in a massive impact on global health. Moreover, apicomplexan-specific adaptations of the ubiquitylation pathway may represent new therapeutic targets for much needed drugs against apicomplexan parasites.

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

Samarzija, Ivana; Beard, Peter, E-mail: peter.beard@epfl.ch

Highlights: Black-Right-Pointing-Pointer Unknown cellular mutations complement papillomavirus-induced carcinogenesis. Black-Right-Pointing-Pointer Hedgehog pathway components are expressed by cervical cancer cells. Black-Right-Pointing-Pointer Hedgehog pathway activators and inhibitors regulate cervical cancer cell biology. Black-Right-Pointing-Pointer Cell immortalization by papillomavirus and activation of Hedgehog are independent. -- Abstract: Human papillomavirus (HPV) infection is considered to be a primary hit that causes cervical cancer. However, infection with this agent, although needed, is not sufficient for a cancer to develop. Additional cellular changes are required to complement the action of HPV, but the precise nature of these changes is not clear. Here, we studied the function of themore » Hedgehog (Hh) signaling pathway in cervical cancer. The Hh pathway can have a role in a number of cancers, including those of liver, lung and digestive tract. We found that components of the Hh pathway are expressed in several cervical cancer cell lines, indicating that there could exists an autocrine Hh signaling loop in these cells. Inhibition of Hh signaling reduces proliferation and survival of the cervical cancer cells and induces their apoptosis as seen by the up-regulation of the pro-apoptotic protein cleaved caspase 3. Our results indicate that Hh signaling is not induced directly by HPV-encoded proteins but rather that Hh-activating mutations are selected in cells initially immortalized by HPV. Sonic Hedgehog (Shh) ligand induces proliferation and promotes migration of the cervical cancer cells studied. Together, these results indicate pro-survival and protective roles of an activated Hh signaling pathway in cervical cancer-derived cells, and suggest that inhibition of this pathway may be a therapeutic option in fighting cervical cancer.« less

MESSI: metabolic engineering target selection and best strain identification tool.

PubMed

Kang, Kang; Li, Jun; Lim, Boon Leong; Panagiotou, Gianni

2015-01-01

Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. © The Author(s) 2015. Published by Oxford University Press.

The Anti-Oxidant and Antitumor Properties of Plant Polysaccharides.

PubMed

Jiao, Rui; Liu, Yingxia; Gao, Hao; Xiao, Jia; So, Kwok Fai

2016-01-01

Oxidative stress has been increasingly recognized as a major contributing factor in a variety of human diseases, from inflammation to cancer. Although certain parts of signaling pathways are still under investigation, detailed molecular mechanisms for the induction of diseases have been elucidated, especially the link between excessive oxygen reactive species (ROS) damage and tumorigenesis. Emerging evidence suggests anti-oxidant therapy can play a key role in treating those diseases. Among potential drug resources, plant polysaccharides are natural anti-oxidant constituents important for human health because of their long history in ethnopharmacology, wide availability and few side effects upon consumption. Plant polysaccharides have been shown to possess anti-oxidant, anti-inflammation, cell viability promotion, immune-regulation and antitumor functions in a number of disease models, both in laboratory studies and in the clinic. In this paper, we reviewed the research progress of signaling pathways involved in the initiation and progression of oxidative stress- and cancer-related diseases in humans. The natural sources, structural properties and biological actions of several common plant polysaccharides, including Lycium barbarum, Ginseng, Zizyphus Jujuba, Astragalus lentiginosus, and Ginkgo biloba are discussed in detail, with emphasis on their signaling pathways. All of the mentioned common plant polysaccharides have great potential to treat oxidative stress and cancinogenic disorders in cell models, animal disease models and clinical cases. ROS-centered pathways (e.g. mitochondrial autophagy, MAPK and JNK) and transcription factor-related pathways (e.g. NF-[Formula: see text]B and HIF) are frequently utilized by these polysaccharides with or without the further involvement of inflammatory and death receptor pathways. Some of the polysaccharides may also influence tumorigenic pathways, such as Wnt and p53 to play their anti-tumor roles. In addition, current problems and future directions for the application of those plant polysaccharides are also listed and discussed.

