Miracle-dz/UniFAR-FTUs huggingface dataset:
LOXL2 Mediates Airway Smooth Muscle Cell Matrix Stiffness and Drives Asthmatic Airway Remodelling

Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin mouse model of asthma. These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.
The effect of combined treatment of vitamin C and loperamide on intestinal sodium and potassium ion ATPase, alkaline phosphatase and lipid peroxidation on castor oil induced diarrheal rats

Background Diarrhea is distinguished by prevalence of bowel movement accompanied by a loose consistency of stools, resulting from hyper peristalsis of the small intestine or colon, Diarrhea is a major challenge among infants and growing children. The study was carried out to assess the result of combined treatment of vitamin C and loperamide on intestinal Na+, K+ - ATPase, alkaline phosphatase, and lipid peroxidation in castor oil induced diarrheal wistar rats. Method A total of 18 wistar rats weighing 180-200g were randomly divided into 6 groups, (Group 1 Normal control no castor oil, no treatment administered, Group 2 Experimental control were given castor oil 3.0 ml/kg body weight with no treatment, Group 3 Standard control were given castor oil 3.0 ml/kg body weight + loperamide, Group 4 Treatment 1 were administered 3.0 ml/kg body weight + 25 mg/kg combined effect of vitamin C and loperamide, Group 5 Treatment 2 were administered 3.0 ml/kg body weight + 50 mg/kg combined effect of vitamin C and loperamide, and Group 6 were administered 3.0 ml/kg body weight + 100 mg/kg combined effect of vitamin C and loperamide) with 3 rats per group; the experiment lasted for 24 hours. The action of intestinal alkaline phosphatase, Na+, K+ - ATPase and malondialdehyde were determined. Result Descriptive statistical analysis was adopted using SPSS version 20. Combined effect of vitamin C and loperamide significantly (p<0.05) lowered the elevated levels of malondialdehyde caused by castor oil induced diarrhea; the Na+, K+ - ATPase intestinal activity treatment with both vitamin C and loperamide significantly elevated the activity of Na+, K+ ATPase when compared with the normal control, but both treatments (loperamide alone and vitamin C plus loperamide were not significantly different (p<0.05) to themselves. However, at 50 mg/kg body weight of combined effect of vitamin C and loperamide it showed significant difference in the action of intestinal alkaline phosphatase. Conclusion Findings of this study therefore, indicate that a combined effect of loperamide and vitamin C will be an effective therapeutic agent in the management of diarrhea by scavenging of free radicals generated in the cause of diarrheal to reduce lipid peroxidation. Therefore, combined effect of vitamin C and loperamide should be encouraged in the management of diarrhea. Further research should be directed towards assessing the therapeutic action of vitamin C only in the management of diarrhea.
Bridging Brain and Cognition: A Multilayer Network Analysis of Brain Structural Covariance and General Intelligence in a Developmental Sample of Struggling Learners

Network analytic methods that are ubiquitous in other areas, such as systems neuroscience, have recently been used to test network theories in psychology, including intelligence research. The network or mutualism theory of intelligence proposes that the statistical associations among cognitive abilities (e.g. specific abilities such as vocabulary or memory) stem from causal relations among them throughout development. In this study, we used network models (specifically LASSO) of cognitive abilities and brain structural covariance (grey and white matter) to simultaneously model brain-behavior relationships essential for general intelligence in a large (behavioral, N=805; cortical volume, N=246; fractional anisotropy, N=165), developmental (ages 5-18) cohort of struggling learners (CALM). We found that mostly positive, small partial correlations pervade both our cognitive and neural networks. Moreover, calculating node centrality (absolute strength and bridge strength) and using two separate community detection algorithms (Walktrap and Clique Percolation), we found convergent evidence that subsets of both cognitive and neural nodes play an intermediary role between brain and behavior. We discuss implications and possible avenues for future studies.
3D architecture and structural flexibility revealed in the subfamily of large glutamate dehydrogenases by a mycobacterial enzyme

Glutamate dehydrogenases (GDHs) are widespread metabolic enzymes that play key roles in nitrogen homeostasis. Large glutamate dehydrogenases composed of 180 kDa subunits (L-GDHs 180 ) contain long N- and C-terminal segments flanking the catalytic core. Despite the relevance of L-GDHs 180 in bacterial physiology, the lack of structural data for these enzymes has limited the progress of functional studies. Here we show that the mycobacterial L-GDH 180 (mL-GDH 180 ) adopts a quaternary structure that is radically different from that of related low molecular weight enzymes. Intersubunit contacts in mL-GDH 180 involve a C-terminal domain that we propose as a new fold and a flexible N-terminal segment comprising ACT-like and PAS-type domains that could act as metabolic sensors for allosteric regulation. These findings uncover unique aspects of the structure-function relationship in the subfamily of L-GDHs. Lázaro et. al . report the first 3D structure of a large glutamate dehydrogenase (L-GDH), the one corresponding to the Mycobacterium smegmatis enzyme composed of 180 kDa subunits (mL-GDH 180 ), obtained by X-ray crystallography and cryo-electron microscopy. This structure reveals that mL-GDH 180 assembles as tetramers with the N- and C-terminal domains being involved in inter-subunit contacts and unveils unique features of the subfamily of L-GDHs.
The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ERα and decreased ERβ in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ERα and increased apoptosis, gliosis, inflammation, ERβ, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.
Multiscale PHATE Exploration of SARS-CoV-2 Data Reveals Multimodal Signatures of Disease

