The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
The trans-boundary Amu River Basin (ARB), which is shared among Afghanistan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan, is a primary source for human population and ecosystem. Future water demand in Afghanis...The trans-boundary Amu River Basin (ARB), which is shared among Afghanistan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan, is a primary source for human population and ecosystem. Future water demand in Afghanistan is likely to increase due to ambitious development plans after long-term unrest in the country. In accordance with high water abstraction in the Afghan part of ARB and its impacts on the downstream countries, water cooperation mechanisms are analyzed using the desk study approach. The results concerning regional water cooperation on the ARB show that, the level of cooperation between Afghanistan and central Asian riparian countries is reasonably weak. There are certain issues causing lack of cooperation between Afghanistan and central Asian riparian countries. Developmental and political interests of riparian states are key impediments to regional water cooperation on ARB. Technical impediments include the lack of human capacity, no application of basin approach and, lack of donor coordination at regional level. The policy analysis as a result of this study envisaged that initiatives to improve water management practices and increase productivity are highly needed in the study area to mitigate the foreseeing increase in irrigated water demand. The international framework law of UNWCC 1997 cannot be applied generally in central Asia and particularly in Afghanistan. Thirdly, Afghanistan’s participation in regional water cooperation framework i.e. ICWC is highly needed though participation as permanent member requires a “revise water demand assessment by ICWC” on the basis of reliable data, current infrastructural development and irrigation expansion plans of Afghanistan albeit donor agencies could play a mediation role in establishing agreement on water allocation between Afghanistan and other riparian countries.展开更多
Length of stay in treatment is thought to be the best predictors for long-term recovery from substance use disorders. The objective of this study was to examine the relationship between participation in mind-body-spir...Length of stay in treatment is thought to be the best predictors for long-term recovery from substance use disorders. The objective of this study was to examine the relationship between participation in mind-body-spirit (MBS) therapeutic programs and length of stay in a residential treatment facility. A retrospective analysis of data from 1719 subjects who were admitted to a 30-day residential program for substance use disorders (SUD) was conducted. Subjects participated in MBS programs that included yoga, acupuncture and meditation. We examined the effects of subject participation in MBS programs for subjects who left against staff advice (ASA) and those who successfully completed the residential program. A higher percentage of subjects with severe heroin use disorder left ASA compared with subjects with severe alcohol use disorder (16% vs. 9%, respectively). Most subjects from both substance groups who failed to complete the 30-day treatment program, left within the first two weeks of stay (59% of alcohol group and 75% of heroin group);however, again, the percentage of heroin users leaving during the first two weeks was significantly greater compared with that of alcohol subjects. We found a highly significant, positive correlation (r = 0.56, p < 0.01) and a statistically significant increase in LOS for all subjects, regardless of the substance type, and the number of MBS program sessions attended showing an association between MBS participation and increased LOS. These data support the inclusion of MBS programs as part of a comprehensive treatment strategy for SUD in combination with traditional counseling to help develop a sustainable long-term recovery.展开更多
Carboxypeptidase E （CPE） is a prohormone-processing enzyme and sorting receptor that functions intracellularly. However, recent studies have demonstrated that CPE acts as atrophic factor extracellularly to up-regula...Carboxypeptidase E （CPE） is a prohormone-processing enzyme and sorting receptor that functions intracellularly. However, recent studies have demonstrated that CPE acts as atrophic factor extracellularly to up-regulate the expression of a pro-survival gene. This mini-review summarizes the roles of CPE in neuroprotection and the implications for neurodegenerative diseases.展开更多
Different driving decisions will cause different processes of phase transition in traffic flow. To reveal the inner mechanism, this paper built a new cellular automaton （CA） model, based on the driving decision （DD...Different driving decisions will cause different processes of phase transition in traffic flow. To reveal the inner mechanism, this paper built a new cellular automaton （CA） model, based on the driving decision （DD）. In the DD model, a driver＇s decision is divided into three stages： decision-making, action, and result. The acceleration is taken as a decision variable and three core factors, i.e. distance between adjacent vehicles, their own velocity, and the preceding vehicle＇s velocity, are considered. Simulation results show that the DD model can simulate the synchronized flow effectively and describe the phase transition in traffic flow well. Further analyses illustrate that various density will cause the phase transition and the random probability will impact the process. Compared with the traditional NaSch model, the DD model considered the preceding vehicle＇s velocity, the deceleration limitation, and a safe distance, so it can depict closer to the driver preferences on pursuing safety, stability and fuel-saving and has strong theoretical innovation for future studies.展开更多