Adolescent physical activity and health: a systematic review.

PubMed

Hallal, Pedro C; Victora, Cesar G; Azevedo, Mario R; Wells, Jonathan C K

2006-01-01

Physical activity in adolescence may contribute to the development of healthy adult lifestyles, helping reduce chronic disease incidence. However, definition of the optimal amount of physical activity in adolescence requires addressing a number of scientific challenges. This article reviews the evidence on short- and long-term health effects of adolescent physical activity. Systematic reviews of the literature were undertaken using a reference period between 2000 and 2004, based primarily on the MEDLINE/PubMed database. Relevant studies were identified by examination of titles, abstracts and full papers, according to inclusion criteria defined a priori. A conceptual framework is proposed to outline how adolescent physical activity may contribute to adult health, including the following pathways: (i) pathway A--tracking of physical activity from adolescence to adulthood; (ii) pathway B--direct influence of adolescent physical activity on adult morbidity; (iii) pathway C--role of physical activity in treating adolescent morbidity; and (iv) pathway D - short-term benefits of physical activity in adolescence on health. The literature reviews showed consistent evidence supporting pathway 'A', although the magnitude of the association appears to be moderate. Thus, there is an indirect effect on all health benefits resulting from adult physical activity. Regarding pathway 'B', adolescent physical activity seems to provide long-term benefits on bone health, breast cancer and sedentary behaviours. In terms of pathway 'C', water physical activities in adolescence are effective in the treatment of asthma, and exercise is recommended in the treatment of cystic fibrosis. Self-esteem is also positively affected by adolescent physical activity. Regarding pathway 'D', adolescent physical activity provides short-term benefits; the strongest evidence refers to bone and mental health. Appreciation of different mechanisms through which adolescent physical activity may influence adult health is essential for drawing recommendations; however, the amount of exercise needed for achieving different benefits may vary. Physical activity promotion must start in early life; although the 'how much' remains unknown and needs further research, the lifelong benefits of adolescent physical activity on adult health are unequivocal.

Asymmetric life-history decision-making in butterfly larvae

PubMed Central

Aalberg Haugen, Inger M.; Dahlerus, Josefin; Gotthard, Karl; Wiklund, Christer

2010-01-01

In temperate environments, insects appearing in several generations in the growth season typically have to decide during the larval period whether to develop into adulthood, or to postpone adult emergence until next season by entering a species-specific diapause stage. This decision is typically guided by environmental cues experienced during development. An early decision makes it possible to adjust growth rate, which would allow the growing larva to respond to time stress involved in direct development, whereas a last-minute decision would instead allow the larva to use up-to-date information about which developmental pathway is the most favourable under the current circumstances. We study the timing of the larval pathway decision-making between entering pupal winter diapause and direct development in three distantly related butterflies (Pieris napi, Araschnia levana and Pararge aegeria). We pinpoint the timing of the larval diapause decision by transferring larvae from first to last instars from long daylength (inducing direct development) to short daylength conditions (inducing diapause), and vice versa. Results show that the pathway decision is typically made in the late instars in all three species, and that the ability to switch developmental pathway late in juvenile life is conditional; larvae more freely switched from diapause to direct development than in the opposite direction. We contend that this asymmetry is influenced by the additional physiological preparations needed to survive the long and cold winter period, and that the reluctance to make a late decision to enter diapause has the potential to be a general trait among temperate insects. PMID:20953962

An exploration of the hypothesis that testosterone is implicated in the psychological functioning of women with polycystic ovary syndrome (PCOS).

