Putative Evidence Research Articles

A phenome-wide approach to identify causal risk factors for deep vein thrombosis

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

PurposePulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia–, and congenital heart disease–associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. MethodsAn international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. ResultsTwelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. ConclusionWe recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Speculative Aesthetic Expressivism

AbstractIn this paper we sketch a new version of aesthetic expressivism. We argue that one advantage of this view is that it explains various putative norms on the formation and revision of aesthetic judgement. We begin by setting out our proposed explananda and a sense in which they can be understood as governing the correct response to putative higher-order evidence in aesthetics. We then summarise some existing discussions of expressivist attempts to explain these norms, and objections raised to them. This will allow us to identify the pitfalls that a good expressivist explanation needs to avoid. Finally, we sketch our preferred version of aesthetic expressivism which includes as a crucial part a hypothesis concerning the distinctive expressive function of aesthetic practice. We then consider how this theory can explain the putative aesthetic norms whilst avoiding the previous objections.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and Tcell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ Tcells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Dorsal hippocampal muscarinic cholinergic receptors orchestrate behavioral and autonomic changes induced by contextual fear retrieval

Re-exposure of rats to a previously fear-conditioned environment arouses great alterations in behavioral and cardiovascular parameters. Pieces of works provide putative evidence for the contribution of the dorsal hippocampus (dHC) to contextual conditioning. dHC gathers massive cholinergic inputs from the basal forebrain, and dHC acetylcholine (ACh) is often described as triggering the retrieval of defensive behavior. ACh acts partially through muscarinic receptors (mAChRs) M1R and M3R subtypes. Hence, activation of mAChRs facilitates autonomic and behavioral responses associated with threats and dangers. Therefore, this study explored the likely involvement of M1R and M3R in rat dHC to establish the behavioral and autonomic changes associated with contextual fear retrieval. Male Wistar rats had stainless steel guide cannula implanted into the dHC before being submitted to contextual fear conditioning (6 footshocks, 1.5 mA, 3 s). A catheter placed within the femoral artery allowed autonomic recordings. A variety of drugs were delivered into the dHC 10 min before contextual re-exposure. The choline reuptake inhibitor hemicholinium induced a decrease of the fear conditioned responses, while did not modify it in non-conditioned animals. The non-selective mAChR antagonist atropine also reduced the fear-conditioned responses, as did the selective M1/M3 mAChRs antagonist fumarate. On the other hand, the M1 selective mAChR antagonist pirenzepine inhibited all the autonomic fear responses without affecting animal freezing. These findings support that cholinergic neurotransmission present in the dHC acts through mAChRs to coordinate the expression of fear evoked by contextual conditioning.

Moraic tone-bearing units in Kabiye

This article provides evidence that the mora, rather than the syllable, is the tone-bearing unit in Kabiye, an Eastern Gurunsi Gur language of Togo. After presenting the phoneme inventory and a brief overview of the tone system, the concept of phonological weight is introduced in order to precisely characterise the mora and the syllable in this language, as well as the relationship between them. Two observations provide evidence in favour of the mora as the tone-bearing unit: first, contour tones are licenced on heavy syllables but not on light ones; second, tonal processes are sensitive to a unit smaller than the syllable, such that the second constituent of a heavy syllable operates with a degree of independence relative to the first. These observations are explored in four phonological domains: association of the LHL tone pattern, association of two-tone patterns, L tone spreading, and vocalic elision. Two post-lexical processes — contour realignment and HLH plateauing — provide putative evidence of the syllable as tone-bearing unit, but even in these cases, a moraic account is ultimately judged to be preferable.

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity.

SummaryBackgroundRecent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries.MethodsIn this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions.FindingsMR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10−4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10−4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications.InterpretationOur study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets.FundingNo.

The distribution of covert microbial natural enemies of a globally invasive crop pest, fall armyworm, in Africa: Enemy release and spillover events.