The recent accelerated growth rates or efforts to emulate countries that have achieved a rapid pace of economic growth are widely acclaimed as means to uplift millions from poverty. In so doing, however, this rapid ec...The recent accelerated growth rates or efforts to emulate countries that have achieved a rapid pace of economic growth are widely acclaimed as means to uplift millions from poverty. In so doing, however, this rapid economic growth is most likely to coincide with unsustainable levels of consumption, place excessive pressure on life support systems and terrestrial sinks and foreshorten options for the future. Rather than pursuing the "Environmental Kuznets Curve"(EKC) hypothesis that higher income will bring with it the means to reduce the impacts of greater consumption, ecological economists assert that buying our way out of future scarcity with fast growth is indeed contradictory with sustainabil- ity. To better understand these contradictions and explore potential institutional innovations that may enable developing nations to better confront them (in effect,"tunneling under"the EKC), this article refers to recent experience in the BRICS countries (Brazil, Russia, India, China and South Africa). Beginning with a brief comparative summary of major development and environmental indicators, pressures on resources and society in each of the BRICS are discussed, followed by identification of institutional and policy frameworks each country has evolved to confront the challenges of growth and sustainability. The article closes with general conclusions for further research and information sharing among developing nations.展开更多
Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in COPD patients. Methods: In 295 clinically stable and optimally treated COPD patients from 39 outpatient center...Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in COPD patients. Methods: In 295 clinically stable and optimally treated COPD patients from 39 outpatient centers, age, gender, and body composition (body mass index, BMI;fat-free mass index, FFMI;fat mass index, FMI) were related to inflammatory biomarkers: CRP, fibrinogen, TNFα, and its soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence on inflammatory biomarkers. Monovariate and multivariate regression analyses were performed for associations between inflammatory biomarkers. Results: Positive correlations were found for FFMI with sTNFαR1, FMI with CRP and age with TNFα, sTNFαR1 and sTNFαR2 (p < 0.01). FEV1 was not correlated with body composition and inflammatory markers. Mono- and multivariate analysis showed weak correlations between the acute phase markers and the TNFα system after correcting for multiple co-variants. Conclusions: This study highlights the modest role of age and body composition on levels of systemic inflammatory biomarkers in COPD. Results show the degree of airflow limitation does not affect systemic inflammation. Last, a weak relationship between acute phase markers and markers of the TNFα system is present in COPD.展开更多
Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments,so it is critical to find new drugs for this condition.Recently,the cellsurfac...Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments,so it is critical to find new drugs for this condition.Recently,the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain.Here,we used the short peptide GluA_（2-3y）,which specifically inhibits the GluA2-dependent endocytosis of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors,and tested its anti-nociceptive effect in the periaqueductal grey（PAG） of intact rats and rats with neuropathic pain.Intra-PAG injection of 0.15,1.5,7.5,and 15 pmol of GluA_（2-3y） induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats,suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation.Furthermore,GluA_（2-3y） had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation.Interestingly,the intra-PAG injection of 15 pmol GluA_（2-3y） had an analgesic effect similar to 10 ug（35nmol） morphine in rats with neuropathic pain.Taken together,our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation,and inhibiting GluA2 endocytosis with GluA_（2-3y） has potent analgesic effects in rats with neuropathic pain.These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain.展开更多
OBJECTIVE Liguzinediol is a derivative of the natural active ingredient ligustrazine,and we found that liguzinediol has significant positive inotropic effects,which are stronger than that of TMP.Besides,it does not le...OBJECTIVE Liguzinediol is a derivative of the natural active ingredient ligustrazine,and we found that liguzinediol has significant positive inotropic effects,which are stronger than that of TMP.Besides,it does not lead to arrhythmia,hypotension and other side effects.This study aims to investigate the anti-apoptotic effects of liguzinediolon H9C2 cells.METHODS Apoptotic H9C2 cells induced by DOX were observed by electron microscope and FCM analysis.The protein expressions of Bax,Bcl-2,caspases 3 and NF-κB were detected by Western blotting.RESULTS Apoptotic H9C2 cells induced by DOX were observed,but without apoptotic bodies in liguzinediol group.Declined peak of H9C2 cell apoptosis was seen in liguzinediol group by FCM analysis.And downregulation of Bax,caspases 3,NF-κB and upregulation of Bcl-2 were found by Western blotting.CONCLUSION Liguzinediol protected cardiomyocytes against apoptosis through downregulation of Bax and caspases 3 and upregulation of Bcl-2.Liguzinediol can inhibited cardiomyocyte apoptosis through the NF-κB signal pathway.展开更多
Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to...Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to predict by longitudinal studies the probability of divorce in a marriage, with accuracy of up to 94%. Our objective was to investigate whether the occurrence of facial expressions of disgust and contempt in married women is associated with marital dissatisfaction. This is an experimental study that correlated, through filmed interviews, the frequency of facial expressions of disgust and disgust (Facial Action Coding System) to the Marital State’s Golombok Rust Inventory, in a sample composed of 20 women. Data analysis based on the Spearman Correlation Test showed a positive correlation between facial expressions of disgust and disdain and conjugal dissatisfaction (rs = 0.2198, p = 0.0280), corroborating the data in the literature.展开更多
Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 che...Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 chemically induced mutations on the X chromosome in Drosophila fat body clones and discovered that shibire （shi） plays an essential role in starvation-induced autophagy, shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome--lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation （ALR） through its excision activity, Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.展开更多
Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats...Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.展开更多
Sustainable building design is now mainstream.The United States Green Building Council(USGBC)and the LEED Ratings Systems have moved the market,proving that“a rising tide lifts all boats.”Consumers now factor enviro...Sustainable building design is now mainstream.The United States Green Building Council(USGBC)and the LEED Ratings Systems have moved the market,proving that“a rising tide lifts all boats.”Consumers now factor environmental effect into their buying decisions,a trend that looks to continue and intensify with the millennial generation.Renters and homeowners are willing to pay more for high-performing and better quality housing based on environmental standards.Companies recognize that indoor air quality and daylighting improve employee performance and boost retention rates.And even bottom-line businesses are investing in benchmarking and efficiency projects that have the right return on investment rates.The Urban Land Institute’s Greenprint Center for Building Performance serves as a prime example of the ways developers implement benchmarking,energy efficiency,and high-performance standards in the major real estate sectors:office,retail,industrial,multifamily,and hotel.Energy efficiency gains and higher-quality buildings in each of these sectors will be essential to reducing emissions and energy use.While the transportation sector implements its own standards and benchmarking tools to achieve greater levels of sustainability across all modes of transportation,one industry that stands at the nexus of every building type and the transportation modes used to access them is parking.There is a key consideration that links land use and transportation:Parking is often the connection between where we are and where we want to go.Parking may not have been at the forefront of the sustainability discussion or the media surrounding it in previous years,but the professionals who work in the world of parking know exactly how important the role of their industry is to the success of our cities,towns,institutions,and businesses.Parking is big business;it is conservatively estimated to be a$30 billion industry.It directly contributes to the economic vitality and accessibility of where we live,work,and play。展开更多
The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as m...The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associatedcognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use nenrogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.展开更多
Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treatin...Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.展开更多
The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathol...The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathological model systems and facilitated the generation of important hypotheses such as durotaxis and tissue-scale phase transition.There likely are many unexpected aspects of embryo biomechanics we have yet to discover which will change our views of mechanisms that govern development and disease.One area in the blind spot of even the most recent approaches to measuring tissue stiffness is the potentially anisotropic nature of that parameter.Here,we report a magnetic micromanipulation device that generates a uniform magnetic field gradient within a large workspace and permits measurement of the variation of tissue stiffness along three orthogonal axes.By applying the device to the organ-stage mouse embryo,we identify spatially heterogenous and directionally anisotropic stiffness within the mandibular arch.Those properties correspond to the domain of expression and the angular distribution of fibronectin and have potential implications for mechanisms that orient collective cell movements and shape tissues during development.Assessment of anisotropic properties extends the repertoire of current methods and will enable the generation and testing of hypotheses.展开更多
Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diver...Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diverse physicochemical network of specific and non-specific interactions, and seemingly subtle changes in amino acid identity at certain positions may dramatically impact TF：DNA binding. Variation of these specificity-determining residues （SDRs） is a major mechanism of functional divergence between TFs with strong structural or sequence homology. Methods： In this study, we employed a combination of high-throughput specificity profiling by SELEX and Spec-seq, structural modeling, and evolutionary analysis to probe the binding preferences of winged helix-turn-helix TFs belonging to the OmpR sub-family in Escherichia coil Results： We found that E. coli OmpR paralogs recognize tandem, variably spaced repeats composed of＂GT-A＂ or ＂GCT＂-containing half-sites. Some divergent sequence preferences observed within the ＂GT-A＂ mode correlate with amino acid similarity; conversely, ＂GCT＂-based motifs were observed for a subset of paralogs with low sequence homology. Direct specificity profiling of a subset of OmpR homologues （CpxR, RstA, and OmpR） as well as predicted ＂SDR-swap＂ variants revealed that individual SDRs may impact sequence preferences locally through direct contact with DNA bases or distally via the DNA backbone. Conclusions： Overall, our work provides evidence for a common structural code for sequence-specific wHTH：DNA interactions, and demonstrates that surprisingly modest residue changes can enable recognition of highly divergent sequence motifs. Further examination of SDR predictions will likely reveal additional mechanisms controlling the evolutionary divergence of this important class of transcriptional regulators.展开更多
The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense agai...The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.展开更多
The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mou...The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mouse embryo at embryonic day 7.0 and revealed that Nodal inhibition is essential for its formation.Here,we demonstrate that through brief inhibition of Nodal signaling in vitro,mouse embryonic stem cell(ESC)-derived epiblast stem cells(ESD-EpiSCs)could be committed to transient ectodermal progenitor populations,which possess the ability to give rise to neural or epidermal ectoderm in the absence or presence of BMP4,respectively.Mechanistic studies reveal that BMP4 recruits distinct transcriptional targets in ESD-EpiSCs and ectoderm-like cells.Furthermore,FGF–Erk signaling may also be alleviated during the generation of ectoderm-like cells.Thus,our data suggest that instructive interactions among several extracellular signals participate in the commitment of ectoderm from ESD-EpiSCs,which shed new light on the understanding of the formation of ectoderm during the gastrulation in early mouse embryo development.展开更多
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
文摘The trans-boundary Amu River Basin (ARB), which is shared among Afghanistan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan, is a primary source for human population and ecosystem. Future water demand in Afghanistan is likely to increase due to ambitious development plans after long-term unrest in the country. In accordance with high water abstraction in the Afghan part of ARB and its impacts on the downstream countries, water cooperation mechanisms are analyzed using the desk study approach. The results concerning regional water cooperation on the ARB show that, the level of cooperation between Afghanistan and central Asian riparian countries is reasonably weak. There are certain issues causing lack of cooperation between Afghanistan and central Asian riparian countries. Developmental and political interests of riparian states are key impediments to regional water cooperation on ARB. Technical impediments include the lack of human capacity, no application of basin approach and, lack of donor coordination at regional level. The policy analysis as a result of this study envisaged that initiatives to improve water management practices and increase productivity are highly needed in the study area to mitigate the foreseeing increase in irrigated water demand. The international framework law of UNWCC 1997 cannot be applied generally in central Asia and particularly in Afghanistan. Thirdly, Afghanistan’s participation in regional water cooperation framework i.e. ICWC is highly needed though participation as permanent member requires a “revise water demand assessment by ICWC” on the basis of reliable data, current infrastructural development and irrigation expansion plans of Afghanistan albeit donor agencies could play a mediation role in establishing agreement on water allocation between Afghanistan and other riparian countries.
文摘Length of stay in treatment is thought to be the best predictors for long-term recovery from substance use disorders. The objective of this study was to examine the relationship between participation in mind-body-spirit (MBS) therapeutic programs and length of stay in a residential treatment facility. A retrospective analysis of data from 1719 subjects who were admitted to a 30-day residential program for substance use disorders (SUD) was conducted. Subjects participated in MBS programs that included yoga, acupuncture and meditation. We examined the effects of subject participation in MBS programs for subjects who left against staff advice (ASA) and those who successfully completed the residential program. A higher percentage of subjects with severe heroin use disorder left ASA compared with subjects with severe alcohol use disorder (16% vs. 9%, respectively). Most subjects from both substance groups who failed to complete the 30-day treatment program, left within the first two weeks of stay (59% of alcohol group and 75% of heroin group);however, again, the percentage of heroin users leaving during the first two weeks was significantly greater compared with that of alcohol subjects. We found a highly significant, positive correlation (r = 0.56, p < 0.01) and a statistically significant increase in LOS for all subjects, regardless of the substance type, and the number of MBS program sessions attended showing an association between MBS participation and increased LOS. These data support the inclusion of MBS programs as part of a comprehensive treatment strategy for SUD in combination with traditional counseling to help develop a sustainable long-term recovery.
