Defeating cancer:the 150 most important questions in cancer research and clinical oncology

Despite all the human efforts and monetary investment over the last few decades,cancer is still a devastating threat to our life expectancy and quality of life in many parts of the world.The etiology of cancer varies.The genetic and epigenetic causes of cancer are heterogeneous and multifaceted.Early detection is still a

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Influence of confining prestress on the transition from interface defeat topenetration in ceramic targets

Replica scaled impact experiments with unconfined ceramic targets have shown that the transition velocity,i.e.,the impact velocity at which interface defeat ceases and ceramic penetration occurs,decreased as the length scale increased.A possible explanation of how this scale effect is related to the formation of a cone crack in the ceramic has been presented by the authors in an earlier paper.Here,the influence of confinement and prestress on cone cracking and transition velocity is investigated.The hypothesis is that prestress will suppress the formation and growth of the cone crack by lowering the driving stress.A set of impact experiments has been performed in which the transition velocity for four different levels of prestress has been determined.The transition velocities as a function of the level of confining prestress is compared to an analytical model for the influence of prestress on the formation and extension of the cone crack in the ceramic material.Both experiments and model indicate that prestress has a strong influence on the transition from interface defeat to penetration,although the model underestimates the influence of prestress.

Ginsenoside Rb1 produces antidepressant-like effects in chronic social defeat stress model of depression through BDNF-TrkB sig⁃naling pathway

OBJECTIVE Ginsenoside Rb1(Rb1),an important bioactive ingredient of Panax ginseng,has potent neuroprotective effects.The objective of the study is to elucidate the impact of Rb1 treatment on chronic social defeat stress(CSDS)-induced depressive-like behaviors and its related mechanism.METHODS AND RE⁃SULTS The daily oral administration of Rb1(35 and 70 mg·kg-1)and imipramine(15 mg·kg-1)for 28 d significantly reversed the social avoidance behavior,anhedonia,and behavioral despair via CSDS exposure,as demonstrated by the consid⁃erable elevation in the time in the zone in social interaction test and consumption of sucrose solu⁃tion in sucrose preference test and decrease of immobility time in forced swim test.Moreover,Rb1 obviously restored the CSDS-induced decrease of BDNF-signaling pathway and hippo⁃campal neurogenesis.Rb1 significantly increased the hippocampal levels of ERK,AKT,and CREB phosphorylation and increased the number of DCX+cells in DG.Importantly,the antidepres⁃sant effects of Rb1 were completely blocked in mice by using K252a(the nonselective tyrosine kinase B inhibitor).CONCLUSION Rb1 exerts promising antidepressant-like effects in mice with CSDS-induced depression,and its effects was facilitated by enhancing the BDNF signaling cas⁃cade and up-regulation of hippocampal neuro⁃genesis.

Interface defeat studies of long-rod projectile impacting on ceramic targets

The interface defeat phenomenon always occurs when a long-rod projectile impacting on the ceramic target with certain velocity,i.e.,the projectile is forced to flow radially on the surface of ceramic plates for a period of time without significant penetration.Interface defeat has a direct effect upon the ballistic performance of the armor piercing projectile,which is studied numerically and theoretically at present.Firstly,by modeling the projectiles and ceramic targets with the SPH(Smoothed Particle Hydrodynamics)particles and Lagrange finite elements,the systematic numerical simulations on interface defeat are performed with the commercial finite element program AUTODYN.Three different responses,i.e.,complete interface defeat,dwell and direct penetration,are reproduced in different types of ceramic targets(bare,buffered,radially confined and oblique).Furthermore,by adopting the validated numerical algorithms,constitutive models and the corresponding material parameters,the influences of projectile(material,diameter,nose shape),constitutive models of ceramic(JH-1 and JH-2 models),buffer and cover plate(thickness,constraints,material),as well as the prestress acted on the target(radial and hydrostatic) on the interface defeat(transition velocity and dwell time) are syste matically investigated.Finally,based on the energy conservation approach and taking the strain rate effect of ceramic material into account,a modified model for predicting the upper limit of transition velocity is proposed and validated.The present work and derived conclusions can provide helpful reference for the design and optimization of both the long-rod projectile and ceramic armor.

