Miracle-dz/UniFAR-FTUs huggingface dataset:
Cis-acting variation is common across regulatory layers but is often buffered during embryonic development

Precise patterns of gene expression are driven by interactions between transcription factors, regulatory DNA sequences, and chromatin. How DNA mutations affecting any one of these regulatory “layers” are buffered or propagated to gene expression remains unclear. To address this, we quantified allele-specific changes in chromatin accessibility, histone modifications, and gene expression in F1 embryos generated from eight Drosophila crosses at three embryonic stages, yielding a comprehensive data set of 240 samples spanning multiple regulatory layers. Genetic variation (allelic imbalance) impacts gene expression more frequently than chromatin features, with metabolic and environmental response genes being most often affected. Allelic imbalance in cis-regulatory elements (enhancers) is common and highly heritable, yet its functional impact does not generally propagate to gene expression. When it does, genetic variation impacts RNA levels through two alternative mechanisms involving either H3K4me3 or chromatin accessibility and H3K27ac. Changes in RNA are more predictive of variation in H3K4me3 than vice versa, suggesting a role for H3K4me3 downstream from transcription. The impact of a substantial proportion of genetic variation is consistent across embryonic stages, with 50% of allelic imbalanced features at one stage being also imbalanced at subsequent developmental stages. Crucially, buffering, as well as the magnitude and evolutionary impact of genetic variants, is influenced by regulatory complexity (i.e., number of enhancers regulating a gene), with transcription factors being most robust to cis-acting, but most influenced by trans-acting, variation.
RNA therapeutics for retinal diseases

ABSTRACT Introduction In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered levels reported in diseased states. Areas covered MicroRNA (miRNA), a class of ncRNA, regulates post-transcription gene expression through the binding of complementary sites of target messenger RNA (mRNA) with resulting translational repression. Small-interfering RNA (siRNA) is a double-stranded RNA (dsRNA) that regulates gene expression, leading to selective silencing of genes through a process called RNA interference (RNAi). Another form of RNAi involves short hairpin RNA (shRNA). In age-related macular degeneration (AMD) and diabetic retinopathy (DR), miRNA has been implicated in the regulation of angiogenesis, oxidative stress, immune response, and inflammation. Expert opinion Many RNA-based therapies in development are conveniently administered intravitreally, with the potential for pan-retinal effect. The majority of these RNA therapeutics are synthetic ncRNA’s and hold promise for the treatment of AMD, DR, and inherited retinal diseases (IRDs). These RNA-based therapies include siRNA therapy with its high specificity, shRNA to ‘knock down’ autosomal dominant toxic gain of function-mutated genes, antisense oligonucleotides (ASOs), which can restore splicing defects, and translational read-through inducing drugs (TRIDs) to increase expression of full-length protein from genes with premature stop codons.
The enduring effect of prenatal protein malnutrition on brain anatomy, physiology and behavior

ABSTRACT There is increasing evidence that the maternal environment exerts enduring influences on the fetal brain. In response to certain environmental stimuli such as reduced protein content, the fetus changes the course of its brain development, which leads to specific and programed changes in brain anatomy and physiology. These alterations produce a brain with a fundamentally altered organization, which then translates to alterations in adult cognitive function. The effects on brain and behavior may be linked, such that a prenatal stimulus relays a signal to alter brain development and encourage the selection and development of brain circuits and behaviors that would be beneficial for the environment in which the animal was anticipated to emerge. At the same time, the signal would deselect behaviors unlikely to be adaptive. We draw on evidence from rodent models to suggest that the brain that develops after a reduction in protein during the prenatal phase is not uniformly dysfunctional, but simply different. This perspective has implications for the role of prenatal factors in the production and expression of behavior, and may account for the elevation of risk factors for neurological and psychiatric illnesses.
Protein Sequence Analysis Using the MPI Bioinformatics Toolkit