PubMed

Barry, J A; Qu, F; Hardiman, P J

2018-01-01

One of the diagnostic features of polycystic ovary syndrome (PCOS) is elevation of the androgen, testosterone. It is known that women with PCOS are more likely to suffer from psychological problems, especially anxiety and depression, than other women. However, little is known of how much of this is due to testosterone, and if so, what the mechanism(s) might be. This study explores the hypothesis that testosterone impacts women with PCOS both directly and indirectly, via testosterone currently in the bloodstream and through prenatal exposure. It is hypothesised that direct effects occur when testosterone acts directly upon receptors; indirect effects occur where the impact of testosterone is mediated via another variable; activational effects are ephemeral and are caused by testosterone in the bloodstream; organizational effects occur prenatally and cause permanent changes. Four pathways are hypothesised in this paper: 1/ a direct and activational pathway which improves mental rotation ability; 2/ an indirect and activational pathway, whereby distress is caused when the physiological symptoms of testosterone are experienced as embarrassing or otherwise disturbing; 3/ an indirect and organizational effect on mood, where elevated prenatal testosterone predisposes women with PCOS to low blood sugar levels and thus low mood; 4/ and finally, it is suggested that the pathway from biology to psychology can be travelled in reverse, with a direct activational effect of relaxation training on the reduction of adrenal androgens. Testing these hypotheses has important implications for our understanding of PCOS, and our ability to treat this condition more effectively. Copyright © 2017. Published by Elsevier Ltd.

Direct Hospital Cost of Outcome Pathways in Implant-Based Reconstruction with Acellular Dermal Matrices.

PubMed

Qureshi, Ali A; Broderick, Kristen; Funk, Susan; Reaven, Nancy; Tenenbaum, Marissa M; Myckatyn, Terence M

2016-08-01

Current cost data on tissue expansion followed by exchange for permanent implant (TE/I) reconstruction lack a necessary assessment of the experience of a heterogenous breast cancer patient population and their multiple outcome pathways. We extend our previous analysis to that of direct hospital cost as bundling of payments is likely to follow the changing centralization of cancer care at the hospital level. We performed a retrospective analysis (2003-2009) of TE/I reconstructions with or without an acellular dermal matrix (ADM), namely Alloderm RTM. Postreconstructive events were analyzed and organized into outcome pathways as previously described. Aggregated and normalized inpatient and outpatient hospital direct costs and physician reimbursement were generated for each outcome pathway with or without ADM. Three hundred sixty-seven patients were analyzed. The average 2-year hospital direct cost per TE/I breast reconstruction patient was $11,862 in the +ADM and $12,319 in the -ADM groups (P > 0.05). Initial reconstructions were costlier in the +ADM ($6,868) than in the -ADM ($5,615) group, but the average cost of subsequent postreconstructive events within 2 years was significantly lower in +ADM ($5,176) than -ADM ($6,704) patients (P < 0.05). When a complication occurred, but reconstruction was still completed within 2 years, greater costs were incurred in the -ADM than in the +ADM group for most scenarios, leading to a net equalization of cost between study groups. Although direct hospital cost is an important factor for resource and fund allocation, it should not remain the sole factor when deciding to use ADM in TE/I reconstruction.

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

Gibney, Patrick A.; Schieler, Ariel; Chen, Jonathan C.

Trehalose is a highly stable, nonreducing disaccharide of glucose. A large body of research exists implicating trehalose in a variety of cellular phenomena, notably response to stresses of various kinds. However, in very few cases has the role of trehalose been examined directly in vivo. Here, we describe the development and characterization of a system in Saccharomyces cerevisiae that allows us to manipulate intracellular trehalose concentrations independently of the biosynthetic enzymes and independently of any applied stress. We found that many physiological roles heretofore ascribed to intracellular trehalose, including heat resistance, are not due to the presence of trehalose permore » se. We also found that many of the metabolic and growth defects associated with mutations in the trehalose biosynthesis pathway are not abolished by providing abundant intracellular trehalose. Instead, we made the observation that intracellular accumulation of trehalose or maltose (another disaccharide of glucose) is growth-inhibitory in a carbon source-specific manner. We conclude that the physiological role of the trehalose pathway is fundamentally metabolic: i.e., more complex than simply the consequence of increased concentrations of the sugar and its attendant physical properties (with the exception of the companion paper where demonstrate a direct role for trehalose in protecting cells against desiccation).« less

Zero-point Energy is Needed in Molecular Dynamics Calculations to Access the Saddle Point for H+HCN→H2CN* and cis/trans-HCNH* on a New Potential Energy Surface.