基金supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health,Bethesda,MD,USA
文摘Carboxypeptidase E （CPE） is a prohormone-processing enzyme and sorting receptor that functions intracellularly. However, recent studies have demonstrated that CPE acts as atrophic factor extracellularly to up-regulate the expression of a pro-survival gene. This mini-review summarizes the roles of CPE in neuroprotection and the implications for neurodegenerative diseases.
基金Supported by the Program for National High-Tech Research and Development Program of China under Grant No 2007AA11Z233National Key Technology R & D Program under Grant No. 2009BAG13A06China Postdoctoral Science Foundation Funded Project under Grant No. 20090450395
文摘Different driving decisions will cause different processes of phase transition in traffic flow. To reveal the inner mechanism, this paper built a new cellular automaton （CA） model, based on the driving decision （DD）. In the DD model, a driver＇s decision is divided into three stages： decision-making, action, and result. The acceleration is taken as a decision variable and three core factors, i.e. distance between adjacent vehicles, their own velocity, and the preceding vehicle＇s velocity, are considered. Simulation results show that the DD model can simulate the synchronized flow effectively and describe the phase transition in traffic flow well. Further analyses illustrate that various density will cause the phase transition and the random probability will impact the process. Compared with the traditional NaSch model, the DD model considered the preceding vehicle＇s velocity, the deceleration limitation, and a safe distance, so it can depict closer to the driver preferences on pursuing safety, stability and fuel-saving and has strong theoretical innovation for future studies.
文摘The recent accelerated growth rates or efforts to emulate countries that have achieved a rapid pace of economic growth are widely acclaimed as means to uplift millions from poverty. In so doing, however, this rapid economic growth is most likely to coincide with unsustainable levels of consumption, place excessive pressure on life support systems and terrestrial sinks and foreshorten options for the future. Rather than pursuing the "Environmental Kuznets Curve"(EKC) hypothesis that higher income will bring with it the means to reduce the impacts of greater consumption, ecological economists assert that buying our way out of future scarcity with fast growth is indeed contradictory with sustainabil- ity. To better understand these contradictions and explore potential institutional innovations that may enable developing nations to better confront them (in effect,"tunneling under"the EKC), this article refers to recent experience in the BRICS countries (Brazil, Russia, India, China and South Africa). Beginning with a brief comparative summary of major development and environmental indicators, pressures on resources and society in each of the BRICS are discussed, followed by identification of institutional and policy frameworks each country has evolved to confront the challenges of growth and sustainability. The article closes with general conclusions for further research and information sharing among developing nations.
文摘Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in COPD patients. Methods: In 295 clinically stable and optimally treated COPD patients from 39 outpatient centers, age, gender, and body composition (body mass index, BMI;fat-free mass index, FFMI;fat mass index, FMI) were related to inflammatory biomarkers: CRP, fibrinogen, TNFα, and its soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence on inflammatory biomarkers. Monovariate and multivariate regression analyses were performed for associations between inflammatory biomarkers. Results: Positive correlations were found for FFMI with sTNFαR1, FMI with CRP and age with TNFα, sTNFαR1 and sTNFαR2 (p < 0.01). FEV1 was not correlated with body composition and inflammatory markers. Mono- and multivariate analysis showed weak correlations between the acute phase markers and the TNFα system after correcting for multiple co-variants. Conclusions: This study highlights the modest role of age and body composition on levels of systemic inflammatory biomarkers in COPD. Results show the degree of airflow limitation does not affect systemic inflammation. Last, a weak relationship between acute phase markers and markers of the TNFα system is present in COPD.
