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We previously showed that ethanol did not kill fetal neural stem cells (NSCs), but that their numbers nevertheless are decreased due to aberrant maturation and loss of self-renewal. To identify mechanisms that mediate this loss of NSCs, we focused on a family of Gag-like proteins (GLPs), derived from retroviral gene remnants within mammalian genomes. GLPs are important for fetal development, though their role in brain development is virtually unexplored. Moreover, GLPs may be transferred between cells in extracellular vesicles (EVs) and thereby transfer environmental adaptations between cells. We hypothesized that GLPs may mediate some effects of ethanol in NSCs.Sex-segregated male and female fetal murine cortical NSCs, cultured ex vivo as nonadherent neurospheres, were exposed to a dose range of ethanol and to mitogen-withdrawal-induced differentiation. We used siRNAs to assess the effects of NSC-expressed GLP knockdown on growth, survival, and maturation and in silico GLP knockout, in an in vivo single-cell RNA-sequencing dataset, to identify GLP-mediated developmental pathways that were also ethanol-sensitive.PEG10 isoform-1, isoform-2, and PNMA2 were identified as dominant GLP species in both NSCs and their EVs. Ethanol-exposed NSCs exhibited significantly elevated PEG10 isoform-2 and PNMA2 protein during differentiation. Both PEG10 and PNMA2 were mediated apoptosis resistance and additionally, PEG10 promoted neuronal and astrocyte lineage maturation. Neither GLP influenced metabolism nor cell cycle in NSCs. Virtual PEG10 and PNMA2 knockout identified gene transcription regulation and ubiquitin-ligation processes as candidate mediators of GLP-linked prenatal alcohol effects.Collectively, GLPs present in NSCs and their EVs may confer apoptosis resistance within the NSC niche and contribute to the abnormal maturation induced by ethanol.

Microsimulation model research can simulate a large number of micro individuals with different characteristics, build disease progression models, and evaluate the effects and benefits of risk factor control and early intervention strategies used in disease prevention and control, which could overcome the limitations of traditional epidemiological research, such as high investment and long time-consuming, and provide important evidence support for decision-making. This study introduces the definition and methods of microsimulation model, and articulates the application of three modeling methods including Markov model, decision-tree model and discrete event model in the primary and secondary cancer prevention, in order to provide reference for relevant disease prevention and control research in the future.微观模拟模型研究可通过模拟大量具有不同特征的微观个体，构建疾病进展模型，评价危险因素控制和早期干预策略等在疾病预防中的效果和效益，从而克服传统流行病学研究投入高、耗时长等局限性，为疾病预防决策制定提供重要证据支撑。本研究介绍了微观模拟模型的定义和构建方法，并结合研究实例阐述马尔可夫模型、决策树模型以及离散事件模型等3种建模方法在癌症一级和二级预防领域中的应用，以期为未来开展相关疾病防控研究提供参考。.

Peritoneal carcinomatosis (PC) is one of the difficult problems in the treatment of colorectal cancer (CRC). Based on several retrospective analyses of large samples and prospective randomized controlled studies (RCTs), NCCN and PSOGI recommend cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for selected CRC patients with mild to moderate PC. There are two important controversial issues in this field: the survival benefit of second-look surgery plus HIPEC for the patients with high risk of PC, and the specific benefit of HIPEC added to CRS for patients with PC. PROPHYLOCHIP found that second-look surgery plus HIPEC in patients at high risk of PC does not result in increased survival. PRODIGE 7 showed that overall survival (OS, 41.7 months vs. 41.2 months,腹膜转移是结直肠癌治疗领域的热点和难点，NCCN指南和PSOGI推荐肿瘤细胞减灭术（CRS）加腹腔热灌注化疗（HIPEC）治疗轻中度结直肠癌腹膜转移。在CRS+HIPEC治疗结直肠癌腹膜转移领域，腹膜转移高风险患者行二次探查+HIPEC是否有生存获益，以及HIPEC在该整合治疗体系中的价值，是两个争议已久的重要问题。针对上述问题，法国学者开展了两项随机对照研究：PROPHYLOCHIP研究和PRODIGE 7研究。（1）PROPHYLOCHIP研究发现，腹膜转移高风险患者初次手术后，密切观察组与二次探查+HIPEC组的DFS、OS比较差异无统计学意义，认为若初次手术理想、肿瘤细胞减灭完全，则无必要行二次探查+HIPEC；（2）PRODIGE 7研究发现，结直肠癌腹膜转移患者行完全CRS，联合或不联合HIPEC，其OS（41.7个月比41.2个月，

