Miracle-dz/UniFAR-FTUs huggingface dataset:
Inferring disease architecture and predictive ability with LDpred2-auto

LDpred2 is a widely used Bayesian method for building polygenic scores (PGS). LDpred2-auto can infer the two parameters from the LDpred model, the SNP heritability h2 and polygenicity p, so that it does not require an additional validation dataset to choose best-performing parameters. The main aim of this paper is to properly validate the use of LDpred2-auto for inferring multiple genetic parameters. Here, we present a new version of LDpred2-auto that adds an optional third parameter α to its model, for modeling negative selection. We then validate the inference of these three parameters (or two, when using the previous model). We also show that LDpred2-auto provides per-variant probabilities of being causal that are well calibrated, and can therefore be used for fine-mapping purposes. We also derive a new formula to infer the out-of-sample predictive performance r2 of the resulting PGS directly from the Gibbs sampler of LDpred2-auto. Finally, we extend the set of HapMap3 variants recommended to use with LDpred2 with 37% more variants to improve the coverage of this set, and show that this new set of variants captures 12% more heritability and provides 6% more predictive performance, on average, in UK Biobank analyses.
DNA looping mediates cooperative transcription activation

Here, the authors solve sequential structures of binding by the transcription activators NtcA and NtcB, showing that they cooperatively induce looping back of the promoter DNA towards RNA polymerase allowing transcription activation through a DNA looping mechanism. Transcription factors respond to multilevel stimuli and co-occupy promoter regions of target genes to activate RNA polymerase (RNAP) in a cooperative manner. To decipher the molecular mechanism, here we report two cryo-electron microscopy structures of Anabaena transcription activation complexes (TACs): NtcA-TAC composed of RNAP holoenzyme, promoter and a global activator NtcA, and NtcA–NtcB-TAC comprising an extra context-specific regulator, NtcB. Structural analysis showed that NtcA binding makes the promoter DNA bend by ∼50°, which facilitates RNAP to contact NtcB at the distal upstream NtcB box. The sequential binding of NtcA and NtcB induces looping back of promoter DNA towards RNAP, enabling the assembly of a fully activated TAC bound with two activators. Together with biochemical assays, we propose a ‘DNA looping’ mechanism of cooperative transcription activation in bacteria.
Remodeling of yeast vacuole membrane lipidomes from the log (1-phase) to stationary stage (2-phases)

Upon nutrient limitation, budding yeast of Saccharomyces cerevisiae shift from fast growth (the log stage) to quiescence (the stationary stage). This shift is accompanied by liquid-liquid phase separation in the membrane of the vacuole, an endosomal organelle. Recent work indicates that the resulting micron-scale domains in vacuole membranes enable yeast to survive periods of stress. An outstanding question is which molecular changes might cause this membrane phase separation. Here, we conduct lipidomics of vacuole membranes in both the log and stationary stages. Isolation of pure vacuole membranes is challenging in the stationary stage, when lipid droplets are in close contact with vacuoles. Immuno-isolation has previously been shown to successfully purify log-stage vacuole membranes with high organelle specificity, but it was not previously possible to immuno-isolate stationary stage vacuole membranes. Here, we develop Mam3 as a bait protein for vacuole immuno-isolation, and demonstrate low contamination by non-vacuolar membranes. We find that stationary stage vacuole membranes contain surprisingly high fractions of phosphatidylcholine lipids (∼50%), roughly twice as much as log-stage membranes. Moreover, in the stationary stage these lipids have higher melting temperatures, due to longer and more saturated acyl chains. Another surprise is that no significant change in sterol content is observed. These results fit within the predominant view that phase separation in membranes requires at least three types of molecules to be present: lipids with high melting temperatures, lipids with low melting temperatures, and sterols. SIGNIFICANCE STATEMENT When budding yeast shift from growth to quiescence, the membrane of one of their organelles (the vacuole) undergoes liquid-liquid phase separation. What changes in the membrane’s lipids cause this phase transition? Here, we conduct lipidomics of immuno-isolated vacuole membranes. We analyze our data in the context of lipid melting temperatures, inspired by observations that liquid-liquid phase separation in model membranes requires a mixture of lipids with high melting temperatures, lipids with low melting temperatures, and sterols. We find that phase-separated vacuole membranes have higher concentrations of PC lipids, and that those lipids have higher melting temperatures. To conduct our experiments, we developed a tagged version of a protein (Mam3) for immuno-isolation of vacuole membranes.
Novel genetic traits in Xanthomonas unveiled by the complete genome sequencing of three clade-1 xanthomonads

