Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuropeptide Modulation Increases Dendritic Electrical Spread to Restore Neuronal Activity Disrupted by Temperature

Peptide neuromodulation has been implicated to shield neuronal activity from acute temperature changes that can otherwise lead to loss of motor control or failure of vital behaviors. However, the cellular actions neuropeptides elicit to support temperature-robust activity remain unknown. Here, we find that peptide neuromodulation restores rhythmic bursting in temperature-compromised central pattern generator (CPG) neurons by counteracting membrane shunt and increasing dendritic electrical spread. We show that acutely rising temperatures reduced spike generation and interrupted ongoing rhythmic motor activity in the crustacean gastric mill CPG. Neuronal release and extrinsic application of Cancer borealis tachykinin-related peptide Ia (CabTRP Ia), a substance-P-related peptide, restored rhythmic activity. Warming led to a significant decrease in membrane resistance and a shunting of the dendritic signals in the main gastric mill CPG neuron. Using a combination of fluorescent calcium imaging and electrophysiology, we observed that postsynaptic potentials and antidromic action potentials propagated less far within the dendritic neuropil as the system warmed. In the presence of CabTRP Ia, membrane shunt decreased and both postsynaptic potentials and antidromic action potentials propagated farther. At elevated temperatures, CabTRP Ia restored dendritic electrical spread or extended it beyond that at cold temperatures. Selective introduction of the CabTRP Ia conductance using a dynamic clamp demonstrated that the CabTRP Ia voltage-dependent conductance was sufficient to restore rhythmic bursting. Our findings demonstrate that a substance-P-related neuropeptide can boost dendritic electrical spread to maintain neuronal activity when perturbed and reveals key neurophysiological components of neuropeptide actions that support pattern generation in temperature-compromised conditions. SIGNIFICANCE STATEMENT Changes in body temperature can have detrimental consequences for the well-being of an organism. Temperature-dependent changes in neuronal activity can be especially dangerous if they affect vital behaviors. Understanding how temperature changes disrupt neuronal activity and identifying how to ameliorate such effects is critically important. Our study of a crustacean circuit shows that warming disrupts rhythmic neuronal activity by increasing membrane shunt and reducing dendritic electrical spread in a key circuit neuron. Through the ionic conductance activated by it, substance-P-related peptide modulation restored electrical spread and counteracted the detrimental temperature effects on rhythmic activity. Because neuropeptides are commonly implicated in sustaining neuronal activity during perturbation, our results provide a promising mechanism to support temperature-robust activity.
A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection.

BACKGROUND Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).
The last will: Estate divisions as a testament of to whom altruism is directed

We use data on estate divisions to study to whom altruistic preferences are directed. Insofar bequests are given without the prospect of future personal benefits in mind, they are presumably intrinsically motivated. Hence, estate divisions provide a rare opportunity to study intrinsically motivated prosocial behavior in the field. The empirical analysis is based on data from digitized estate reports for all individuals in Sweden who passed away in 2002 and 2003. The data show in detail how the decedents distributed their bequests. We find that family members, both genetic (offspring) and non-genetic (partner), receive the lion’s share of the estates. Other relatives, friends and strangers (represented by charities) receive only very small shares of the total estate wealth. The results suggest that intrinsically motivated altruism is primarily directed towards close family members.
Thermal remodelling of Alternanthera mosaic virus virions and virus-like particles into protein spherical particles

The present work addresses the thermal remodelling of flexible plant viruses with a helical structure and virus-like particles (VLPs). Here, for the first time, the possibility of filamentous Alternanthera mosaic virus (AltMV) virions’ thermal transition into structurally modified spherical particles (SP) has been demonstrated. The work has established differences in formation conditions of SP from virions (SPV) and VLPs (SPVLP) that are in accordance with structural data (on AltMV virions and VLPs). SP originate from AltMV virions through an intermediate stage. However, the same intermediate stage was not detected during AltMV VLPs’ structural remodelling. According to the biochemical analysis, AltMV SPV consist of protein and do not include RNA. The structural characterisation of AltMV SPV/VLP by circular dichroism, intrinsic fluorescence spectroscopy and thioflavin T fluorescence assay has been performed. AltMV SPV/VLP adsorption properties and the availability of chemically reactive surface amino acids have been analysed. The revealed characteristics of AltMV SPV/VLP indicate that they could be applied as protein platforms for target molecules presentation and for the design of functionally active complexes.
An "I" for an "I": A systematic review and meta-analysis of instigated and reciprocal incivility.

