Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection

We previously identified GADPH as one of the cyclic adenosine diphosphoribose (cADPR)’s binding proteins and found that GADPH participates in cADPR-mediated Ca2+ release from ER via RyRs. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR’s binding pocket in GAPDH, and showed that two of these compounds, C244 and C346, are potential cADPR antagonists. We further synthesized several analogs of C346, and found that its analog, G42, also mobilized Ca2+ release from lysosomes. G42 alkalized lysosomal pH, and inhibited autophagosome-lysosome fusion. Moreover, G42 markedly inhibited Zika virus (ZIKV, a flavivirus) or murine hepatitis virus (MHV, a β-coronavirus) infections of host cells. These results suggest that G42 inhibits virus infection, likely by triggering lysosomal Ca2+ mobilization and inhibiting autophagy.
Evidence of hatch‐time based growth compensation in the early life history of two salmonid fishes

Initial body size can indicate quality within-species, with large size increasing the likelihood of survival. However, some populations or individuals may have body size disadvantages due to spatial/temporal differences in temperature, photoperiod, or food availability. Across-populations animals often have locally adapted physiology to compensate for poor environmental influences on development and growth, while within-populations behavioural adjustments that increase food intake after periods of deprivation provide opportunities to catch up (growth compensation). We posit a theoretical extension of growth compensation to include within-population differences related to short growing seasons due to delayed hatch time. We tested the hypothesis that individual fish that hatch later grow faster than those that hatch earlier. The relative magnitude of such a response was compared to growth variation among populations and between related species. We sampled young of the year Arctic charr and brook trout from five rivers in northern Labrador. Daily increments from otoliths were used to back-calculate size to a common age and calculate growth rates. Supporting the hypothesis, older fish were not larger at capture than younger fish, because animals that hatched later grew faster which may indicate age-based growth compensation.
Phenotypic Heterogeneity in the DNA Replication Stress Response Revealed by Quantitative Protein Dynamics Measurements

Cells respond to environmental stressors by activating programs that result in protein abundance and localization changes. The DNA damage and DNA replication stress responses have been heavily studied and provide exemplars of the roles of protein localization and abundance regulation in proper cellular stress response. While vast amounts of data have been collected to describe the dynamics of yeast proteins in response to numerous external stresses, few have assessed and compared both protein localization kinetics and phenotypic heterogeneity in the same context, particularly during DNA replication stress. We developed a robust yet simple quantification scheme to identify and measure protein localization change events (re-localization) and applied it to the 314 yeast proteins whose subcellular distribution changes following DNA replication stress. We captured different kinetics of protein re-localization, identified proteins with localization changes that were not detected in previous analyses, and defined the extent of heterogeneity in stress-induced protein re-localization. Our imaging platforms and analysis pipeline enables efficient measurements of protein localization phenotypes for single cells over time and will guide future work in elucidating the biological parameters that govern cellular heterogeneity.
The restriction factor pastrel is associated with host vigor, viral titer, and variation in disease tolerance during Drosophila C Virus infection

Genetic variation for both resistance and disease tolerance has been described in a range of species infected with bacterial, viral and fungal pathogens. In Drosophila melanogaster, genetic variation in mortality following systemic Drosophila C Virus (DCV) infection has been shown to be driven by large effect polymorphisms in the viral restriction factor pastrel (pst). However, it is unclear if pst impacts variation in DCV titres (i.e. resistance), or if it also contributes to disease tolerance. We investigated systemic infection across a range of DCV challenge doses spanning nine orders of magnitude, in males and females of ten Drosophila Genetic Reference Panel (DGRP) lines carrying either a susceptible (S) or resistant (R) pst allele. Our results uncover among-line variation in fly survival, viral titers, and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We confirm the role of pst in resistance, as fly lines with the resistant (R) pst allele experienced lower viral titers, and we uncover novel effects of pst on host vigor, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. While G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.
Input to cortical layer 1 of somatosensory cortex

1, Institute of Biology, Humboldt Universität zu Berlin Charitéplatz 1, Virchowweg 6, 10117 Berlin, Germany; 2, Institute of Neurophysiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Virchowweg 6, 10117 Berlin, Germany; 3, Institute of Biochemistry, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Virchowweg 6, 10117 Berlin, Germany; 4, Neurocure Center for Excellence Charité – Universitätsmedizin Berlin; 5, Emory University, Atlanta, GA, USA.
Abnormal Isoform-Induced Scaffolding by Mutant Huntingtin as Interacting Proteins in Transcriptional Creation of Abnormal Networks of Assembly in Huntington’s Disease