Evolutionary early-branching xanthomonads, also referred to as clade-1 xanthomonads, include major plant pathogens, most of which colonize monocotyledonous plants. Seven species have been validly described, among them the two sugarcane pathogens Xanthomonas albilineans and Xanthomonas sacchari, and Xanthomonas translucens, which infects small grain cereals, diverse grasses, but also asparagus and pistachio trees. Single-gene sequencing and genomic approaches indicated that this clade likely contains more, yet undescribed species. In this study, we sequenced representative strains of three novel species using long-read sequencing technology. Xanthomonas sp. pv. phormiicola strain CFBP 8444 causes bacterial streak on New Zealand flax, another monocotyledonous plant. Xanthomonas sp. strain CFBP 8443 has been isolated from common bean and Xanthomonas sp. strain CFBP 8445 originated from banana. Complete assemblies of the chromosomes confirmed their unique taxonomic position within clade 1 of Xanthomonas. Genome mining revealed novel genetic traits, hitherto undescribed in other members of the Xanthomonas genus. In strain CFBP 8444, we identified genes related to the synthesis of coronatine-like compounds, a phytotoxin produced by several pseudomonads, which raises interesting questions about the evolution and pathogenicity of this pathogen. In addition, strain CFBP 8444 was found to encode a second, atypical flagellar gene cluster in addition to the canonical flagellar gene cluster. Overall, this research represents an important step toward better understanding the evolutionary history and biology of early-branching xanthomonads.
PRAMEL7/CUL2 axis regulates NuRD stability to establish ground-state pluripotency in embryonic stem cells

Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, they only partially resemble the gene expression signature of developmental ground-state. Induced PRAMEL7 expression, a protein highly expressed in the ICM but lowly expressed in ESCs, reprograms developmentally advanced ESC+serum into ground-state pluripotency by causing DNA hypomethylation and gene expression signature close to developmental ground-state. However, how PRAMEL7 reprograms gene expression remains elusive. Here we show that PRAMEL7 associates with Cullin2 (CUL2) and this interaction is required to establish ground-state gene expression. PRAMEL7 recruits CUL2 to chromatin and targets for proteasomal degradation regulators of repressive chromatin, including NuRD complex. PRAMEL7 antagonizes NuRD-mediated repression of genes implicated in pluripotency by decreasing NuRD stability and promoter association in a CUL2-dependent manner. Our data link proteasome degradation pathways to ground-state gene expression, offering insights to generate in vitro models to reproduce the in vivo ground-state pluripotency.
Controlling neocortical epileptic seizures using forced temporal spike-time stimulation: an in silico computational study

Epileptic seizure is typically characterized by highly synchronized episodes of neural activity. Existing stimulation therapies focus purely on suppressing the pathologically synchronized neuronal firing patterns during the ictal (seizure) period. While these strategies are effective in suppressing seizures when they occur, they fail to prevent the re-emergence of seizures once the stimulation is turned off. Previously, we developed a novel neurostimulation motif, which we refer to as “Forced Temporal Spike-Time Stimulation” (FTSTS) [1] that has shown remarkable promise in long-lasting desynchronization of excessively synchronized neuronal firing patterns by harnessing synaptic plasticity. In this paper, we build upon this prior work [1] by optimizing the parameters of the FTSTS protocol in order to efficiently desynchronize the pathologically synchronous neuronal firing patterns that occur during epileptic seizures using a recently published computational model of neocortical-onset seizures [2]. We show that the FTSTS protocol applied during the ictal period can modify the excitatory-to-inhibitory synaptic weight in order to effectively desynchronize the pathological neuronal firing patterns even after the ictal period. Our investigation opens the door to a possible new neurostimulation therapy for epilepsy.
Recovering part of the boundary between quantum and nonquantum correlations from information causality