基金supported by the National Natural Science Foundation of China (30670658)support from the Minzu University 985 Academic Team-building Fund (YLDX01013, 2015MDTD13C and 25C)the 111 Project of China (B08044)
文摘Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments,so it is critical to find new drugs for this condition.Recently,the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain.Here,we used the short peptide GluA_（2-3y）,which specifically inhibits the GluA2-dependent endocytosis of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors,and tested its anti-nociceptive effect in the periaqueductal grey（PAG） of intact rats and rats with neuropathic pain.Intra-PAG injection of 0.15,1.5,7.5,and 15 pmol of GluA_（2-3y） induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats,suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation.Furthermore,GluA_（2-3y） had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation.Interestingly,the intra-PAG injection of 15 pmol GluA_（2-3y） had an analgesic effect similar to 10 ug（35nmol） morphine in rats with neuropathic pain.Taken together,our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation,and inhibiting GluA2 endocytosis with GluA_（2-3y） has potent analgesic effects in rats with neuropathic pain.These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain.
基金The project supported by the National Natural Science Foundation of China(81072542)Natural Science Foundation of Jiangsu Province(BK2011077)the Research Fund for the Doctoral Program of Higher Education(20123237110010)
文摘OBJECTIVE Liguzinediol is a derivative of the natural active ingredient ligustrazine,and we found that liguzinediol has significant positive inotropic effects,which are stronger than that of TMP.Besides,it does not lead to arrhythmia,hypotension and other side effects.This study aims to investigate the anti-apoptotic effects of liguzinediolon H9C2 cells.METHODS Apoptotic H9C2 cells induced by DOX were observed by electron microscope and FCM analysis.The protein expressions of Bax,Bcl-2,caspases 3 and NF-κB were detected by Western blotting.RESULTS Apoptotic H9C2 cells induced by DOX were observed,but without apoptotic bodies in liguzinediol group.Declined peak of H9C2 cell apoptosis was seen in liguzinediol group by FCM analysis.And downregulation of Bax,caspases 3,NF-κB and upregulation of Bcl-2 were found by Western blotting.CONCLUSION Liguzinediol protected cardiomyocytes against apoptosis through downregulation of Bax and caspases 3 and upregulation of Bcl-2.Liguzinediol can inhibited cardiomyocyte apoptosis through the NF-κB signal pathway.
文摘Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to predict by longitudinal studies the probability of divorce in a marriage, with accuracy of up to 94%. Our objective was to investigate whether the occurrence of facial expressions of disgust and contempt in married women is associated with marital dissatisfaction. This is an experimental study that correlated, through filmed interviews, the frequency of facial expressions of disgust and disgust (Facial Action Coding System) to the Marital State’s Golombok Rust Inventory, in a sample composed of 20 women. Data analysis based on the Spearman Correlation Test showed a positive correlation between facial expressions of disgust and disdain and conjugal dissatisfaction (rs = 0.2198, p = 0.0280), corroborating the data in the literature.
基金supported by the National Natural Science Foundation of China(No.31271432)the National Basic Research Program of China(Nos.2012CB966600 and 2014CB943100)the Specialized Research Fund for the Doctoral Program of Higher Education(No.20130101110116)
文摘Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 chemically induced mutations on the X chromosome in Drosophila fat body clones and discovered that shibire （shi） plays an essential role in starvation-induced autophagy, shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome--lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation （ALR） through its excision activity, Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.
文摘Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.
文摘Sustainable building design is now mainstream.The United States Green Building Council(USGBC)and the LEED Ratings Systems have moved the market,proving that“a rising tide lifts all boats.”Consumers now factor environmental effect into their buying decisions,a trend that looks to continue and intensify with the millennial generation.Renters and homeowners are willing to pay more for high-performing and better quality housing based on environmental standards.Companies recognize that indoor air quality and daylighting improve employee performance and boost retention rates.And even bottom-line businesses are investing in benchmarking and efficiency projects that have the right return on investment rates.The Urban Land Institute’s Greenprint Center for Building Performance serves as a prime example of the ways developers implement benchmarking,energy efficiency,and high-performance standards in the major real estate sectors:office,retail,industrial,multifamily,and hotel.Energy efficiency gains and higher-quality buildings in each of these sectors will be essential to reducing emissions and energy use.While the transportation sector implements its own standards and benchmarking tools to achieve greater levels of sustainability across all modes of transportation,one industry that stands at the nexus of every building type and the transportation modes used to access them is parking.There is a key consideration that links land use and transportation:Parking is often the connection between where we are and where we want to go.Parking may not have been at the forefront of the sustainability discussion or the media surrounding it in previous years,but the professionals who work in the world of parking know exactly how important the role of their industry is to the success of our cities,towns,institutions,and businesses.Parking is big business;it is conservatively estimated to be a$30 billion industry.It directly contributes to the economic vitality and accessibility of where we live,work,and play。
文摘The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associatedcognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use nenrogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.