浅析fault, defeat, falling, flaw, shortcoming

Fault, defeat, falling, flaw, shortcoming,这组词(n．)都指人或物在某方面有缺陷，不够完善，以faulI和defeat为常用。

Rapid destruction of sarin surrogates by gas phase reactions with focus on diisopropyl methylphosphonate(DIMP)

Rapid destruction of stockpiles of sarin and other chemical weapon agents(CWA)requires understanding and quantitative description of the relevant chemical reactions.Rapid reactions at elevated temperatures are of particular interest for prompt agent defeat scenarios.Diisopropyl methylphosphonate(DIMP)is a sarin surrogate particularly well suited to model sarin thermal decomposition and is often used in experiments.This article is a review of different experimental methods addressing decomposition of gasified DIMP,respective results and their interpretations.Major early decomposition products are propene,methylphosphonic acid,methyl(oxo)phosphoniumolate,and isopropanol.Early computational work using available kinetic data for fluorine and the phosphorus-fluorine bond predicted the decomposition under incineration conditions.Experiments using an isothermal flow reactor operated at 700-800 K were used to model DIMP decomposition as unimolecular reaction with results that were consistent with the earlier theoretical work.Decomposition in dynamic environments was studied using DIMP supported on rapidly heated substrates.The results showed different decomposition products and product sequences forming at different heating rates,suggesting the need for revised reaction kinetics.However,species quantification in such experiments is difficult because of inherent large temperature gradients.Plasma produced in a corona discharge was also reported to lead to rapid DIMP decomposition at low temperatures.Decomposition products were distinct from those observed at high temperatures.Shock tube experiments may be well suited to study decomposition of organophosphorus compounds like DIMP following their rapid heating in diverse environments.However,presently,only sarin surrogates other than DIMP have been investigated,and no intermediate reaction products,important for developing a validated mechanism,could be detected.

Vapor-phase decomposition of dimethyl methylphosphonate (DMMP),a sarin surrogate,in presence of metal oxides

Chemical warfare agents(CWA)are stockpiled in large quantities across the globe.Agents stored in inaccessible facilities need to be destroyed rapidly without dispersing the compounds to surrounding areas.Metal-based energetic formulations are used in such prompt defeat applications to rapidly decompose the CWA by generating a high temperature environment.An alternate,and possibly a more effective decomposition pathway could be provided by chemicidal action of aerosolized condensed combustion products,which typically consist of metal oxides.Toxic fumes that escape the high temperature blast zone can be neutralized by smoke generated during combustion,depending on the particle size,surface characteristics,chemical properties,and concentration of this smoke.This review considers relevant experimental and modeling studies quantifying decomposition of CWA comprising organophosphorus compounds and their surrogates on the surface of various metal oxides.Dimethyl methylphosphonate(DMMP),a sarine surrogate,was used most commonly for such experiments.Many reported efforts focused on the mechanisms of adsorption of DMMP to various metal oxides and initial reaction steps cleaving various bonds from the chemisorbed molecules.For selected oxides,these experiments were supported by quantum-mechanical calculations.In other studies,the capacity of oxide surfaces to adsorb and decompose DMMP was quantified.In most cases,porous catalysts were used although limited experimental data are available for aerosolized nonporous oxide particles.The reported experimental data applicable to scenarios involving prompt decomposition of CWA are summarized.It is noted that information is lacking describing respective heterogeneous reaction kinetics.Preliminary estimates of aerosolized smoke particle concentrations required to destroy CWA are made considering gas phase diffusion rates and reported values of the oxide capacity to decompose CWA or their surrogates.

Pathogenesis of chronic social defeat stress model induced depressive-like mouse model according to LC-MS/MS-based metabolomics

OBJECTIVE To explore the pathogenesis of depression according to the LC-MS/MS-based metabolomics in the mouse model which exhibits social avoidance state induced by the chronic social defeat stress model(CSDS).METHODS Twenty male C57BL/6N mice were randomly divided into control group and model group suffering CSDS,and the ICR retired breeder mice were used to attack the model group for 14 d of chronic social defeated stress.The open field test and source preference test were both used to observe depression-like behavior.Besides,the social interaction test is used to observe the social interaction state,especially.After the stress,the serum samples of mice were collected,and the changes of endogenous metabolites were analyzed by LC-MS metabolomics technology,and the pathway analysis of the differential metabolites was performed to explore the pathogenesis of the CSDS induced depressive-like mouse model.RESULTS After the stress of CSDS was completed,the mice in the model group showed a significant slowdown in body weight growth,a reduction in the source preference rate,and a significant reduction in the total distance and the number of rearing in the open field test.Distinctively,the social interaction rate is remarkably decreasing.There are 24 differential metabolites found in the serum of CSDS model mice.CONCLUSION The mouse who suffered CSDS stress would show depressive-like behavior.Based on the LC-MS/MS metabolomics,24 differential metabolites were found in the serum of CSDS model mice.The amino acid metabolism might be significant to the pathogenesis of the CSDS induced depressive-like mouse model.