Incivility and its negative impacts on individuals, teams, and organizations have been widely studied in workplace contexts, but the literature lacks a comprehensive understanding of incivility from the instigator's perspective. This meta-analysis of instigated incivility included 35,344 workers from 76 independent samples. Results showed that instigated incivility was related to several correlates including psychological ill-being, ρ = . 36, and well-being, ρ = -. 17; physical well-being, ρ = -. 25; personal dispositions that are risk factors, ρ = . 47, and preventative factors, ρ = -. 34; negative, ρ = . 28, and positive, ρ = -. 33, job attitudes; positive team characteristics, ρ = -. 28; job demands, ρ = . 10; and experienced, ρ = . 61, and observed, ρ = . 58, incivility. Moderator analyses showed that the relationship between experienced and instigated incivility was weaker for older participants and under conditions of greater job control and work-group civility. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
PGC‐1α regulates myonuclear accretion after moderate endurance training

The transcriptional demands of skeletal muscle fibres are high and require hundreds of nuclei (myonuclei) to produce specialised contractile machinery and multiple mitochondria along their length. Each myonucleus spatially regulates gene expression in a finite volume of cytoplasm, termed the myonuclear domain (MND), which positively correlates with fibre cross‐sectional area (CSA). Endurance training triggers adaptive responses in skeletal muscle, including myonuclear accretion, decreased MND sizes and increased expression of the transcription co‐activator peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α). Previous work has shown that overexpression of PGC‐1α in skeletal muscle regulates mitochondrial biogenesis, myonuclear accretion and MND volume. However, whether PGC‐1α is critical for these processes in adaptation to endurance training remained unclear. To test this, we evaluated myonuclear distribution and organisation in endurance‐trained wild‐type mice and mice lacking PGC‐1α in skeletal muscle (PGC‐1α mKO). Here, we show a differential myonuclear accretion response to endurance training that is governed by PGC‐1α and is dependent on muscle fibre size. The positive relationship of MND size and muscle fibre CSA trended towards a stronger correlation in PGC‐1a mKO versus control after endurance training, suggesting that myonuclear accretion was slightly affected with increasing fibre CSA in PGC‐1α mKO. However, in larger fibres, the relationship between MND and CSA was significantly altered in trained versus sedentary PGC‐1α mKO, suggesting that PGC‐1α is critical for myonuclear accretion in these fibres. Accordingly, there was a negative correlation between the nuclear number and CSA, suggesting that in larger fibres myonuclear numbers fail to scale with CSA. Our findings suggest that PGC‐1α is an important contributor to myonuclear accretion following moderate‐intensity endurance training. This may contribute to the adaptive response to endurance training by enabling a sufficient rate of transcription of genes required for mitochondrial biogenesis.
Grape skin extract modulates neuronal stem cell proliferation and improves spatial learning in senescence-accelerated prone 8 mice