文摘Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.
基金This work was funded by the Canadian Institutes of Health Research(CIHR)Natural Sciences and Engineering Research Council of Canada(NSERC),Ontario Research Funds,and Medicine by Design–New Ideas Program.
文摘The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathological model systems and facilitated the generation of important hypotheses such as durotaxis and tissue-scale phase transition.There likely are many unexpected aspects of embryo biomechanics we have yet to discover which will change our views of mechanisms that govern development and disease.One area in the blind spot of even the most recent approaches to measuring tissue stiffness is the potentially anisotropic nature of that parameter.Here,we report a magnetic micromanipulation device that generates a uniform magnetic field gradient within a large workspace and permits measurement of the variation of tissue stiffness along three orthogonal axes.By applying the device to the organ-stage mouse embryo,we identify spatially heterogenous and directionally anisotropic stiffness within the mandibular arch.Those properties correspond to the domain of expression and the angular distribution of fibronectin and have potential implications for mechanisms that orient collective cell movements and shape tissues during development.Assessment of anisotropic properties extends the repertoire of current methods and will enable the generation and testing of hypotheses.
文摘Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diverse physicochemical network of specific and non-specific interactions, and seemingly subtle changes in amino acid identity at certain positions may dramatically impact TF：DNA binding. Variation of these specificity-determining residues （SDRs） is a major mechanism of functional divergence between TFs with strong structural or sequence homology. Methods： In this study, we employed a combination of high-throughput specificity profiling by SELEX and Spec-seq, structural modeling, and evolutionary analysis to probe the binding preferences of winged helix-turn-helix TFs belonging to the OmpR sub-family in Escherichia coil Results： We found that E. coli OmpR paralogs recognize tandem, variably spaced repeats composed of＂GT-A＂ or ＂GCT＂-containing half-sites. Some divergent sequence preferences observed within the ＂GT-A＂ mode correlate with amino acid similarity; conversely, ＂GCT＂-based motifs were observed for a subset of paralogs with low sequence homology. Direct specificity profiling of a subset of OmpR homologues （CpxR, RstA, and OmpR） as well as predicted ＂SDR-swap＂ variants revealed that individual SDRs may impact sequence preferences locally through direct contact with DNA bases or distally via the DNA backbone. Conclusions： Overall, our work provides evidence for a common structural code for sequence-specific wHTH：DNA interactions, and demonstrates that surprisingly modest residue changes can enable recognition of highly divergent sequence motifs. Further examination of SDR predictions will likely reveal additional mechanisms controlling the evolutionary divergence of this important class of transcriptional regulators.
基金a National Research Foundation of Korea(NRF)grant funded by the Korean Government(Ministry of Science,ICT and Future Planning)(2020R1A2C1010703).
文摘The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.
基金Thisworkwas supported in part by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01010201)the National Key Basic Research and Development Program of China(2014CB964804,2015CB964500)the National Natural Science Foundation of China(91219303,31430058).
文摘The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mouse embryo at embryonic day 7.0 and revealed that Nodal inhibition is essential for its formation.Here,we demonstrate that through brief inhibition of Nodal signaling in vitro,mouse embryonic stem cell(ESC)-derived epiblast stem cells(ESD-EpiSCs)could be committed to transient ectodermal progenitor populations,which possess the ability to give rise to neural or epidermal ectoderm in the absence or presence of BMP4,respectively.Mechanistic studies reveal that BMP4 recruits distinct transcriptional targets in ESD-EpiSCs and ectoderm-like cells.Furthermore,FGF–Erk signaling may also be alleviated during the generation of ectoderm-like cells.Thus,our data suggest that instructive interactions among several extracellular signals participate in the commitment of ectoderm from ESD-EpiSCs,which shed new light on the understanding of the formation of ectoderm during the gastrulation in early mouse embryo development.