Recently, the principle of information causality has appeared as a good candidate for an information-theoretic principle that would single out quantum correlations among more general nonsignaling models. Here, we present results going in this direction, namely, we show that part of the boundary of quantum correlations actually emerges from information causality.
Spherical explosion with a central energy source

We present a novel semi-analytic solution describing the propagation of a spherical blast wave driven by a central energy source. The initial density profile has a power-law function of the distance from the center and the energy is injected only into the central region at a rate given by a power-law function of time. This solution is composed of three regions separated by the contact surface and the shock front. The innermost region is assumed to be uniform and the outside of the contact surface includes the shocked matter described by self-similar solutions. We analytically derive the applicable range of parameters of this solution from requirements to satisfy boundary conditions. We perform numerical simulations for flows with various values of parameters, some of which reside out of the thus derived applicable range, and compare with the semi-analytic solutions.
The investigation on metabolites, genes and open chromatins involved in colored leaves of Eucommia ulmoides ‘Ziye’

Eucommia ulmoides Oliver ‘Ziye’ has unique purple-red leaves, which contain a variety of flavonoids, so it has high ornamental and medicinal value. However, the categories of flavonoids and molecular mechanism of specific accumulation of flavonoids in ‘Ziye’ leaves is still unclear. Here, differences in metabolic level, gene expression level, chromatin accessibility and cis-regulatory elements were compared between ‘Ziye’ and ‘Huazhong 1’ with green leaf color by metabolome profiling, RNA-seq, and ATAC-seq. A total of 205 flavonoids were identified from these two varieties using ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). The accumulation of most delphinidin, cyaniding, quercetin, myricetin, and isorhamnetin derivatives peaked in old leaves of ‘Ziye’. Single-molecule long-read sequencing indicated that genes in the phenylpropanoid biosynthesis and flavonoid biosynthetic pathway, as well as many transcription factors including MYB, ERF, and WRKY were highly expressed in ‘Ziye’ leaves. ATAC-seq revealed the presence of cell preferentially enriched peaks, which annotated to 6114 genes. Analysis of the genomic regions preferentially accessible in each cell type identified hundreds of overrepresented TF-binding motifs, highlighting sets of TFs such as MYB, ERF, and WRKY that are probably important for color formation of ‘Ziye’ cell. Interestingly, the TFs within each of these cell type-enriched sets also showed evidence of extensively co-regulating each other. Our work demonstrated how chromatin accessibility and TF expression level influenced the expression of flavonoid biosynthesis associated genes, resulted in flavonoids accumulation in ‘Ziye’ leaf. Our results could lay a foundation for further studies of gene expression and functional genomics in E. ulmoides.
Quantifying orthogonal barcodes for sequence census assays

Barcode-based sequence census assays utilize custom or random oligonucloetide sequences to label various biological features, such as cell-surface proteins or CRISPR perturbations. These assays all rely on barcode quantification, a task that is complicated by barcode design and technical noise. We introduce a modular approach to quantifying barcodes that achieves speed and memory improvements over existing tools. We also introduce a set of quality control metrics, and accompanying tool, for validating barcode designs.
A TMT-based quantitative proteomics approach toward α-syn PFF associated Lewy Body Dementia (LBD) using α-syn PFF-injected mouse brain tissues