PubMed

Wang, Xiaohong; Bowman, Joel M

2013-02-12

We calculate the probabilities for the association reactions H+HCN→H2CN* and cis/trans-HCNH*, using quasiclassical trajectory (QCT) and classical trajectory (CT) calculations, on a new global ab initio potential energy surface (PES) for H2CN including the reaction channels. The surface is a linear least-squares fit of roughly 60 000 CCSD(T)-F12b/aug-cc-pVDZ electronic energies, using a permutationally invariant basis with Morse-type variables. The reaction probabilities are obtained at a variety of collision energies and impact parameters. Large differences in the threshold energies in the two types of dynamics calculations are traced to the absence of zero-point energy in the CT calculations. We argue that the QCT threshold energy is the realistic one. In addition, trajectories find a direct pathway to trans-HCNH, even though there is no obvious transition state (TS) for this pathway. Instead the saddle point (SP) for the addition to cis-HCNH is evidently also the TS for direct formation of trans-HCNH.

Multiplex bioimaging of piRNA molecular pathway-regulated theragnostic effects in a single breast cancer cell using a piRNA molecular beacon.

PubMed

Lee, Youn Jung; Moon, Sung Ung; Park, Min Geun; Jung, Woon Yong; Park, Yong Keun; Song, Sung Kyu; Ryu, Je Gyu; Lee, Yong Seung; Heo, Hye Jung; Gu, Ha Na; Cho, Su Jeong; Ali, Bahy A; Al-Khedhairy, Abdulaziz A; Lee, Ilkyun; Kim, Soonhag

2016-09-01

Recently, PIWI-interacting small non-coding RNAs (piRNAs) have emerged as novel cancer biomarkers candidate because of their high expression level in various cancer types and role in the control of tumor suppressor genes. In this study, a novel breast cancer theragnostics probe based on a single system targeting the piRNA-36026 (piR-36026) molecular pathway was developed using a piR-36026 molecular beacon (MB). The piR-36026 MB successfully visualized endogenous piR-36026 biogenesis, which is highly expressed in MCF7 cells (a human breast cancer cell line), and simultaneously inhibited piR-36026-mediated cancer progression in vitro and in vivo. We discovered two tumor suppressor proteins, SERPINA1 and LRAT, that were directly regulated as endogenous piR-36026 target genes in MCF7 cells. Furthermore, multiplex bioimaging of a single MCF7 cell following treatment with piR-36026 MB clearly visualized the direct molecular interaction of piRNA-36026 with SERPINA1 or LRAT and subsequent molecular therapeutic responses including caspase-3 and PI in the nucleus. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple functions of the E3 ubiquitin ligase CHIP in immunity.

PubMed

Zhan, Shaohua; Wang, Tianxiao; Ge, Wei

2017-09-03

The carboxyl terminal of Hsp70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a pivotal role in the protein quality control system by shifting the balance of the folding-refolding machinery toward the degradative pathway. However, the precise mechanisms by which nonnative proteins are selected for degradation by CHIP either directly or indirectly via chaperone Hsp70 or Hsp90 are still not clear. In this review, we aim to provide a comprehensive model of the mechanism by which CHIP degrades its substrate in a chaperone-dependent or direct manner. In addition, through tight regulation of the protein level of its substrates, CHIP plays important roles in many physiological and pathological conditions, including cancers, neurological disorders, cardiac diseases, bone metabolism, immunity, and so on. Nonetheless, the precise mechanisms underlying the regulation of the immune system by CHIP are still poorly understood despite accumulating developments in our understanding of the regulatory roles of CHIP in both innate and adaptive immune responses. In this review, we also aim to provide a view of CHIP-mediated regulation of immune responses and the signaling pathways involved in the model described. Finally, we discuss the roles of CHIP in immune-related diseases.