Invasive species pose a significant threat to biodiversity and agriculture world‐wide. Natural enemies play an important part in controlling pest populations, yet we understand very little about the presence and prevalence of natural enemies during the early invasion stages.Microbial natural enemies of fall armyworm Spodoptera frugiperda are known in its native region, however, they have not yet been identified in Africa where fall armyworm has been an invasive crop pest since 2016. Larval samples were screened from Malawi, Rwanda, Kenya, Zambia, Sudan and Ghana for the presence of four different microbial natural enemies; two nucleopolyhedroviruses, Spodoptera frugiperda NPV (SfMNPV) and Spodoptera exempta NPV (SpexNPV); the fungal pathogen Metarhizium rileyi; and the bacterium Wolbachia. This study aimed to identify which microbial pathogens are present in invasive fall armyworm, and determine the geographical, meteorological and temporal variables that influence prevalence.Within 3 years of arrival, fall armyworm was exposed to all four microbial natural enemies. SfMNPV probably arrived with fall armyworm from the Americas, but this is the first putative evidence of host spillover from Spodoptera exempta (African armyworm) to fall armyworm for the endemic pathogen SpexNPV and for Wolbachia. It is also the first confirmed incidence of M. rileyi infecting fall armyworm in Africa.Natural enemies were localised, with variation being observed both nationally and temporally. The prevalence of SfMNPV (the most common natural enemy) was predominantly explained by variables associated with the weather; declining with increasing rainfall and increasing with temperature. However, virus prevalence also increased as the growing season progressed.The infection of an invasive species with a natural enemy from its native range and novel pathogens specific to its new range has important consequences for understanding the population ecology of invasive species and insect–pathogen interactions. Additionally, while it is widely known that temporal and geographic factors affect insect populations, this study reveals that these are important in understanding the distribution of microbial natural enemies associated with invasive pests during the early stages of invasion, and provide baseline data for future studies.

17. Multi-consortia initiative to standardize the representation and curation of oncogenic fusions

Despite the well-established role of gene fusions in oncogenic processes, current practices for characterizing and annotating gene fusion events in the clinical setting and in biomedical literature are inconsistent. Consequently, evidence-based interpretation of functional and clinical significance of fusion variants requires laborious and time-consuming gathering and review of putative evidence. A lack of community standards inhibits the uniform communication of fusion events as well as the interoperability of tools, resources, and pipelines, ultimately impeding data sharing and downstream utility.

Experimental evolution reveals sex-specific dominance for surviving bacterial infection in laboratory populations of Drosophila melanogaster.

Males and females are subjected to distinct kinds of selection pressures, often leading to the evolution of sex‐specific genetic architecture, an example being sex‐specific dominance. Sex‐specific dominance reversals (SSDRs), where alleles at sexually antagonistic loci are at least partially dominant in the sex they benefit, have been documented in Atlantic salmon, rainbow trout, and seed beetles. Another interesting feature of many sexually reproducing organisms is the asymmetric inheritance pattern of X chromosomes, which often leads to distinct evolutionary outcomes on X chromosomes compared to autosomes. Examples include the higher efficacy of sexually concordant selection on X chromosomes, and X chromosomes being more conducive to the maintenance of sexually antagonistic polymorphisms under certain conditions. Immunocompetence is a trait that has been extensively investigated for sexual dimorphism with growing evidence for sex‐specific or sexually antagonistic variation. X chromosomes have been shown to harbor substantial immunity‐related genetic variation in the fruit fly, Drosophila melanogaster. Here, using interpopulation crosses and cytogenetic cloning, we investigated sex‐specific dominance and the role of the X chromosome in improved postinfection survivorship of laboratory populations of D. melanogaster selected against pathogenic challenge by Pseudomonas entomophila. We could not detect any contribution of the X chromosome to the evolved immunocompetence of our selected populations, as well as to within‐population variation in immunocompetence. However, we found strong evidence of sex‐specific dominance related to surviving bacterial infection. Our results indicate that alleles that confer a survival advantage to the selected populations are, on average, partially dominant in females but partially recessive in males. This could also imply an SSDR for overall fitness, given the putative evidence for sexually antagonistic selection affecting immunocompetence in Drosophila melanogaster. We also highlight sex‐specific dominance as a potential mechanism of sex differences in immunocompetence, with population‐level sex differences primarily driven by sex differences in heterozygotes.