In recent years, the number of patients with neurodegenerative illness such as Alzheimer’s disease (AD) has increased with the aging of the population. In this study, we evaluated the effect of Grape skin extract (GSE) on neurotypic SH-SY5Y cells as an in vitro AD model, murine neurospheres as an ex vivo neurogenesis model and SAMP8 mice as an in vivo AD model. Our in vitro result showed that pre-treatment of SH-SY5Y cells with GSE ameliorated Aβ-induced cytotoxicity. Moreover, GSE treatment significantly decreased the number of neurospheres, but increased their size suggesting reduced stem cell self-renewal but increased proliferation. Our in vivo Morris water maze test indicated that GSE improves learning and memory in SAMP8 mice. To detect proliferation and newborn neurons, we measured BrdU+ cells in the dentate gyrus (DG). GSE treatment increased the number of BrdU+ cells in the DG of SAMP8 mice. Finally, we showed that GSE induced a decrease in inflammatory cytokines and an increase in neurotransmitters in the cerebral cortex of SAMP8 mice. These results suggested that GSE increased neurogenic zone proliferation and memory but decreased oxidative stress associated with pro-inflammatory cytokines in aging, thus protecting neurons.
Insight into the Growth and Control of Single-Crystal Layers of Ge–Sb–Te Phase-Change Material

Employed for a long time in optical disks, Ge2Sb2Te5 is nowadays considered the most promising material also for phase-change nonvolatile memories. In the current paper, Ge–Sb–Te phase-change material thin films with a nominal composition of Ge2Sb2Te5 were grown by molecular beam epitaxy on slightly mismatched GaSb and InAs substrates with (001) and (111) orientations. In situ quadrupole mass spectrometry and reflection high-energy electron diffraction allowed tight control of the growth parameters, revealing that Ge2Sb2Te5 grows in epitaxial fashion only within a narrow window of substrate temperatures around 200 °C. Smooth surfaces were achieved solely on (111)-oriented substrates. Rough surfaces and interfaces were observed by transmission electron microscopy for films grown on (001)-oriented substrates. Whereas films deposited on (001) substrates possess two different vertical epitaxial orientations, single-crystalline layers exclusively (111) oriented were achieved on (111) substrates, as shown by sy.
MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer

Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear. Methods Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy. Results With transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the ‘inflamed’ and ‘non-inflamed’ subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC. Conclusions Our work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.
Machine learning predicts treatment sensitivity in multiple myeloma based on molecular and clinical information coupled with drug response

Providing treatment sensitivity stratification at the time of cancer diagnosis allows better allocation of patients to alternative treatment options. Despite many clinical and biological risk markers having been associated with variable survival in cancer, assessing the interplay of these markers through Machine Learning (ML) algorithms still remains to be fully explored. Here, we present a Multi Learning Training approach (MuLT) combining supervised, unsupervised and self-supervised learning algorithms, to examine the predictive value of heterogeneous treatment outcomes for Multiple Myeloma (MM). We show that gene expression values improve the treatment sensitivity prediction and recapitulates genetic abnormalities detected by Fluorescence in situ hybridization (FISH) testing. MuLT performance was assessed by cross-validation experiments, in which it predicted treatment sensitivity with 68.70% of AUC. Finally, simulations showed numerical evidences that in average 17.07% of patients could get better response to a different treatment at the first line.
Global burden of post-traumatic stress disorder and major depression in countries affected by war between 1989 and 2019: a systematic review and meta-analysis