Conditional activation and propagation of neuronal injury are accumulative and result from isoform network abnormalities mediated by the creation of a mutant huntingtin molecule in Huntington’s disease. Further considerations of putative functions of the huntingtin molecule attest to a propagation of pathologic effects within neurons and axons that is primarily determined by the specific length of the polyglutamine tract that inherently lengthens. Proposed mechanisms in the creation of the mutant huntingtin are integral phenomena to subsequent involvement of neurons as created by isoforms of the scaffolding dysfunctionalities that result both from selective enzymatic cleavage and of subsequent protein-protein interactions involving in particular transcriptional dysregulation. In such context, transcriptional abnormalities bridge the dual phenomena of etiologic cause and of pathogenic propagation in neuronal injury in patients suffering from Huntington’s disease.
Factors Undermining the Use of Seasonal Climate Forecasts Among Farmers in South Africa and Zimbabwe: Implications for the 1st and 2nd Sustainable Development Goals

The adverse effects of climate change on food production coupled with growing inconsistencies in Indigenous knowledge systems have necessitated some farmers' willingness to rely on seasonal climate forecasts (SCFs) to make informed farming decisions. SCFs provide information regarding the likelihood that the rainfall in the forthcoming season will be higher, lower or normal. While SCFs have scaled up food production among some rural households in Sub-Saharan Africa (SSA), some farmers find it difficult to plug into this vital technology. Failure to utilize SCFs could have severe consequences for household food and nutrition security, especially in semi-arid countries like South Africa and Zimbabwe. By systematically unpacking the literature in South Africa and Zimbabwe from 2011 to 2021, this article seeks to demystify the factors that hamper the use of SCFs in the aforementioned countries. Results indicate that failure to comprehensively understand and interpret probabilistic forecasts as well as ill-timing of forecast dissemination, among others, are factors that undermine the use of SCFs. These issues are discussed both within the broader theoretical debates revolving around ways to dismantle the barriers undermining the use of SCFs in SSA, which could hamper the attainment of both the first and second sustainable development goals.
Chronic Traumatic Encephalopathy as a Preventable Environmental Disease

In this Perspective we explore the evolution of our understanding of chronic traumatic encephalopathy (CTE) and its relationship with repetitive head injury. As with many neurodegenerative conditions, there is an imperfect correspondence between neuropathology and clinical phenotype, but unlike other neurodegenerative diseases, CTE has a discrete and easily modifiable risk factor: exposure to repetitive head injury. Consequently, evaluation of the evidence regarding exposure to repetitive head injury and CTE risk should be undertaken using public or occupational health frameworks of medical knowledge. The current debate over the existence of CTE as a disease of concern is fuelled in part by immediate medico-legal considerations, and the involvement of high-profile athletes, with inevitable media interest. Moving beyond this debate has significant potential to address and reduce disease impact in the near future, and provide novel insights into mechanisms underlying abnormal protein accumulation in CTE and other neurodegenerative diseases.
Does Nice or Nasty Matter? The Intensity of Touch Modulates the Rubber Hand Illusion

Our sense of body ownership results from the ongoing integration of perceptual information coming from the different senses (i.e., multisensory integration). The Rubber Hand Illusion (RHI) has been extensively studied to investigate the malleability of body ownership through contrasting multisensory information. Indeed, during the RHI, stroking a visible rubber hand synchronously to participants’ hand hidden from sight generates the illusion of ownership of the rubber hand (embodiment) and the mis-location of participants’ hand as closer to the rubber hand (proprioceptive drift). It is well known that the RHI is optimally evoked by a pleasant stroking (affective) touch, but what of an unpleasant (painful) stroking touch – does hedonic valence matter? To this aim, participants repeated the RHI while receiving different types of touch: pleasant, painful, and neutral. Results showed, for the first time, that the subjective intensity of the tactile stimulation experienced across the different conditions modulates the strength of the proprioceptive drift. Notably, participants reported a stronger RHI (mis-placed body ownership) from stimulation rated as more intense and involving an interoceptive activation (pain and pleasantness vs. neutral). We propose that interoceptive information, regardless of the valence of the stimuli (positive or negative), are perceived as more intense and enhance, through the activation of the limbic system, multisensory integration. In the context of the RHI, this translates to a stronger illusion in terms of proprioceptive drift.
Loss-of-Function Models of the Metabotropic Glutamate Receptor Genes Grm8a and Grm8b Display Distinct Behavioral Phenotypes in Zebrafish Larvae (Danio rerio)