The MPI Bioinformatics Toolkit (https://toolkit.tuebingen.mpg.de) provides interactive access to a wide range of the best‐performing bioinformatics tools and databases, including the state‐of‐the‐art protein sequence comparison methods HHblits and HHpred. The Toolkit currently includes 35 external and in‐house tools, covering functionalities such as sequence similarity searching, prediction of sequence features, and sequence classification. Due to this breadth of functionality, the tight interconnection of its constituent tools, and its ease of use, the Toolkit has become an important resource for biomedical research and for teaching protein sequence analysis to students in the life sciences. In this article, we provide detailed information on utilizing the three most widely accessed tools within the Toolkit: HHpred for the detection of homologs, HHpred in conjunction with MODELLER for structure prediction and homology modeling, and CLANS for the visualization of relationships in large sequence datasets. © 2020 The Authors.
Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies’ recommended “supportive care only” avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of “what was working and what wasn’t working,” the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.
Coxiella burnetii in the environment: A systematic review and critical appraisal of sampling methods

Q fever is a zoonotic disease caused by the intracellular bacterium, Coxiella burnetii. Its primary mode of transmission is by inhalation of aerosols originating from infected animals and contaminated environments. The organism has a very low infective dose, can persist in the environment for long periods of time and large outbreaks fuelled by windborne spread have been previously reported. Detection of C. burnetii in the environment is therefore important during human and animal outbreak investigations and for the control and prevention of Q fever. This study aimed to systematically review and critically appraise the published literature on sampling methods used to detect C. burnetii from different environmental samples. A search of four electronic databases with subsequent hand searching identified 47 eligible articles published since 1935. These articles described sampling of dust, air, soil and liquids in attempts to detect C. burnetii during 19 Q fever outbreaks and in 28 endemic settings. Environmental positivity was most commonly associated with ruminant livestock populations. Evidence describing spatio‐temporal characteristics and associated geographical dispersion gradients was limited. The most commonly tested sample type was dust which also yielded the highest bacterial loads of >108 bacteria/cloth. The MD8 (Sartorius) air sampler was used widely for air sampling. Soil was the only sample type for which a validated laboratory protocol was established specifically for C. burnetii. Each environmental sample type has its advantages and limitations which are discussed in detail and a simplified framework to guide decisions around environmental sampling for C. burnetii is provided. In any type of environmental sampling, it is recommended to use standardized and validated methods and to match the most ideal sampling strategy and timing with the research context. These conditions are essential to be considered when designing future Q fever management plans that involve environmental sampling for C. burnetii.
Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug‐drug interactions according to CYP2D6 phenotypes

The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O‐desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug‐drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co‐administered with the CYP2D6 inhibitors duloxetine and paroxetine.
Multilayer Connector Hub Mapping Reveals Key Brain Regions Supporting Expressive Language

How components of the distributed brain networks that support cognition participate in typical functioning remains a largely unanswered question. An important subgroup of regions in the larger network are connector hubs, which are areas that are highly connected to several other functionally-specialized sets of regions, and are likely important for sensorimotor integration. The present study attempts to characterize connector hubs involved in typical expressive language functioning using a data-driven, multimodal, full multilayer MEG connectivity-based pipeline. Twelve adolescents, 16-18 years of age (5 male) participated in this study. Participants underwent MEG scanning during a verb generation task. MEG and structural connectivity were calculated at the whole-brain level. Amplitude-amplitude coupling (AAC) was used to compute functional connections both within and between discrete frequency bins. AAC values were then multiplied by a binary structural connectivity matrix, then entered into full multilayer network analysis. Initially, hubs were defined based on multilayer versatility and subsequently re-ranked by a novel measure called delta centrality on interconnectedness (DCI). DCI is defined as the percent change in inter-frequency interconnectedness after removal of a hub. We resolved regions that are important for between-frequency communication among other areas during expressive language, with several potential theoretical and clinical applications that can be generalized to other cognitive domains. Our multilayer, data-driven framework captures nonlinear connections that span across scales that are often missed in conventional analyses. The present study suggests that crucial hubs may be conduits for inter-frequency communication between action and perception systems that are crucial for typical functioning.
The effect of probiotics, parabiotics, synbiotics, fermented foods and other microbial forms on immunoglobulin production: a systematic review and meta-analysis of clinical trials