Effect and regulation ofα-dstroglycan glyco⁃sylation on chronic social defeat induced depressive-like behaviors of mice

OBJECTIVEα-Dstroglycan(α-DG)is a predominant component in the dystrophin-glycoprotein complex(DGC)and a recently char⁃acterized receptor for several extracellular matrix components with high affinity.Recent research⁃es have reported that hypoglycosylation ofα-DG is associated with the pathophysiology of diseas⁃es,especially muscular dystrophy,but little is known about major depressive disorder(MDD).Like-acetylglucosaminyl transferase(Large)is a key enzyme for glycosylation ofα-DG,which mainly modifies two points in the middle domain ofα-DG:Thr-317 and Thr-319.Glycosylatedα-DG(GLY-α-DG)can bind with high affinity to extracellular matrix(ECM)molecules that con⁃tain laminin globular(LG)domains,including per⁃lecan,agrin and neurexin.Agrin is mainly derived from neurons rather than glial cells.In cultured hippocampal neurons,it was found that agrin could regulate the homeostatic plasticity of inhibi⁃tory neurons by acting on GLY-α-DG.Mdx mice are transgenetic models for the investigation of Duchenne muscular dystrophy.Many studies have shown that the expression of GLY-α-DG in the peripheral and brain tissues of Mdx mice is significantly down-regulated.Mdx mice show cognitive impairment and high levels of anxiety.In this study,we employed chronic social defeat stress(CSDS)to establish an animal model of depression and detected the expression of GLY-α-DG among the brain areas associated with the pathophysiology of depression.METHODS So⁃cial interaction test(SIT)and sucrose preference test(SPT)were used to evaluate depressive-like behavior.Open field(OF)and elevated plus maze(EPM)test were used to determine the anxiety-like behavior of Mdx mice.Novelty-sup⁃pressed feeding test(NSFT)forced swim test(FST)and tail suspension test(TST)were used to detect the depressive-like behavior of Mdx mice.Novel object recognition test(NOR)was applied to evaluate the cognition of Mdx mice.Subthreshold social defeat stress was used to explore the susceptibility to stress in Mdx mice.Stereotactic infusion of agrin into the ventral hippocampus(vHip),FST and TST were used to investigate the antidepressant effects of agrin.Adeno-associated virus(AAV)-mediated overex⁃pression techniques,behavior tests and whole-cell path-clamp technique were conducted to determine the impact of Large overexpression on CSDS susceptible mice.RESULTS The expres⁃sion ofα-DG and GLY-α-DG were significantly decreased in the vHip of CSDS susceptible mice.Mdx mice showed decreased expression of GLY-α-DG and increased anxiety-like behav⁃iors.Mdx mice displayed some depressive-like behaviors,and the susceptibility to stress was significantly increased.Downregulation of the expressionα-DG in the vHip by lentivirus increased the susceptibility to stress.Administra⁃tion of agrin to CSDS susceptible mice exerted antidepressant effects,and this effect could par⁃tially sustain for a week.The expression of Large was decreased in vHip.Overexpression of Large through AAV-Large reversed the depressive-like behaviors and restored the decreased frequency and amplitude of mIPSC.CONCLUSION GLY-α-DG and its glycosylase are significantly decreased in CSDS susceptible mice.Adminis⁃tration of agrin and overexpression of Large displays antidepressant effect,which may be related to its promotion of inhibitory synaptic transmission.

Resilience to the effects of social stress on vulnerability to developing drug addiction

We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse.We define the concept of resilience and how it is applied to the field of drug addiction research.We also describe the internal and external protective factors associated with resilience,such as individual behavioral traits and social support.We then explain the physiological response to stress and how it is modulated by resilience factors.In the subsequent section,we describe the animal models commonly used in the study of resilience to social stress,and we focus on the effects of chronic social defeat(SD),a kind of stress induced by repeated experience of defeat in an agonistic encounter,on different animal behaviors(depression-and anxiety-like behavior,cognitive impairment and addiction-like symptoms).We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depressionand anxiety-related behaviors in rodents.Finally,we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse,describing the current state of knowledge and suggesting future research directions.