SummaryReal world memories are formed in a particular context and are not acquired or recalled in isolation 1-5. Time is a key variable in the organization of memories, since events experienced close in time are more likely to be meaningfully associated, while those experienced with a longer interval are not1-4. How does the brain segregate events that are temporally distinct? Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection6,7, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed CCR5 expression in mouse dorsal CA1 (dCA1) neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dCA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking. Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in aged mice, which could be reversed with a CCR5 knockout and an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Tracking animal behavior by video is one of the most common tasks in neuroscience. Previously, we have validated ezTrack, a free, flexible, and easy-to-use software for the analysis of animal behavior. ezTrack's Location Tracking Module can be used for the positional analysis of an individual animal and is applicable to a wide range of behavioral tasks. Separately, ezTrack's Freeze Analysis Module is designed for the analysis of defensive freezing behavior. ezTrack supports a range of desirable tools, including options for cropping and masking portions of the field of view, defining regions of interest, producing summary data for specified portions of time, algorithms to remove the influence of electrophysiology cables and other tethers, batch processing of multiple videos, and video down-sampling. Moreover, ezTrack produces a range of interactive plots and visualizations to promote users' confidence in their results. In this protocols paper, we provide step-by-step instructions for the use of ezTrack, from tips for recording behavior to instructions for using the software for video analysis. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Software environment installation Basic Protocol 2: Using the Location Tracking Module Basic Protocol 3: Using the Freeze Analysis Module.

Background Our previous study had found that the abundance of Lactobacillaceae in stool of acute coronary syndrome patients was significantly decreased. Experiments have confirmed that Lactobacillus has the effects of anti-inflammation, regulating blood lipids and improving cardiac injury after myocardial infarction. Purpose To explore the relationship between Lactobacillus and prognosis of acute myocardial infarction (AMI) patients treated by percutaneous coronary intervention (PCI) and its possible mechanism. Methods Patients with AMI who received emergency PCI from July 2017 to December 2018 in department of CCU were enrolled.Stool and blood samples were collected from all patients. The fecal 16S rDNA gene sequencing data from subjects were analyzed and subjects were categorized into Low, Medium and High level groups according to stool Lactobacillus measurements. The primary endpoints were major adverse cardiac events (MACE). Univariate and multivariate Cox regression were used to analyze the relationship between Lactobacillus and prognosis. Kaplan-Meier survival curve was used to characterize the association between the risk of MACE and Lactobacillus levels. Spearman correlation analysis and trend test were used to assess the relationship between Lactobacillus and Clinical index. Results A total of 254 patients were included in the analysis. The age was 65.90±11.56 years old,and 152 (59.84%) were male. The follow-up time was 652 (548.25, 753) days. Multivariate Cox regression showed that patients with Lactobacillus >7.1 copies/g presented lower risk of MACE (HR=0.179, 95% CI 0.076–0.422, P Conclusion Lactobacillus can significantly reduce the risk of MACE in STEMI patients treated by PCI, especially for male smokers over 60 years old. The underlying mechanism may be related to the fact that Lactobacillus can reduce inflammatory reaction, lessen cardiac injury and improve cardiac function. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): the Key Project of Scientific and Technological Support Plan of Tianjin in 2020 Correlation analysis between LactobacillSubgroup analysis in different patients