The biomedical community is producing increasingly high dimensional datasets, integrated from hundreds of patient samples, which current computational techniques struggle to explore. To uncover biological meaning from these complex datasets, we present an approach called Multiscale PHATE, which learns abstracted biological features from data that can be directly predictive of disease. Built on a continuous coarse graining process called diffusion condensation, Multiscale PHATE creates a tree of data granularities that can be cut at coarse levels for high level summarizations of data, as well as at fine levels for detailed representations on subsets. We apply Multiscale PHATE to study the immune response to COVID-19 in 54 million cells from 168 hospitalized patients. Through our analysis of patient samples, we identify CD16hi CD66blo neutrophil and IFNγ+GranzymeB+ Th17 cell responses enriched in patients who die. Further, we show that population groupings Multiscale PHATE discovers can be directly fed into a classifier to predict disease outcome. We also use Multiscale PHATE-derived features to construct two different manifolds of patients, one from abstracted flow cytometry features and another directly on patient clinical features, both associating immune subsets and clinical markers with outcome.
Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such as MKLN1, LMO4 and FN1. Comparable sex-specific methylation differences in MKLN1 also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.
Stimulus-specific plasticity of macaque V1 spike rates and gamma

When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Natural genetic diversity in the potato resistance gene RB confers suppression avoidance from Phytophthora effector IPI-O4

RB is a potato gene that provides resistance to a broad spectrum of genotypes of the late blight pathogen Phytophthora infestans. RB belongs to the CC-NB-LRR (coiled-coil, nucleotide-binding, leucine-rich repeat) class of resistance (R) genes, a major component of the plant immune system. It directly interacts with Class I and II IPI-O effectors from P. infestans to initiate a hypersensitive resistance response, but this activity is suppressed in the presence of the Class III effector IPI-O4. Using natural genetic variation of RB within potato wild relatives, we identified two amino acids in the CC domain that alter interactions needed for suppression of resistance by IPI-O4. We have found that separate modification of these amino acids in RB can diminish or enhance the resistance capability of this protein against P. infestans in both Nicotiana benthamiana and potato. Our results demonstrate that increased knowledge of the molecular mechanisms that determine resistance activation and R protein suppression by effectors can be utilized to tailor-engineer genes with the potential to provide increased durability.
osr1 couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation

Transcriptional regulatory networks refine gene expression boundaries throughout embryonic development to define the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that establish the boundary between the IM and its neighboring vessel progenitors are poorly understood. Here, we delineate new roles for the zinc finger transcription factor Osr1 in kidney and vessel progenitor development. Zebrafish osr1 mutants display decreased IM formation and premature emergence of neighboring lateral vessel progenitors (LVPs). These phenotypes contrast with the increased IM and absent LVPs observed with loss of the bHLH transcription factor Hand2, and loss of hand2 partially suppresses the osr1 mutant phenotypes. hand2 and osr1 are both expressed in the posterior lateral mesoderm, but osr1 expression decreases dramatically prior to LVP emergence. Overexpressing osr1 inhibits LVP development while enhancing IM formation. Together, our data demonstrate that osr1 modulates both the extent of IM formation and the temporal dynamics of LVP development, suggesting that a balance between levels of osr1 and hand2 expression is essential to demarcate the dimensions of kidney and vessel progenitor territories. SUMMARY STATEMENT Analysis of the osr1 mutant phenotype reveals roles in determining the extent of intermediate mesoderm formation while inhibiting premature differentiation of neighboring vessel progenitors.
Effects of water content and mesh size on tea bag decomposition

The tea bag method was developed to provide uniform litter bags that enable comparison of organic matter decomposition rates on a large scale. However, it remains uncertain whether tea bag decomposition in response to wetness is representative of that of natural litters. We performed incubation experiments to examine whether the effect of soil water on tea bag decomposition becomes inhibitory at higher water contents, as was demonstrated in natural leaf litters. In addition, we performed field studies in a mixed forest and cedar plantation in Japan to compare two litter bag mesh sizes: 0.25-mm mesh, the size previously used by a major manufacturer of tea bags (Lipton), and nonwoven bags with mesh sizes finer than 0.25 mm, which are currently produced by Lipton. Both green tea and rooibos tea exhibited higher decomposition rates at higher water contents, but decomposition was inhibited at the highest water content, consistent with conceptual models of natural litters. The nonwoven tea bags did not show lower decomposition rates, despite the finer mesh size. Rather, the nonwoven rooibos tea bags exhibited slightly higher decomposition rates than the 0.25-mm mesh bags in the cedar plantation, possibly due to a greater abundance of microorganisms that decompose litters in the nonwoven bags, due to the decrease in predation by mesofauna. Our findings provide essential information for future studies of tea bag decomposition.
Understanding Volume Kinetics: The Role of Pharmacokinetic Modeling and Analysis in Fluid Therapy