Informatics approaches in the Biological Characterization of ...

EPA Pesticide Factsheets

Adverse Outcome Pathways (AOPs) are a conceptual framework to characterize toxicity pathways by a series of mechanistic steps from a molecular initiating event to population outcomes. This framework helps to direct risk assessment research, for example by aiding in computational prioritization of chemicals, genes, and tissues relevant to an adverse health outcome. We have designed and implemented a computational workflow to access a wealth of public data relating genes, chemicals, diseases, pathways, and species, to provide a biological context for putative AOPs. We selected three AOP case studies: ER/Aromatase Antagonism Leading to Reproductive Dysfunction, AHR1 Activation Leading to Cardiotoxicity, and AChE Inhibition Leading to Acute Mortality, and deduced a taxonomic range of applicability for each AOP. We developed computational tools to automatically access and analyze the pathway activity of AOP-relevant protein orthologs, finding broad similarity among vertebrate species for the ER/Aromatase and AHR1 AOPs, and similarity extending to invertebrate animal species for AChE inhibition. Additionally, we used public gene expression data to find groups of highly co-expressed genes, and compared those groups across organisms. To interpret these findings at a higher level of biological organization, we created the AOPdb, a relational database that mines results from sources including NCBI, KEGG, Reactome, CTD, and OMIM. This multi-source database connects genes,

Simple rules describe bottom-up and top-down control in food webs with alternative energy pathways.

PubMed

Wollrab, Sabine; Diehl, Sebastian; De Roos, André M

2012-09-01

Many human influences on the world's ecosystems have their largest direct impacts at either the top or the bottom of the food web. To predict their ecosystem-wide consequences we must understand how these impacts propagate. A long-standing, but so far elusive, problem in this endeavour is how to reduce food web complexity to a mathematically tractable, but empirically relevant system. Simplification to main energy channels linking primary producers to top consumers has been recently advocated. Following this approach, we propose a general framework for the analysis of bottom-up and top-down forcing of ecosystems by reducing food webs to two energy pathways originating from a limiting resource shared by competing guilds of primary producers (e.g. edible vs. defended plants). Exploring dynamical models of such webs we find that their equilibrium responses to nutrient enrichment and top consumer harvesting are determined by only two easily measurable topological properties: the lengths of the component food chains (odd-odd, odd-even, or even-even) and presence vs. absence of a generalist top consumer reconnecting the two pathways (yielding looped vs. branched webs). Many results generalise to other looped or branched web structures and the model can be easily adapted to include a detrital pathway. © 2012 Blackwell Publishing Ltd/CNRS.

Pathogenesis and Management of Serrated Polyps: Current Status and Future Directions

PubMed Central

Anderson, Joseph C.

2014-01-01

Hyperplastic or serrated polyps were once believed to have little to no clinical significance. A subset of these polyps are now considered to be precursors to colorectal cancers (CRC) in the serrated pathway that may account for at least 15% of all tumors. The serrated pathway is distinct from the two other CRC pathways and involves an epigenetic hypermethylation mechanism of CpG islands within promoter regions of tumor suppressor genes. This process results in the formation of CpG island methylator phenotype tumors. Serrated polyps are divided into hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The SSA/P and the TSA have the potential for dysplasia and subsequent malignant transformation. The SSA/Ps are more common and are more likely to be flat than TSAs. Their flat morphology may make them difficult to detect and thus explain the variation in detection rates among endoscopists. Challenges for endoscopists also include the difficulty in pathological interpretation as well surveillance of these lesions. Furthermore, serrated polyps may be inadequately resected by endoscopists. Thus, it is not surprising that the serrated pathway has been linked with interval cancers. This review will provide the physician or clinician with the knowledge to manage patients with serrated polyps. PMID:25368744

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PubMed

Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Regulation and function of DNA methylation in plants and animals

PubMed Central

He, Xin-Jian; Chen, Taiping; Zhu, Jian-Kang

2011-01-01

DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review. PMID:21321601

Bridge-bonded formate: active intermediate or spectator species in formic acid oxidation on a Pt film electrode?