Background Elevated blood pressure (BP) is associated with substantial morbidity and mortality in stroke survivors. China has approximately 7.5 million stroke survivors, and accounts for one third of stroke mortality worldwide, but little is known about the prevalence and management of elevated BP as well as its effect on cardiovascular death at the national level. Purpose We aim to describe the prevalence and treatment of elevated BP and assess the cardiovascular mortality attributable to elevated BP among stroke survivors in China. Methods Based on 3 million participants aged 35–75 years from all 31 provinces in mainland China recruited from September 2014 through August 2019, we assessed the prevalence and treatment of elevated BP (systolic BP ≥140mmHg or diastolic BP ≥90mmHg) among those with self-reported stroke. Cardiovascular death was recorded before December 31st 2019. The age- and sex- specific population attributable fractions of cardiovascular death from elevated BP were estimated based on hazard ratios derived by Cox regression analysis. Results Among 91,628 stroke survivors, the mean (SD) age was 62 (8) years, 49% were male sex. The median (IQR) stroke duration was 4 (2,7) years. 61.3% of the individuals had elevated BP, and the prevalence increased with age (from 47.6% at 35–44 years of age to 64.7% at 65–75 years of age) and was slightly higher in rural area (63.2%) than urban area (58.8%). 32.7% of the overall population were treated, and 23.4% of those with elevated BP were treated. Among stroke survivors, elevated BP accounted for 26% of cardiovascular death at 35–75 years of age, and about one third at 35–54 years of age. The age- and sex- specific results were shown in the Table. Conclusions In this nationwide cohort of stroke survivors from China, over 60% had elevated BP, and about one third were treated. Elevated BP was associated with particularly substantial cardiovascular mortality for young and middle-aged stroke survivors. National strategies targeting elevated BP are required to improve the prognosis of stroke survivors in China. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Key Research and Development Program from the Ministry of Science and Technology of China Age- and sex-specific HRs and PAFs

Memory formation is thought to occur in the brain through dynamic remodeling of the synaptic architecture between neurons. The cellular mechanisms underlying these dynamics remain unclear. In this issue, Nguyen et al. demonstrate a novel role for microglia in regulating synaptic formation by clearing extracellular matrix proteins that embed neurons.

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.

Background & Aims Data on the economic and humanistic burden of non-alcoholic steatohepatitis (NASH) are scarce. This study assessed the comparative burden of NASH, relative to a representative sample from the general population and a type 2 diabetes mellitus (T2DM) cohort, in terms of health-related quality of life, work productivity and activity impairment (WPAI), and healthcare resource use. Methods Data across 5 European countries came from the 2016 National Health and Wellness Survey, a nationally representative patient-reported outcomes survey. Outcomes included mental (MCS) and physical (PCS) component scores from the Short-Form (SF)-36v2, WPAI scores, self-reported physician diagnosis of sleep difficulties, anxiety, and depression, and healthcare resource use: healthcare professional visits, hospital visits, and emergency room visits in the previous 6 months. Bivariate and multivariable analyses were conducted for each outcome and comparative group. Results After adjusting for matching criteria and covariates, patients with NASH (n = 184) reported significantly worse health-related quality of life, worse WPAI scores, and more healthcare resource use than the general population (n = 736) (MCS 39.22 vs. 45.16, PCS 42.84 vs. 47.76; overall work impairment 49.15% vs. 30.77%, healthcare professional visits 10.73 vs. 6.01, emergency room visits 0.57 vs. 0.22, hospitalizations 0.47 vs. 0.17, p ≪0.05 for all). Patients with NASH did not differ from patients with T2DM (n = 368) on PCS and WPAI scores, suggesting a similar impairment on work and daily activities, but did report significantly worse mental status (MCS 39.64 vs. 43.64, p ≪0.05) and more healthcare resource use than those with T2DM (healthcare professional visits 10.85 vs. 7.86, emergency room visits 0.65 vs. 0.23, hospitalizations 0.39 vs. 0.19, p ≪0.05 for all). Conclusions These findings suggest that the burden of NASH may be underestimated, highlighting the unmet needs of patients with NASH. Lay summary These findings show that patients with non-alcoholic steatohepatitis (NASH) experience a significant burden of illness, in terms of health-related quality of life, work productivity and activity impairment, and healthcare resource use. As there is currently no approved treatment for NASH, these findings highlight the unmet medical need of patients with NASH., Graphical abstract Unlabelled Image, Highlights • Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease. • NASH imposes a significant humanistic and economic burden on individuals and society. • NASH impairs health-related quality of life, work productivity and activity, while increasing healthcare resource use. • This study highlights the unmet need of patients with NASH in the absence of any approved treatment.