Fluid therapy is a rapidly evolving yet imprecise clinical practice based upon broad assumptions, species-to-species extrapolations, obsolete experimental evidence, and individual preferences. Although widely recognized as a mainstay therapy in human and veterinary medicine, fluid therapy is not always benign and can cause significant harm through fluid overload, which increases patient morbidity and mortality. As with other pharmaceutical substances, fluids exert physiological effects when introduced into the body and therefore should be considered as “drugs. ” In human medicine, an innovative adaptation of pharmacokinetic analysis for intravenous fluids known as volume kinetics using serial hemoglobin dilution and urine output has been developed, refined, and investigated extensively for over two decades. Intravenous fluids can now be studied like pharmaceutical drugs, leading to improved understanding of their distribution, elimination, volume effect, efficacy, and half-life (duration of effect) under various physiologic conditions, making evidence-based approaches to fluid therapy possible. This review article introduces the basic concepts of volume kinetics, its current use in human and animal research, as well as its potential and limitations as a research tool for fluid therapy research in veterinary medicine. With limited evidence to support our current fluid administration practices in veterinary medicine, a greater understanding of volume kinetics and body water physiology in veterinary species would ideally provide some evidence-based support for safer and more effective intravenous fluid prescriptions in veterinary patients.
Intersubject MVPD: Empirical comparison of fMRI denoising methods for connectivity analysis

Noise is a major challenge for the analysis of fMRI data in general and for connectivity analyses in particular. As researchers develop increasingly sophisticated tools to model statistical dependence between the fMRI signal in different brain regions, there is a risk that these models may increasingly capture artifactual relationships between regions, that are the result of noise. Thus, choosing optimal denoising methods is a crucial step to maximize the accuracy and reproducibility of connectivity models. Most comparisons between denoising methods require knowledge of the ground truth: of what is the ‘real signal’. For this reason, they are usually based on simulated fMRI data. However, simulated data may not match the statistical properties of real data, limiting the generalizability of the conclusions. In this article, we propose an approach to evaluate denoising methods using real (non-simulated) fMRI data. First, we introduce an intersubject version of multivariate pattern dependence (iMVPD) that computes the statistical dependence between a brain region in one participant, and another brain region in a different participant. iMVPD has the following advantages: 1) it is multivariate, 2) it trains and tests models on independent folds of the real fMRI data, and 3) it generates predictions that are both between subjects and between regions. Since whole-brain sources of noise are more strongly correlated within subject than between subjects, we can use the difference between standard MVPD and iMVPD as a ‘discrepancy metric’ to evaluate denoising techniques (where more effective techniques should yield smaller differences). As predicted, the difference is the greatest in the absence of denoising methods. Furthermore, a combination of removal of the global signal and CompCorr optimizes denoising (among the set of denoising options tested).
Live Streams on Twitch Help Viewers Cope With Difficult Periods in Life

Live streaming platforms such as Twitch that facilitate participatory online communities have become an integral part of game culture. Users of these platforms are predominantly teenagers and young adults, who increasingly spend time socializing online rather than offline. This shift to online behavior can be a double-edged sword when coping with difficult periods in life such as relationship issues, the death of a loved one, or job loss. On the one hand, platforms such as Twitch offer pleasure, distraction, and relatedness with others to help with coping, and the increased sense of anonymity and control could stimulate self-disclosure. However, the prevalence of trolling and memes may also discourage people from opening up, and relationships that are built online—especially those with microcelebrity streamers—could be perceived as more meaningful than they actually are. To create a deeper understanding of Twitch as a new media platform embedded in game culture, and how users perceive its potential as a coping mechanism, we have conducted a first exploration by means of a survey. The questions focused on general Twitch behavior, the difficult period in life, and the role of Twitch during this period. It was distributed online among people who considered themselves active Twitch users, and who had gone through a difficult period. Eighty-four participants completed the entire survey. The majority of participants indicated that Twitch helped them cope, and that it became a larger part of their lives during the difficult period compared to regular viewing. Recurring themes were the entertainment, distraction, and sense of community Twitch offers. Viewing behavior during difficult periods appears to remain largely the same in terms of the streamers that are watched, although time spent viewing increases, and there is a change toward more time spent actively watching rather than having the stream on in the background. With this work, we aim to create a deeper understanding of Twitch as a platform, and its importance for gamers that are going through difficult periods in life.