Abstract The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics, parabiotics, synbiotics, fermented foods and other microbial forms on immunoglobulin production. We searched PubMed, Scopus, Web of Science, National Institute of Health Clinical Trials Register, and Cochrane Central Register of Clinical Trials, up to February 2020. All clinical trials that investigated the effects of oral intake of probiotics, parabiotics, synbiotics, fermented foods and other microbial forms on immunoglobulin (Ig)A, IgE, Japanese cedar pollen (JCP)-specific IgE, IgG, and IgM, for a duration of >7 days were included. Fifty-nine studies met the inclusion criteria, of these 54 studies were included in the analysis. The results indicated a significant increase in salivary IgA secretion rate (SMD = 0.21, 95% CI 0.02–0.39), while no significant effect was observed on other Igs. In conclusion, mentioned supplementation induced a small but significant effect on salivary secretion rate of IgA.
Thermal Behaviour of the Twist Viscosity in a Series of Homologous Nematic Liquid Crystals

Abstract We have measured the twist viscosity Y′(T) by the rotating field method, over the entire nematic range of the 4,4′-di-n-alkoxyazoxybenznes (mOAB) from m = 2 to m = 7. The results of these measurements are presented here together with a new development of our previous theory of γ1(T) which accounts for the free volume variation with temperature and gives the following main result: where S is the order parameter, ϵS is the height of the Maier-Saupe potential, TO is the temperature of motional “freezing” of the nematic director, and g and o are nearly constant parameters which may be either computed from other physical data or extracted from the data discussed here. This the oretical result fits very well to the experimental data over the entire nematic range of all the above mentioned materials.
A non-proteinaceous Fusarium cell wall extract triggers receptor-like protein-dependent immune responses in Arabidopsis and cotton.

Fusarium wilt caused by the ascomycete fungus Fusarium oxysporum is a devastating disease of many economically important crops. The mechanisms underlying plant responses to F. oxysporum infections remain largely unknown. We demonstrate here that a water-soluble, heat-resistant, and non-proteinaceous F. oxysporum cell wall extract (FoCWE) component from multiple F. oxysporum isolates functions as a race-nonspecific elicitor, also termed pathogen-associated molecular pattern (PAMP). FoCWE triggers several demonstrated immune responses, including MAP kinase phosphorylation, ROS burst, ethylene production, and stomatal closure, in cotton and Arabidopsis. Pre-treated FoCWE protects cotton seeds against infections by virulent F. oxysporum f. sp. vasinfectum (Fov), and Arabidopsis plants against the virulent bacterium, Pseudomonas syringae, suggesting the potential application of FoCWEs in crop protection. Host-mediated responses to FoCWE do not appear to require LYKs/CERK1, BAK1, or SOBIR1, that are commonly involved in PAMP perception and/or signalling. However, FoCWE responses and Fusarium resistance in cotton partially require two receptor-like proteins, GhRLP20 and GhRLP31. Transcriptome analysis suggests that FoCWE preferentially activates cell wall-mediated defence, and Fov has evolved virulence mechanisms to suppress FoCWE-induced defence. These findings suggest that FoCWE is a classical PAMP that is potentially recognized by a novel pattern recognition receptor to regulate cotton resistance to Fusarium infections.
Arts Therapies Interventions and Their Outcomes in the Treatment of Eating Disorders: Scoping Review Protocol

Arts therapies (AsTs) are considered a valuable intervention for people with eating disorders, however the range of research studies and the comparison between the types of arts therapies are unknown. The goal of the future scoping review is to explore the therapeutic outcomes addressed by arts therapists in research studies on people with eating disorders and compare the different types of arts-based interventions. This scoping review will be conducted in accordance with the Joanna Briggs Institute methodology. Included will be research studies and sources oriented towards people with eating disorders of all ages and AsTs of any type (art therapy, drama therapy, music therapy, dance/movement therapy, and expressive therapies). There is no language/publication period limitation. The following databases will be searched: CINAHL Plus, EMBASE, MEDLINE (OvidSP), ProQuest Central, PsycINFO, PubMed, Scopus, and Web of Science. Sources of unpublished studies and grey literature will include Google Scholar, MedNar, clinical trials, and current controlled trials. Titles/abstracts and full texts of studies will be assessed against the inclusion criteria, and the data extracted by two independent reviewers. Based on the results, we will compare the types of AsTs according to the research designs, country/settings, intervention methods/materials, adverse effects reported, and therapeutic outcomes related to AsTs.
Development of Quantitative Ion Character–Activity Relationship Models to Address the Lack of Toxicological Data for Technology‐Critical Elements