Seeking Prehistoric Fermented Food in Japan and Korea

As in many other parts of the world, fermentation forms the basis of both Japanese and Korean cuisine, represented by well-known fermented foods such as shoyu, miso, and kimchi. Despite its nutritional, economic, and cultural importance as well as popularity today, very little is known about the origins or development of fermentation, especially in prehistory. Based on the ingredients and cooking methods reconstructed from archaeological records from this area, and on the ethnography more broadly, this paper reviews the putative evidence of fermented foods in East Asian prehistory and considers how biomolecular and archaeological investigations could be better integrated for the robust identification of this practice in the past.

Sperm Accumulation Induced by the Female Reproductive Fluid: Putative Evidence of Chemoattraction Using a New Tool.

There is considerable evidence that female reproductive fluid (FRF) interacts intimately with sperm, affecting several sperm traits, including sperm motility and longevity, and ultimately fertilization success. One of the first documented interactions between FRF and sperm is the ability of FRF to attract and guide sperm towards the eggs. However, most of the evidence of FRF’s chemoattraction proprieties comes from a limited number of taxa, specifically mammals and invertebrate broadcasting spawners. In other species, small FRF volumes and/or short sperm longevity often impose methodological difficulties resulting in this gap in chemoattraction studies in non-model species. One of the outcomes of sperm chemotaxis is sperm accumulation towards high chemoattractant concentrations, which can be easily quantified by measuring sperm concentration. Here, we tested sperm accumulation towards FRF in the zebrafish, Danio rerio, using an ad hoc developed, 3D printed, device (‘sperm selection chamber’). This easy-to-use tool allows to select and collect the sperm that swim towards a chemical gradient, and accumulate in a chemoattractant-filled well thus providing putative evidence for chemoattraction. We found that sperm accumulate in FRF in zebrafish. We also found that none of the sperm quality traits we measured (sperm swimming velocity and trajectory, sperm motility, and longevity) were correlated with this response. Together with the 3D printable project, we provide a detailed protocol for using the selection chamber. The chamber is optimized for the zebrafish, but it can be easily adapted for other species. Our device lays the foundation for a standardized way to measure sperm accumulation and in general chemoattraction, stimulating future research aimed at understanding the role and the mechanisms of sperm chemoattraction by FRF.

Abstract 449: A standard operating procedure for the curation of gene fusions

Abstract Despite the well-established role of recurrent gene fusions as oncogenic drivers, current practices for characterizing and interpreting gene fusion events in clinical testing and in biomedical literature are inconsistent. From the conceptual definition of gene fusions to the salient elements that characterize these alterations, a lack of community-driven standards for the curation of gene fusions has resulted in a disparate landscape of fusion representations and supporting tools. Consequently, the evidence-based clinical evaluation of gene fusions requires extensive expert review for accurate interpretation of observed gene fusions with respect to putative evidence from biomedical literature. Furthermore, the lack of these standards inhibits the interoperability of tools, resources, and pipelines - impeding data sharing and downstream utility.To address these challenges, a cross-consortia initiative between the Variant Interpretation for Cancer Consortium and ClinGen was formed to develop a standard operating procedure (SOP) for the curation of gene fusions. The SOP is under development by an international and diverse set of experts in the representation, detection, and clinical interpretation of gene fusions. Participating stakeholders across academic, government, and industry sectors showcased challenges and solutions, and participated in community surveys and discussions to define and develop the SOP for this diverse class of alterations.An initial result of this effort was the precise molecular definition of genomic events and features constituting gene fusions. We distinguish these from similar but distinct classes of structural alterations through clinically-relevant examples. Next, we discuss our findings on community practices around the description and evaluation of gene fusions. We provide our recommendations for characterization and representation of gene fusions from these practices, and compare these recommendations to existing variant representation standards and formats (e.g. HGVS variant nomenclature). We also discuss the concurrent application of formats for standardized human- and machine-readable representations of gene fusion events.We conclude with discussion of the salient elements to enable rapid, scalable, and consistent evaluation of fusions curated from the biomedical literature. Recommendations are provided for the standardized capture of these elements to enable both intuitive and precise characterization of this diverse class of alterations in clinical reporting and literature. In summary, we provide a clinical-practice driven framework and nomenclature for gene fusions, including recommendations for human readability, computational precision, and data integrity within the SOP. This work is a substantial advancement towards standardized communication, investigation, and sharing of gene fusion data across clinical and research domains and specialties. Citation Format: Alex H. Wagner, Ioannis S. Vlachos, Dmitriy Sonkin, Panieh Terraf, Chimene Kesserwan, Andrea Sboner, Thomas Coard, Christian Reich, Deborah I. Ritter, Peter Horak, Ying S. Zou, Anna Tanska, Aaron M. Berlin, Anna Lu, Daniel Cameron, Heather E. Williams, Wan-Hsin Lin, Gokce Toruner, Arpad Danos, Jason Saliba, Huiling Xu, Xinjie Xu, Georgina Ryland, Michele Ceccarelli, Liying Zhang, Sarah Rapisardo, Catherine Rehder, Xuelu Liu, Aparna Pallavajjala, Nicole Park, Laveniya Satgunaseelan, Kristy Lee, Jie Liu, Obi Griffith, Robert R. Freimuth, Albrecht Stenzinger, Linda B. Baughn, Michael Baudis, Jennifer Lee, Marilyn Li, Angshumoy Roy, Gordana Raca. A standard operating procedure for the curation of gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 449.