Members of the family of metabotropic glutamate receptors are involved in the pathomechanism of several disorders of the nervous system. Besides the well-investigated function of dysfunctional glutamate receptor signaling in neurodegenerative diseases, neurodevelopmental disorders (NDD), like autism spectrum disorders (ASD) and attention-deficit and hyperactivity disorder (ADHD) might also be partly caused by disturbed glutamate signaling during development. However, the underlying mechanism of the type III metabotropic glutamate receptor 8 (mGluR8 or GRM8) involvement in neurodevelopment and disease mechanism is largely unknown. Here we show that the expression pattern of the two orthologs of human GRM8, grm8a and grm8b, have evolved partially distinct expression patterns in the brain of zebrafish (Danio rerio), especially at adult stages, suggesting sub-functionalization of these two genes during evolution. Using double in situ hybridization staining in the developing brain we demonstrate that grm8a is expressed in a subset of gad1a-positive cells, pointing towards glutamatergic modulation of GABAergic signaling. Building on this result we generated loss-of-function models of both genes using CRISPR/Cas9. Both mutant lines are viable and display no obvious gross morphological phenotypes making them suitable for further analysis. Initial behavioral characterization revealed distinct phenotypes in larvae. Whereas grm8a mutant animals display reduced swimming velocity, grm8b mutant animals show increased thigmotaxis behavior, suggesting an anxiety-like phenotype. We anticipate that our two novel metabotropic glutamate receptor 8 zebrafish models may contribute to a deeper understanding of its function in normal development and its role in the pathomechanism of disorders of the central nervous system.
Differentiation of T Helper 17 Cells May Mediate the Abnormal Humoral Immunity in IgA Nephropathy and Inflammatory Bowel Disease Based on Shared Genetic Effects

Background IgA nephropathy (IgAN) is the most frequent glomerulonephritis in inflammatory bowel disease (IBD). However, the inter-relational mechanisms between them are still unclear. This study aimed to explore the shared gene effects and potential immune mechanisms in IgAN and IBD. Methods The microarray data of IgAN and IBD in the Gene Expression Omnibus (GEO) database were downloaded. The differential expression analysis was used to identify the shared differentially expressed genes (SDEGs). Besides, the shared transcription factors (TFs) and microRNAs (miRNAs) in IgAN and IBD were screened using humanTFDB, HMDD, ENCODE, JASPAR, and ChEA databases. Moreover, weighted gene co-expression network analysis (WGCNA) was used to identify the shared immune-related genes (SIRGs) related to IgAN and IBD, and R software package org.hs. eg.db (Version3.1.0) were used to identify common immune pathways in IgAN and IBD. Results In this study, 64 SDEGs and 28 SIRGs were identified, and the area under the receiver operating characteristic curve (ROC) of 64 SDEGs was calculated and two genes (MVP, PDXK) with high area under the curve (AUC) in both IgAN and IBD were screened out as potential diagnostic biomarkers. We then screened 3 shared TFs (SRY, MEF2D and SREBF1) and 3 miRNAs (hsa-miR-146, hsa-miR-21 and hsa-miR-320), and further found that the immune pathways of 64SDEGs, 28SIRGs and 3miRNAs were mainly including B cell receptor signaling pathway, FcγR-mediated phagocytosis, IL-17 signaling pathway, toll-like receptor signaling pathway, TNF signaling pathway, TRP channels, T cell receptor signaling pathway, Th17 cell differentiation, and cytokine-cytokine receptor interaction. Conclusion Our work revealed the differentiation of Th17 cells may mediate the abnormal humoral immunity in IgAN and IBD patients and identified novel gene candidates that could be used as biomarkers or potential therapeutic targets.
Science Communication in Public Radio: The Case Study of MindTap

Radio broadcasting is an integral medium for the public understanding of science. Yet, as a poorly recognized health disorder, mental health was not commonly discussed in U.S radio broadcasts until the early 1980s. Since then, mental health has increasingly been the subject of societal discourse and is now frequently the topic of focus for radio programming. Despite the increased attention on mental health, little academic inquiry has considered how science communicators may navigate locally complex and sensitive themes, such as those related to mental health. To address this gap, we discuss our experiences in producing a radio series on mental health called MindTap. Using the exemplar of MindTap, we explore models of science communication and their application within radio communication. Specifically, we suggest that topics, such as mental health, are best approached using the dialogue model of communication, which recognizes the value of integrating experiential and culturally situated knowledge with that of expert knowledge. We also illustrate how this form of communication supports narrative creation, and as such, identify practical insights for practitioners seeking to produce a mental health radio series.
Is the Discount Really Favorable? The Effect of Numeracy on Price Magnitude Judgment: Evidence From Electroencephalography

Attractive price promotion will induce an unreasonable willingness to purchase, especially through shopping. However, it is not clear how numeracy, one of the essential abilities for understanding and applying numbers, influences the process of purchase judgment. In total, 61 participants were recruited to perform a price promotion task using electroencephalography. The results showed that consumers with low numeracy performed worse than their peers with high numeracy at the behavioral level, and they also had lower P3b amplitude and less alpha desynchronization, regardless of price promotion frameworks. These findings provided evidence on the processing of price information and provided further insights into how numeracy impacts price magnitude judgment.
Non-Invasive Quantification of Layer-Specific Intrinsic Fluorescence From Mucosa of the Uterine Cervix Using Monte-Carlo-Based Models