The aggregation of α-synuclein in the nervous system leads to a class of neurodegenerative disorders termed α-synucleinopathies. A form of primary degenerative dementia called Lewy body dementia (LBD) often develops in the case these aggregations develop into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). Despite the high frequency of LBD, being the leading cause of dementia following Alzheimer’s disease (AD), there is relatively little information discovered about its pathological pathway or diagnostic criteria. In this report, we attempt to address such shortcomings via utilizing a proteomic approach to identify the proteomic changes following intrastriatal injection of α-synuclein preformed fibril (α-syn PFF). Through mass spectrometry, we have identified a total of 179 proteins that were either up- or down-regulated at different time points, with the four proteins – TPP3, RAB10, CAMK2A, and DYNLL1 – displaying the most significant changes throughout the timeframe. Further examining the modulated proteins with network-based enrichment analyses, we have found that 1) the most significantly associated neurodegenerative pathways were Parkinson’s (pV = 3.0e-16) and Huntington’s (pV = 1.9e-15) disease, and 2) the majority of molecular functions specific to the pathology only appeared at later time points. While these results do not expose a conclusive biomarker for LBD, they suggest a potential framework that may be utilized to diagnose and differentiate LBD pathology from other forms of dementia by focusing on the cortical proteomic changes which occur in a later time span.
Morphometrics, Distribution, and DNA Barcoding: An Integrative Identiﬁcation Approach to the Genus Odontotermes (Termitidae: Blattodea) of Khyber Pakhtunkhwa, Pakistan

Simple Summary: Termites are social insects that invade plantations, agricultural crops, and man-made structures throughout the world. The districts Buner, Haripur, and Swabi belong to different agro-ecological zones and a neglected area of Khyber Pakhtunkhwa (Pakistan: Oriental region) for work on the distribution and identity of termites. Termites were collected and identiﬁed morphologically and with DNA barcoding of the COII region. Odontotermes assmuthi , Odontotermes obesus , Odontotermes parvidens , and Odontotermes horai were identiﬁed, and a key to the genus Odontotermes of the area was made along with a distribution map. The identiﬁed species were found feeding on different forage substrates. Four novel COII sequences were submitted to GenBank. Abstract: The neglected area of Khyber Pakhtunkhwa (Pakistan: Oriental region), consisting of Buner, Haripur, and Swabi districts, were surveyed for termites during the summer of 2016–2019 for identiﬁcation and assessment of the distribution of colonies. Collections were made either directly from visible galleries or using traps with ethanol. Soldiers were used for morphometric identiﬁcation and DNA extraction. Morphometric identiﬁcation was carried out based on the available literature through measurements of 20 characters/indices and evaluating species differences statistically. Based on these characteristics, we generated a key and a distribution map of the genus Odontotermes for the study area. This is the ﬁrst record of Odontotermes assmuthi and Odontotermes obesus in these three districts, the ﬁrst record of Odontotermes parvidens for the Buner and Swabi districts, and the ﬁrst record of Odontotermes horai for Haripur. We subsequently used barcoding of the mtDNA COII to verify species assignments of colonies and for phylogenetic analyses using Neighbor-Joining and Maximum Likelihood analyses.
On not Recognizing Dis(cid:13)uencies in Dialogue

This paper tests the hypothesis that listeners miss dis(cid:13)uen-cies or fail to transcribe them accurately because dis(cid:13)uen-cies interfere with the normal relationship between speech sound and linguistic context in human spoken word recognition. In a word-level gating experiment 16 listeners heard a total of 56 dis(cid:13)uent utterances selected from a corpus of spontaneous speech, 56 length-matched (cid:13)uent controls, and 56 (cid:13)uent foils. The proportion of words never recognized was greater in dis(cid:13)uent utterances than in controls. The failures clustered around the point where the dis(cid:13)uency interrupted the utterance, ocurring particularly within the reparanda, but were not found at corresponding locations in uninterrupted controls. Repetition dis(cid:13)uencies, where pre-and post-interruption portions might easily be construed to-gether, allowed more successful word recognitions than recast dis(cid:13)uencies, where reconstruction of a single intended utterance would be di(cid:14)cult, if not impossible. The results have implications both for understanding human speech recognition and for improving the robustness of ASR systems.
Predictive performance of some nonparametric linear and nonl-inear smoothers for noisy data