Multiple quantum phase transitions of different nature in the topological kagome magnet Co3Sn2\u2212xInxS2

The exploration of topological electronic phases that result from strong electronic correlations is a frontier in condensed matter physics. One class of systems that is currently emerging as a platform for such studies are so-called kagome magnets based on transition metals. Using muon spin-rotation, we explore magnetic correlations in the kagome magnet Co3Sn2−xInxS2 as a function of In-doping, providing putative evidence for an intriguing incommensurate helimagnetic (HM) state. Our results show that, while the undoped sample exhibits an out-of-plane ferromagnetic (FM) ground state, at 5% of In-doping the system enters a state in which FM and in-plane antiferromagnetic (AFM) phases coexist. At higher doping, a HM state emerges and becomes dominant at the critical doping level of only xcr,1 ≃ 0.3. This indicates a zero temperature first order quantum phase transition from the FM, through a mixed state, to a helical phase at xcr,1. In addition, at xcr,2 ≃ 1, a zero temperature second order phase transition from helical to paramagnetic phase is observed, evidencing a HM quantum critical point (QCP) in the phase diagram of the topological magnet Co3Sn2−xInxS2. The observed diversity of interactions in the magnetic kagome lattice drives non-monotonous variations of the topological Hall response of this system.

The case against economic values in the orbitofrontal cortex (or anywhere else in the brain).

Much of traditional neuroeconomics proceeds from the hypothesis that value is reified in the brain, that is, that there are neurons or brain regions whose responses serve the discrete purpose of encoding value. This hypothesis is supported by the finding that the activity of many neurons covaries with subjective value as estimated in specific tasks, and has led to the idea that the primary function of the orbitofrontal cortex is to compute and signal economic value. Here we consider an alternative: That economic value, in the cardinal, common-currency sense, is not represented in the brain and used for choice by default. This idea is motivated by consideration of the economic concept of value, which places important epistemic constraints on our ability to identify its neural basis. It is also motivated by the behavioral economics literature, especially work on heuristics, which proposes value-free process models for much if not all of choice. Finally, it is buoyed by recent neural and behavioral findings regarding how animals and humans learn to choose between options. In light of our hypothesis, we critically reevaluate putative neural evidence for the representation of value and explore an alternative: direct learning of action policies. We delineate how this alternative can provide a robust account of behavior that concords with existing empirical data. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Leaders on a Mindfulness-Based Program: Experience, Impact, and Effect on Leadership Role