Net community production (NCP) in the surface water of the northern Gulf of Mexico (nGOM) and its coupling with the CO2 system were examined during the productive spring season. NCP was estimated using multiple approaches: (1) underway O2 and Ar ratio, (2) oxygen changes during light/dark bottle oxygen incubations, and (3) non-conservative changes in dissolved inorganic carbon or nutrients. These methods all showed high spatial variability of NCP and displayed similar patterns along the river–ocean mixing gradient, showing high production rates in plume regions. NCPO2Ar estimated from high-resolution O2 and Ar underway measurement indicated heterotrophic conditions at the high-nutrient and high-turbidity Mississippi River end (-51.3±11.9 mmol C m−2 d−1 when salinity O2Ar rates (105.0±59.2 mmol C m−2 d−1, up to 235.4 mmol C m−2 d−1) were observed in the Mississippi and Atchafalaya plumes at intermediate salinities between 15 and 30 where light and nutrients were both favorable for phytoplankton production. NCPO2Ar rates observed in the high-salinity, oligotrophic offshore waters (salinity > 35.5) were close to zero due to nutrient limitation. Air–sea CO2 fluxes generally showed corresponding changes, from being a strong CO2 source in the river channel (55.5±7.6 mmol C m−2 d−1), to a CO2 sink in the plume (-13.4±5.5 mmol C m−2 d−1), and to being nearly in equilibrium with the atmosphere in offshore waters. Overall, the surface water of the nGOM was net autotrophic during spring 2017, with an area-weighted mean NCPO2Ar of 21.2 mmol C m−2 d−1, and was a CO2 sink of −6.7 mmol C m−2 d−1. A temporal mismatch between in situ biological production and gas exchange of O2 and CO2 was shown through a box model to result in decoupling between NCPO2Ar and CO2 flux (e.g., autotrophic water as a CO2 source outside the Mississippi River mouth and heterotopic water as a CO2 sink in the Atchafalaya coastal water). This decoupling was a result of in situ biological production superimposed on the lingering background pCO2 from the source water because of the slow air–sea CO2 exchange rate and the buffering effect of the carbonate system.

Individuals affected with different neuropsychiatric disorders such as autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD), may share similar clinical manifestations, suggesting shared genetic influences and common biological mechanisms underlying these disorders. Using brain transcriptome data gathered from postmortem donors affected with AUT, SCZ and BPD, it is now possible to identify shared dysregulated gene sets, i.e., those abnormally expressed in brains of neuropsychiatric patients, compared to non-psychiatric controls. Here, we apply a novel aberrant gene expression analysis method, coupled with consensus co-expression network analysis, to identify gene sets with shared dysregulated expression in cortical brains of individuals affected with AUT, SCZ and BPD. We identify eight gene sets with dysregulated expression shared by AUT, SCZ and BPD, 23 by AUT and SCZ, four by AUT and BPD, and two by SCZ and BPD. The identified genes are enriched with functions relevant to amino acid transport, synapse, neurotransmitter release, oxidative stress, nitric oxide synthase biosynthesis, immune response, protein folding, lysophosphatidic acid-mediated signaling and glycolysis. Our method has been proven to be effective in discovering and revealing multigene sets with dysregulated expression shared by different neuropsychiatric disorders. Our findings provide new insights into the common molecular mechanisms underlying the pathogenesis and progression of AUT, SCZ and BPD, contributing to the study of etiological overlap between these neuropsychiatric disorders.

In order to cultivate new high-quality lily cultivars with good ornamental and edible traits, hybridization between Lilium brownii var. viridulum and L. davidii var. unicolor was conducted with cut style pollination and embryo rescue. 39 progenies were obtained. FISH with 5S rDNA and 45S rDNA as probes were used to analyze the parents and four progenies. The results showed that all of them are diploid (2n=2x=24); L. brownii has 10 loci of 5S rDNA on chromosomes (CH)-1, -2, -4, -8 and -11 and has 6 loci of 45S rDNA on CH-3, -9 and -10; L. davidii has 6 loci of 5S rDNA distributed on chromosomes CH-8, CH-10, and CH-11 and has 8 loci of 45S rDNA on chromosome CH-1, CH-5, CH-7 and CH-10; all four progenies have 8 loci of 5S rDNA and 7 loci of 45S rDNA, unambiguously, it was concluded that they are true hybrids coming from L. brownii and L. davidii.

随着高分辨胸部CT的普及，儿童肺结节的检出率逐年升高，但现有的肺结节评估和随访指南主要针对中老年群体制定，儿童肺结节的处理策略仍无统一意见。临床和放射学界日益关注儿童肺结节危险因素的研究，希望通过评估肺结节大小、边缘特征、钙化、在肺叶中的分布等特征，建立适当的风险评分及随访建议。本文介绍健康儿童及肿瘤患儿群体中肺结节的检出率、影像学特征，以及通过影像学特点鉴别良恶性儿童肺结节的可行性，为制定儿童肺结节的处理策略提供依据。.