Recent industrial developments have resulted in an increase in the use of so‐called technology‐critical elements (TCEs), for which the potential impacts on aquatic biota remain to be evaluated. In the present study, quantitative ion character–activity relationships (QICARs) have been developed to relate intrinsic metal properties to their toxicity toward freshwater aquatic organisms. In total, 23 metal properties were tested as predictors of acute median effect concentration (EC50) values for 12 data‐rich metals, for algae, daphnids, and fish (with and without species distinction). Simple and multiple linear regressions were developed using the toxicological data expressed as a function of the total dissolved metal concentrations. The best regressions were then tested by comparing the predicted EC50 values for the TCEs (germanium, indium, gold, and rhenium) and platinum group elements (iridium, platinum, palladium, rhodium, and ruthenium) with the few measured values that are available. The 8 “best” QICAR models (adjusted r2 > 0.6) used the covalent index as the predictor. For a given metal ion, this composite parameter is a measure of the importance of covalent interactions relative to ionic interactions. Toxicity was reasonably well predicted for most of the TCEs, with values falling within the 95% prediction intervals for the regressions of the measured versus predicted EC50 values. Exceptions included Au(I) (all test organisms), Au(III) (algae and fish), Pt(II) (algae, daphnids), Ru(III) (daphnids), and Rh(III) (daphnids, fish). We conclude that QICARs show potential as a screening tool to review toxicity data and flag “outliers,” which might need further scrutiny, and as an interpolating or extrapolating tool to predict TCE toxicity. Environ Toxicol Chem 2021;40:1139–1148. © 2020 SETAC
A thiol‐bound drug reservoir enhances APR‐246‐induced mutant p53 tumor cell death

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR‐246 (PRIMA‐1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR‐246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR‐246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione‐conjugated MQ (GS‐MQ). Due to the reversibility of MQ conjugation, GS‐MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53‐targeted cancer therapy.
Making and shaping endochondral and intramembranous bones

Skeletal elements have a diverse range of shapes and sizes specialized to their various roles including protecting internal organs, locomotion, feeding, hearing, and vocalization. The precise positioning, size, and shape of skeletal elements is therefore critical for their function. During embryonic development, bone forms by endochondral or intramembranous ossification and can arise from the paraxial and lateral plate mesoderm or neural crest. This review describes inductive mechanisms to position and pattern bones within the developing embryo, compares and contrasts the intrinsic vs extrinsic mechanisms of endochondral and intramembranous skeletal development, and details known cellular processes that precisely determine skeletal shape and size. Key cellular mechanisms are employed at distinct stages of ossification, many of which occur in response to mechanical cues (eg, joint formation) or preempting future load‐bearing requirements. Rapid shape changes occur during cellular condensation and template establishment. Specialized cellular behaviors, such as chondrocyte hypertrophy in endochondral bone and secondary cartilage on intramembranous bones, also dramatically change template shape. Once ossification is complete, bone shape undergoes functional adaptation through (re)modeling. We also highlight how alterations in these cellular processes contribute to evolutionary change and how differences in the embryonic origin of bones can influence postnatal bone repair.
OH reaction kinetics of gas-phase α- and γ-hexachlorocyclohexane and hexachlorobenzene

Rate constants for the gas-phase reactions of the hydroxyl radical (OH) with α- and γ-hexachlorocyclohexane (α- and γ-HCH) and hexachlorobenzene (HCB) were measured over the temperature range 346−386 K. The experiments were carried out in He diluent gas at approximately 1 atm, in a 160-mL quartz chamber. OH was produced by the photolysis of ozone in the presence of H2O, and reactants in the chamber were monitored by online mass spectrometry. The rate constants measured at elevated tem peratures were extrapolated by the Arrhenius equation, and OH reaction rate constants at 298 K were estimated for each compound. These rate constants at 298 K (in units of 10-13 cm3 s-1) were α-HCH, 1.4; γ-HCH, 1.9; and HCB, 0.27. Atmospheric lifetimes based on OH reactions (τOH) were also estimated (in units of days): α-HCH, 120; γ-HCH, 96; and HCB, 940. These relatively high atmospheric lifetimes indicate that these compounds can be transported great distances through the atmosphere before removal processes associated wit.