Although there is putative evidence that mindfulness-based programs (MBPs) may contribute to leadership skills, little is known about the direct experience of leaders who attend such programs. It is therefore unknown how MBPs delivered in the corporate environment are experienced by leaders, or how MBPs may facilitate leadership development. This qualitative study explored how leaders experienced an MBP, introduced as a part of a wider leadership development program, and the impact of this intervention on their work lives and leadership role. Participants (N = 10) were leaders who worked for a global manufacturing organization and who had attended a three-day mindfulness-based program as part of a leadership development program. They were interviewed and the data was analysed using thematic analysis. Following the MBP, eight participants reported enhanced emotional awareness, and a greater understanding of the impact of work-related stress, which in turn helped their leadership role. Two did not see how mindfulness could enhance their leadership skills although the MBP was well received by most of the participants. Three superordinate themes were identified: (1) The participant journey: Mixed experiences of the MBP; (2) A clash of cultures: The challenge of integrating mindfulness into the workplace, and (3) Impact on leadership. These results may inform future research, program design, and implementation.

Anemia in primary hyperparathyroidism

Introduction. Anaemia is a complication of primary hyperparathyroidism (PHPT). Pathogenesis of PHPT-induced anaemia involves inhibited erythroid cell proliferation associated with the underlying disease and non-specific factors (blood loss, chronic kidney disease). However, its specific mechanisms remain unclear.Aim. Clinical description of a PHPT case with multifactorial complicating anaemia.Main findings. With putative evidence existing on relationships between PHPT and anaemia, no large clinical trials substantiated suitable algorithms for such patients’ management. The genesis of anaemia reported in this case was multifactorial and not decisively excluding PHPT from putative causes.

MicroRNAs Bioinformatics Analyses Identifying HDAC Pathway as a Putative Target for Existing Anti-COVID-19 Therapeutics.

Over 313,000 SARS-CoV-2 positive cases have been confirmed in Italy as of 30 September 2020, and the number of deaths exceeding thirty-five thousand makes Italy among the list of most significantly affected countries in the world. Such an enormous occurrence of infections and death raises the urgent demand for effective available treatments. Discovering the cellular/molecular mechanisms of SARS-CoV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and how to plan any therapeutic approach. In this regard, we performed an in silico analysis to predict the putative virus targets and evidence the already available therapeutics. Literature experimental results identified angiotensin-converting enzyme ACE and Spike proteins particularly involved in COVID-19. Consequently, we investigated the signalling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets, and functions. Our bioinformatics analysis predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with histone deacetylate (HDAC) pathway. Notably, our results identified ACE/ACE2-ATR1-Cholesterol-HDAC axis signals that also matched with some available clinical data. We hypothesize that the current and EMA-approved, SARS-CoV-2 off-label HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. Moreover, a ranked list of compounds is provided for further evaluation for safety, efficacy, and effectiveness.

What do leave-one-person-out pattern analyses really tell us about the neural representation of visual object symmetries?

A key challenge in human neuroscience is to gain information about neural population codes using indirect measures of neural activity. Recently, a multivariate pattern analysis method termed Leave-One-Person-Out (LOPO) has been used to support inferences regarding neural coding. Two key caveats, however, have been overlooked by users of this method: (1) its sensitivity to low-level feature imbalances across conditions (e.g. image contrast, luminance, and their variability over instances of each stimulus class), and (2) implausibility of the methods’ assumption that spatial normalization meaningfully aligns neural patterns of activation across subjects. Here, we show with simulations instantiating multilayered randomly connected feedforward networks that LOPO leads to erroneous conclusions when the methods’ assumptions are not met. In particular, low-level properties of the images chosen by an experimenter are shown to largely determine the observed pattern of results, and not the covariance structure of the underlying spatial patterns of activation. We further show how deceptively complex representational structures emerge due to specifics of the LOPO analysis scheme. Interestingly, simulations initially intended to study the general behavior of LOPO led to concrete predictions regarding the relative norms, means and variances of images from an image database recently used in multiple recent neuroimaging studies. Low-level feature imbalances of the precise form predicted by our model were confirmed by ensuig direct analyses of these images. We argue that under plausible assumptions regarding the fMRI measurement process, the observed confounds may account for recent putative evidence of mirror-symmetric tuning of neural populations in a human face-selective area. In sum, we conclude that (1) LOPO is particularly sensitive to low-level image feature imbalances across conditions, and (2) the method’s sound interpretation hinges on implausible assumptions. Our observations cast doubts on the validity of LOPO analyses to support inferences that require the detection of spatially structured brain patterns.