Hyperactivity and Abnormal Exploratory Activity Developing in CD-1 Male Mice under Chronic Experience of Aggression and Social Defeats

Chronic social defeat stress induces diverse effects in mice of different strains and even in animals of the same strain. This paper aims to study the effect of repeated social defeats and, for contrast, repeated aggression in daily agonistic interactions on the behaviors of CD-1 male mice. The behavior of animals that have the same winning and losing track record during 3, 10, 21 days is studied in different tests. The level of aggressiveness, as estimated by the number and total time of attacks, decreases;nevertheless, direct and indirect forms of aggression demonstrated by the aggressive mice (winners) remain significantly high. The number of stereotypic behaviors (rotations and jumps) and total time of digging behaviors are significantly increased in the winners after 21 days compared to 3 and 10 days of intermale confrontations. Among the losers, chronic experience of social defeats is accompanied by the development of pronounced anxiety and a depression-like state estimated by the elevated plus-maze and the Porsolt test scores, respectively. Both groups of male mice with alternative social behaviors demonstrate abnormal locomotor and exploratory behaviors in the open-field test. This phenomenon may be viewed as hyperactivity developed under chronic agonistic interactions and specific for the outbred CD-1 mice. We believe that these animals may be potentially used for modeling the key symptoms of bipolar disorder.

Effects of the Novel Anti-Asthenic Drug Ladasten on Behavior and T-Cell Subsets Alterations in a Social Defeat Animal Model of Depression

The aim of the present study was to investigate the effects of the anti-asthenic drug ladasten on behavioral patterns and T-cell subsets in blood, spleen, and thymus in socially stressed male C57Bl/6 mice. Mice subjected to social defeat stress (SDS) for 25 days developed a depressive-like phenotype. The submissive SDS animals were assigned to one of two treatment groups: one group was treated with ladasten (30 mg/kg, i.p.) for up to 5 days, and the other one was administered vehicle as a control. Twenty four hours after the last injection, behavioral parameters were tested, and trunk blood and tissue samples were collected. SDS mice from the vehicle-treated group showed a subordinate and passive avoidance behavior with significantly decreased spontaneous locomotor activity (SLA) and exhibited impaired parameters in the forced swimming test (FST). Changes in behavioral status were correlated with an increase spleen weight, a decrease in thymic index and a shift in the CD4/CD8 balance toward T-cytotoxic cells. The behavior parameters were reversed in the group treated with ladasten compared to the untreated SDS group and were similar to those of unstressed mice. Treatment of socially stressed mice with ladasten normalized the amount of T-lymphocyte cells in the blood, spleen, and thymus. These findings support the notion that depression is accompanied by cell-mediated immune activation and that targeting this pathway may be a new therapeutic approach for treatment. Furthermore, our data support further investigations of ladasten as a potent anti-depressive drug which can be used alone as well as in combination with other anti-depressants.

Academician Glushkov and Grandmaster Fisher

In the first part of the article, the incomprehensible victories of the American grandmaster Robert Fisher over the candidates Mark Taimanov, Bent Larsen and Tigran Petrosyan in 1971 for the right to play the match for the World Chess Champion title with the former champion Boris Spassky and the victory over the champion himself in 1972 are first served as a detective story hypothesis proposed by Academician Viktor Glushkov. According to this hypothesis, R. Fisher used the prompts of a super-productive computer installed in the United States, in which a highly efficient computer chess program was played along with the matches. Communication with the computer provided a team of employees of the CIA. In the second part, the author, having reviewed briefly the history of computer chess programs, rejects the hypothesis of the academician and proposes his own.

An Atlas Lion As a rising hope in African football, Moroccan forward Ayoub El Kaabi was quick to impress fans with his skills, proving that he already feels at home in China

With two defeats and one victory in its first three games played in March 2019, Hebei China Fortune FC started the 2019 season of the Chinese Super League in a bittersweet manner. But the enthusiastic supporters in the Langfang Stadium in north China's Hebei Province, where the Hebei China Fortune is based, are full of hope for the future. Indeed, the local Chinese fans of the club are placing their hope on their new forward: Ttyoub El Kaabi from Morocco, who has been given the nickname “Atlas Lion”.