Fluorescence spectroscopy has been demonstrated to non-invasively detect changes related to precursors of epithelial cancers, which include decreased fluorescence emission from collagen crosslinks in the connective tissue and increased fluorescence emission from reduced nicotinamide adenine dinucleotide (NADH) in the epithelial tissue. We implemented two-layer forward Monte Carlo models to predict diffuse reflectance and fluorescence intensities at the surface of cervical mucosa given tissue absorption, scattering, and fluorescence properties. The absorption and scattering coefficients of the upper epithelial layer and underlying connective tissue, as well as the epithelial thickness, were estimated from diffuse reflectance spectra using iterative curve fitting. The estimated parameters were used by the fluorescence forward model to obtain quantities needed to relate the intrinsic fluorescence of tissue fluorophores to measured fluorescence intensity. The emission spectra of tissue fluorophores were modeled by skew normal functions, and together with the efficiency of the fluorophores were extracted by fitting the modeled fluorescence spectra to measured spectra using the genetic algorithm. Compared to conventional one-layer forward models, the proposed two-layer models showed significantly smaller errors both in tissue properties estimated from simulated spectra, and in spectral errors of fitting to in-vivo data. Results of a preliminary in-vivo study showed that in seven of eight subjects with histopathologically confirmed dysplasia, the NADH-to-collagen intrinsic fluorescence ratio estimated from the biopsied site was at least two times greater than that estimated from the normal site on the same subject. The ability to more accurately estimate layer-specific intrinsic fluorescence from cervical mucosa could aid the detection of precancers in the cervix as well as other sites including oral and esophageal mucosae.
Investigating the Impact of Climate Change Mitigation Technology on the Transport Sector CO2 Emissions: Evidence From Panel Quantile Regression

Carbon emissions from the transport sector (COE) has witnessed unprecedented growth, which calls for special measures to control these emissions to achieve carbon neutrality by 2050. One of the measures taken to limit these emissions is climate change mitigation technology related to the transport sector (CCMT). However, there exists relatively scant literature that explores the CCMT-COE nexus. Hence, the present study explores whether CCMT curbs COE in the top transport sector carbon-emitting countries. For this purpose, we employ a panel quantile regression (PQR) approach, which probes the impact of CCMT on COE in low-, middle, and high-emission countries. The result shows that CCMT does not affect COE at the lowest quantile (i.e., 10th quantile) while CCMT plunges the emissions at all other quantiles. In particular, a 1% increase in CCMT curbs COE by 0.13% at the 25th, 50th, and 75th quantile, while a 1% upsurge in CCMT impedes COE by 0.22% at the 90th quantile. In the light of these findings, the carbon policy in the transport sector should invest in climate change mitigating technology in the transport sector and scale it up and out.
A Functional Variant in the Aquaporin-3 Promoter Modulates Its Expression and Correlates With Resistance to Porcine Epidemic Virus Infection in Porcine Intestinal Epithelial Cells

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious intestinal disease in neonatal pigs. Aquaporin-3 (AQP3) plays important roles in maintenance of intestinal barrier function and regulation of immune responses. However, the roles of AQP3 in mediating PEDV infection to host cells and the regulatory mechanisms of AQP3 expression remain poorly understood. Here, we identified one 16 bp (GGGCGGGGTTGCGGGC) insertion mutation in the AQP3 gene promoter in Large White pigs, with the frequencies of 49.3% of heterozygotes and 31.3% of mutant homozygotes. Functional analysis by luciferase activity assay indicated that the insertion mutation results in significant enhancement in AQP3 transcriptional activity (P < 0.01). Mechanistic analysis showed that the inserted sequence adds binding sites for transcription factor CEBPA, which promotes the expression of AQP3. Downregulation of AQP3 by shRNA silencing in porcine intestinal epithelial cells revealed obvious increases in genome copies and viral titers of PEDV. Expression of proinflammatory cytokines (IL-6, IL-8, and IL-18) and interferons (IFN-α and IFN-β) were significantly reduced (P < 0.01) in AQP3 knockdown cells upon PEDV infection. Furthermore, decreased level of ZO-1 protein was also detected in AQP3 knockdown cells in response to PEDV infection. Our findings suggested a previously unknown mechanism linking the effects of promoter genetic variants on the expression of AQP3, revealed the roles of AQP3 in response to PEDV pathogenesis, and indicated the potential associations of the 16 bp insertion mutation with resistance to PEDV infection in porcine intestinal epithelial cells.