Objective Extensive research has demonstrated high prevalences of post-traumatic stress disorder (PTSD) and major depression (MD) in war-surviving populations. However, absolute estimates are lacking, which may additionally inform policy making, research and healthcare. We aimed at estimating the absolute global prevalence and disease burden of adult survivors of recent wars (1989–2019) affected by PTSD and/or MD. Methods We conducted a systematic literature search and meta-analysis of interview-based epidemiological surveys assessing the prevalence of PTSD and/or MD in representative samples from countries with a recent war history (1989–2019). Drawing on the war definition and geo-referenced data of the Uppsala Conflict Database Programme and population estimates of the United Nations for 2019, we extrapolated the meta-analytic results to absolute global numbers of affected people. Drawing on disability-adjusted life years (DALYs) data of the Global Burden of Diseases Study 2019, we further calculated the PTSD-associated and MD-associated DALYs. Results Twenty-two surveys (N=15 420) for PTSD, 13 surveys for MD (N=9836) and six surveys on the comorbidity of PTSD and MD (N=1131) were included. Random effects meta-analyses yielded point prevalences of 26.51% for PTSD and 23.31% for MD. Of those affected by PTSD, 55.26% presented with comorbid MD. Prevalence rates were not significantly associated with war intensity and length, time since war, response rate or survey quality. The extrapolation yielded 316 million adult war-survivors globally who suffered from PTSD and/or MD in 2019. War-survivors were almost exclusively living in low/middle-income countries (LMICs) and carried a burden of 3 105 387 and 4 083 950 DALYs associated with PTSD and MD, respectively. Conclusions Since LMICs lack sufficient funding and qualified professionals to provide evidence-based psychological treatments for such large numbers of affected people, alternative and scalable strategies using existing resources in primary care and communities are required. Research is required to assist upscaling.
How to Choose a Survival Period? The Impact of Antibiotic Use on OS or PFS in NSCLC Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Background: The development of immunotherapy has dramatically changed the treatment of non-small-cell lung cancer. The negative association of antibiotics on the clinical activity of immune checkpoint inhibitors in patients with NSCLC is well known. Methods: PubMed, Embase, and Medline databases were searched until January 11, 2020. We included retrospective studies of ICIs (e.g., PD-1, PD-L1, and CTLA-4). The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup and sensitivity analyses were performed. Results: Our results indicated that the use of antibiotics reduced the survival of NSCLC patients treated with ICIs. The pooled HRs of PFS and OS were HR = 1.41 (95% CI = 1.23-1.61; P < 0.001) and HR = 2.16 (95% CI = 1.79-2.60; P < 0.001). We divided the studies into 5 subgroups according to antibiotic exposure time. Subgroup analysis showed that the patients that were administered antibiotics [−60 days; 0 days] or [−30 days; 0 days] before the initiation of ICIs treatment had a poorer OS rate, whereas those patients that were administered antibiotics [0 days; 30 days] after the initiation of ICIs treatment had a poorer PFS rate. In summary, ATB treatment in patients [−60 days; +30 days] near the initiation of ICIs treatment significantly reduced the survival in NSCLC patients. Conclusion: Our results indicated that ATB use is negatively associated with survival in NSCLC patients treated with ICIs immunotherapy. Similar studies involving a larger sample of cases are still being published. This meta-analysis identified that the timing of ATB treatment in NSCLC patients receiving ICIs immunotherapy has different effects on the OS and PFS of these patients. ATB treatment prior to the initiation of ICIs treatment affects OS, whereas ATB treatment after the initiation of ICIs treatment affects PFS.
Direct identification of neoantigen-specific TCRs from tumor specimens by high-throughput single-cell sequencing

Background Recognition of neoantigens by T cells plays a major role in cancer immunotherapy. Identification of neoantigen-specific T-cell receptors (TCRs) has become a critical research tool for studying T cell-mediated responses after immunotherapy. In addition, neoantigen-specific TCRs can be used to modify the specificity of T cells for T cell-based therapies targeting tumor-specific mutations. Although several techniques have been developed to identify TCR sequences, these techniques still require a significant amount of labor, making them impractical in the clinical setting. Methods Thanks to the availability of high-throughput single-cell sequencing, we developed a new process to isolate neoantigen-specific TCR sequences. This process included the isolation of tumor-infiltrating T cells from a tumor specimen and the stimulation of T cells by neoantigen-loaded dendritic cells, followed by single-cell sequencing for TCR and T-cell activation markers, interferon-γ and interleukin-2. Results In this study, potential neoantigen-specific TCRs were isolated from three melanoma and three colorectal tumor specimens. These TCRs were then synthesized and transduced into autologous T cells, followed by testing the recognition of neoantigens. A total of 28 neoantigen-specific TCRs were identified by this process. If identical TCR sequences were detected from two or more single cells, this approach was highly reliable (100%, 19 out of 19 TCRs). Conclusion This single-cell approach provides an efficient process to isolate antigen-specific TCRs for research and clinical applications.