Victory in Defeat

AFRICAN women have been making headlines this year, with South Africa＇s Home Affairs Minister Nkosazama Dhlamini-Zuma lobbying for the post of African Union chief, Joyce Banda being sworn in as Malawi president and now Nigeria＇s Ngozi Okonjo-Iweala nominated for the top job at the World Bank.

Anxiolytic Effect of Increased NREM Sleep after Acute Social Defeat Stress in Mice

Social defeat stress(SDS)plays a major role in the pathogenesis of psychiatric disorders like anxiety and depression.Sleep is generally considered to involve recovery of the brain from prior experience during wakefulness and is altered after acute SDS.However,the effect of acute SDS on sleep/wake behavior in mice varies between studies.In addition,whether sleep changes in response to stress contribute to anxiety is not well established.Here,we first investigated the effects of acute SDS on sleep/wake states in the active period in mice.Our results showed that total sleep time(time in rapid eyemovement[REM]and non-REM[NREM]sleep)increased in the active period after acute SDS.NREM sleep increased mainly during the first 3 h after SDS,while REM sleep increased at a later time.Then,we demonstrated that the increased NREM sleep had an anxiolytic benefit in acute SDS.Mice deprived of sleep for 1 h or 3 h after acute SDS remained in a highly anxious state,while in mice with ad libitum sleep the anxiety rapidly faded away.Altogether,our findings suggest an anxiolytic effect of NREM sleep,and indicate a potential therapeutic strategy for anxiety.

Xiaoyao San,a Chinese herbal formula,ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus

Objective Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes.Current research is focused on the possible role of adiponectin in regulating common biological mechanisms.Xiaoyao San(XYS),a classic Chinese medicine compound,has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders.However,the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.Methods An in vivo animal model of depression was established by chronic social defeat stress(CSDS).XYS and fluoxetine were administered by gavage to the drug intervention group.Depression-like behaviors were analyzed by the social interaction test,open field test,forced swim test,and elevated plus maze test.Glucose levels were measured using the oral glucose tolerance test.The involvement of certain molecules was validated by immunofluorescence,histopathology,and Western blotting.In vitro,hypothalamic primary neurons were exposed to high glucose to induce neuronal damage,and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay.Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1(AdipoR1),adenosine 5’-monophosphate-activated protein kinase(AMPK),acetyl-coenzyme A carboxylase(ACC)and other related proteins.Results XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin.XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage.In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.Conclusion Adiponectin may be a key regulator linking depression and metabolic disorders;regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.

Cymbopogon citratus aqueous leaf extract attenuates neurobehavioral and biochemical changes induced by social defeat stress in mice

Objective:Psychosocial stress has been implicated in the genesis of psychiatric disorders such as memory deficits,depression,anxiety and addiction.Aqueous leaf extract of Cymbopogon citratus(CYC)otherwise known as lemongrass tea has antidepressant,anxiolytic and anti-amnesic effects in rodents.This study was designed to evaluate if C citratus could reverse the neurobehavioral and biochemical derangements induced by social defeat stress(SDS)in the resident/intruder paradigm.Methods:Intruder male mice were divided into five groups(n=7):group 1 received saline(10 mL/kg,p.o.;non-stress control),group 2 also received saline(10 mL/kg,p.o.;SDS control)while groups 3-5 had C.citratus(50,100 and 200 mg/kg,p.o.)daily for 14 d.The SDS was carried out 30 min after each treatment from day 7 to day 14 by exposing each intruder mouse in groups 2-5 to a 10 min confrontation in the home cage of an aggressive resident counterpart.The neurobehavioral features(spontaneous motor activity-SMA,anxiety,memory,social avoidance and depression were then evaluated.The concentrations of nitrite,malondialdehyde and glutathione as well as acetylcholinesterase activity in the brain tissues were also determined.Results:C.citratus(50,100 and 200 mg/kg)attenuated hypolocomotion,heightened anxiety,depressive-like symptom,memory deficit and social avoidance induced by SDS.The altered levels of oxidative stress and acetyl-cholinesterase in SDS-mice were positively modulated by C.citratus.Conclusion:The results of this study suggest that C.citratus might mitigate psychosocial stress-induced neurologic diseases in susceptible individuals.

Comic Relief?

On April 21, 41 -year-old Volodymyr Zelensky defeated incumbent Petro Poroshenko to sweep Ukraine's presidential run-off election. Zelensky, a political freshman who played a schoolteacher-tumed-president on a popular TV show titled Servant of the People, won 73 percent of the vote, almost triple the 24 percent for Poroshenko.