PubMed

Chen, Y-X; Heinen, M; Jusys, Z; Behm, R J

2006-12-05

We present and discuss the results of an in situ IR study on the mechanism and kinetics of formic acid oxidation on a Pt film/Si electrode, performed in an attenuated total reflection (ATR) flow cell configuration under controlled mass transport conditions, which specifically aimed at elucidating the role of the adsorbed bridge-bonded formates in this reaction. Potentiodynamic measurements show a complex interplay between formation and desorption/oxidation of COad and formate species and the total Faradaic current. The notably faster increase of the Faradaic current compared to the coverage of bridge-bonded formate in transient measurements at constant potential, but with different formic acid concentrations, reveals that adsorbed formate decomposition is not rate-limiting in the dominant reaction pathway. If being reactive intermediate at all, the contribution of formate adsorption/decomposition to the reaction current decreases with increasing formic acid concentration, accounting for at most 15% for 0.2 M DCOOH at 0.7 VRHE. The rapid build-up/removal of the formate adlayer and its similarity with acetate or (bi-)sulfate adsorption/desorption indicate that the formate adlayer coverage is dominated by a fast dynamic adsorption-desorption equilibrium with the electrolyte, and that formate desorption is much faster than its decomposition. The results corroborate the proposal of a triple pathway reaction mechanism including an indirect pathway, a formate pathway, and a dominant direct pathway, as presented previously (Chen, Y. X.; et al. Angew. Chem. Int. Ed. 2006, 45, 981), in which adsorbed formates act as a site-blocking spectator in the dominant pathway rather than as an active intermediate.

Photochemistry of the Stilbenes in Methanol. Trapping the Common Phantom Singlet State.

PubMed

Saltiel, Jack; Gupta, Shipra

2018-06-21

A comparative study of the photochemistry of cis- and trans-stilbene in methanol shows that both isomers undergo methanol photoaddition giving similar yields of α-methoxybibenzyl in competition with cis-trans photoisomerization. Methanol addition occurs primarily following torsional relaxation of the lowest excited singlet states of each isomer, 1 c* and 1 t*, to a common twisted singlet excited state intermediate, 1 p*, initially called the phantom singlet state. The addition is consistent with the zwitterionic character of 1 p*. Ether forms by direct 1,2-addition of CH 3 OH to the central carbon atoms and by 1,1-addition following rearrangement to 1-benzyl-1-phenylcarbene. Use of CD 3 OD and GC/MS (gas chromatographic/mass spectroscopic) analysis of the ether products revealed that the ratio of carbene/direct addition pathways is higher starting from cis-stilbene. We conclude that 1 p* formed from 1 c* is hotter than 1 p* formed from 1 t*. Surprisingly, except for favoring the carbene pathway, the use of higher energy photons (254 vs 313 nm) does not affect the overall ether quantum yield starting from cis-stilbene, but significantly enhances both pathways starting from trans-stilbene. It appears that carbene formation and direct methanol addition to higher trans-stilbene excited state(s) compete with relaxation to S 1 . Substitution of D for the vinyl Hs of stilbene enhances the direct addition pathway more than two-fold and strongly suppresses the carbene insertion pathway, revealing a large, k pc d0 / k pc d2 = 6.3, primary deuterium isotope effect in the carbene rearrangement. The two-fold increase in the ether quantum yield is due primarily to a 2.75-fold increase in the lifetime of 1 p* on deuterium substitution of the vinyl hydrogens.

Biodegradation of RDX and MNX with Rhodococcus sp. Strain DN22: New Insights into the Degradation Pathway

DTIC Science & Technology

2010-11-15

denitrosation of MNX by DN22 did not involve direct participation of either oxygen or water, but both played major roles in subsequent secondary chemical and... secondary reactions and products distributions would pro- vide new insights into the degradation pathway of RDX and thus help in the development of...not involve direct participation of either oxygen or water, but both played major roles in subsequent secondary chemical and biochemical reactions of