The purpose of this study is to discuss the weighting systems of several linear and non linear smoothers and to evaluate their predictive performances when applied to noisy time series. On this regard, we illustrate with three Canadian leading indicators which are representative of larger sets of time series characterised by a low, medium and high signal to noise ratio. The smoothers discussed are: (a) loess (a locally weighted regression smoother), (b) Gaussian Kernel smoother, (c) supersmoother, (d) cubic smoothing spline and (e) Dagum’s modified 13-term Henderson filter. Their performances are evaluated on the basis of three following main criteria for current economic analysis: (1) number of unwanted ripples or false turning points in the final estimated trend, (2) time lag in detecting ‘true’ turning points and (3) size of total revision of the concurrent trend estimates.
Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome

Hantaan virus is the causative agent of hemorrhagic fever with renal syndrome (HFRS). The Hantaan virus strain, Korean hemorrhagic fever virus clone-5 (KHF5), causes weight loss and renal hemorrhage in laboratory mice. Clone-4 (KHF4), which has a single E417K amino acid change in its glycoprotein, is an avirulent variant. In this study, KHF4 and KHF5 were compared to evaluate pathological differences in mice in vitro and in vivo. The characteristics of the two glycoproteins were not significantly different in vitro. However, the virulent KHF5 strain targeted the lungs and caused pneumonia and edema in vivo. Both strains induced high infectivity levels in the liver and caused hepatitis; however, petechial hemorrhage and glycogen storage reduction were observed in KHF5-infected mice alone. Renal hemorrhage was observed using viral antigens in the tubular region of KHF5-infected mice. In addition, an increase in white blood cell levels and neutrophilia were found in KHF5-infected mice. Microarray analysis of liver cells showed that CD8+ T cell activation, acute-phase protein production, and neutrophil activation was induced by KHF5 infection. KHF5 infectivity was significantly increased in vivo and the histological and clinicopathological findings were similar to those in patients with HFRS.
Layer-by-Layer Formation of Oligoelectrolyte Multilayers: A Combined Experimental and Computational Study

For the first time, the combination of experimental preparation and results of fully atomistic simulations of an oligoelectrolyte multilayer (OEM) made of poly(diallyl dimethyl ammonium chloride)/poly(styrene sulfonate sodium salt) (PDADMAC/PSS) is presented. The layer-by-layer growth was carried out by dipping silica substrates in oligoelectrolyte solutions and was modeled by means of atomistic molecular dynamics simulations with a protocol that mimics the experimental procedure up to the assembly of four layers. Measurements of OEM thickness, surface roughness and amount of adsorbed oligoelectrolyte chains obtained from both approaches are compared. A good agreement between simulated and experimental results was found, with some deviations due to intrinsic limitations of both methods. However, the combination of information extracted from simulations to support the analysis of experimental data can overcome such restrictions and improve the interpretation of experimental results. On the other hand, processes dominated by slower kinetics, such as the destabilization of adsorbed layers upon equilibration with the surrounding environment, are out of reach for the simulation modeling approach, but they can be investigated by monitoring in situ the oligoelectrolyte adsorption during the assembly process. This demonstrates how the synergistic use of simulation and experiments improves the knowledge of OEM properties down to the molecular scale.
Simple modeling of self-oscillations in nanoelectromechanical systems

We present here a simple analytical model for self-oscillations in nanoelectromechanical systems. We show that a field emission self-oscillator can be described by a lumped electrical circuit and that this approach is generalizable to other electromechanical oscillator devices. The analytical model is supported by dynamical simulations where the electrostatic parameters are obtained by finite element computations.
Weak lensing of large scale structure in the presence of screening

A number of alternatives to general relativity exhibit gravitational screening in the non-linear regime of structure formation. We describe a set of algorithms that can produce weak lensing maps of large scale structure in such theories and can be used to generate mock surveys for cosmological analysis. By analysing a few basic statistics we indicate how these alternatives can be distinguished from general relativity with future weak lensing surveys.