Miracle-dz/UniFAR-FTUs huggingface dataset:
The Clade Displacement Index: how to detect hotizontal gene transfers in unrooted gene trees

While most genes of any organism are inherited vertically - i.e. from its parent organisms - sometimes they can be exchanged between unrelated species in a process known as the horizontal gene transfer (HGT). Studies of HGT contribute to our knowledge about the mechanisms of evolution, including the emergence of new pathogens, and a great deal of effort has been put into different methods of finding transferred genes. The golden standard of HGT detection is the analysis of the incongruence between the gene and the species trees. Those methods typically require rooted trees, in which the direction of evolution is known. Gene trees are typically unrooted, and rooting them is yet another step in HGT analysis, prone to errors which may lead to wrong conclusions. A natural question arises: can HGTs be detected in gene trees without rooting them at all? It turns out that, for a particular, yet broad, class of transfers, the answer to this question is: yes. It also turns out that the same methodology can be applied to complement the bootstrap support in assessing the stability of gene tree topology. In this article, we present the Clade Displacement Index, a measure of shift of a given clade’s location between two trees. We derive algorithms to compute it and give several examples of its applications to HGT detection and gene tree stability analysis. We finish by pointing out directions for further studies and an example that shows that not all HGTs are detectable without knowing the location of the root of the gene tree. A Jupyter Notebook with the implementation and applications of CDI described in this paper is available at https://github.com/mciach/CDI
Highly reliable thin hafnium oxide gate dielectric

HfO 2 is the one of the potential high-k dielectrics for replacing SiO 2 as a gate dielectric. HfO 2 is thermodynamically stable when in direct contact with Si and has a reasonable band gap (∼5.65eV). In this study, MOS capacitors (Pt/HfO 2 /Si) were fabricated by depositing HfO 2 using reactive DC magnetron sputtering in the range of 33∼135A followed by Pt deposition. During the HfO 2 deposition, O 2 flow was modulated to control interface quality and to suppress interfacial layer growing. By optimizing the HfO 2 deposition process, equivalent oxide thickness (EOT) can be reduced down to ∼11.2 A with the leakage current as low as 1X10 −2 A/cm 2 at +1.0V and negligible frequency dispersion. HfO 2 films also show excellent breakdown characteristics and negligible hysteresis after high temperature annealing. From the high resolution TEM, there is a thin interfacial layer after annealing, suggesting a composite of Si-Hf-O with a dielectric constant of ≈ 2 X K SiO 2 .
Panel Informativity Optimizer (PIO): an R package to improve cancer NGS panel informativity

Mutation detection by next generation sequencing (NGS) is routinely used for cancer diagnosis. Selecting an optimal set of genes for a given cancer is not trivial as it has to optimize informativity (i.e. the number of patients with at least one mutation in the panel), while minimizing panel length in order to reduce sequencing costs and increase sensitivity. We propose herein Panel Informativity Optimizer (PIO), an open-source software developed as an R package with a user-friendly graphical interface to help optimize cancer NGS panel informativity. Using patient-level mutational data from either private datasets or preloaded dataset of 91 independent cohort from 31 different cancer type, PIO selects an optimal set of genomic intervals to maximize informativity and panel size in a given cancer type. Different options are offered such as the definition of genomic intervals at the gene or exon level, and the use of optimization strategy at the patient or patient per kilobase level. PIO can also propose an optimal set of genomic intervals to increase informativity of custom panels. A panel tester function is also available for panel benchmarking. Using public databases, as well as data from real-life settings, we demonstrate that PIO allows panel size reduction of up to 1000kb, and accurately predicts the performance of custom or commercial panels. PIO is available online at https://vincentalcazer.shinyapps. io/Panel_informativity_optimizer/ or can be set on a locale machine from https://github.com/VincentAlcazer/PIO.
Annealing synchronizes the 70S ribosome into a minimum-energy conformation

Significance In metallurgy, annealing heats a metal or alloy to a predetermined temperature, holds this temperature for a certain time, and then decreases the metal to room temperature to change the physical and sometimes also the chemical properties of the material. Researchers introduce a similar concept to simulated annealing to predict minimum-energy conformations of biological macromolecules. In this work, we experimentally verify that annealing at a fast cooling rate can synchronize the 70S ribosome into a nonrotated state with minimum energy in our free-energy landscape analysis. Our results not only offer a facile yet robust approach to stabilizing proteins for high-resolution structural analysis but also contribute to understanding of protein folding and temperature adaptation. Researchers commonly anneal metals, alloys, and semiconductors to repair defects and improve microstructures via recrystallization. Theoretical studies indicate that simulated annealing on biological macromolecules helps predict the final structures with minimum free energy. Experimental validation of this homogenizing effect and further exploration of its applications are fascinating scientific questions that remain elusive. Here, we chose the apo-state 70S ribosome from Escherichia coli as a model, wherein the 30S subunit undergoes a thermally driven intersubunit rotation and exhibits substantial structural flexibility as well as distinct free energy. We experimentally demonstrate that annealing at a fast cooling rate enhances the 70S ribosome homogeneity and improves local resolution on the 30S subunit. After annealing, the 70S ribosome is in a nonrotated state with respect to corresponding intermediate structures in unannealed or heated ribosomes. Manifold-based analysis further indicates that the annealed 70S ribosome takes a narrow conformational distribution and exhibits a minimum-energy state in the free-energy landscape. Our experimental results offer a facile yet robust approach to enhance protein stability, which is ideal for high-resolution cryogenic electron microscopy. Beyond structure determination, annealing shows great potential for synchronizing proteins on a single-molecule level and can be extended to study protein folding and explore conformational and energy landscapes.
Efficient prestimulus network integration of FFA biases face perception during binocular rivalry

Ongoing fluctuations in neural excitability and connectivity influence whether or not a stimulus is seen. Do they also influence which stimulus is seen? We recorded magnetoencepahlography data while participants viewed face or house stimuli, either one at a time or under bi-stable conditions induced through binocular rivalry. Multivariate pattern analysis revealed common neural substrates for rivalrous vs. non-rivalrous stimuli with an additional delay of ~36ms for the bi-stable stimulus and poststimulus signals were source-localized to the fusiform face area (FFA). Prior to stimulus onset followed by a face-vs. house-report, FFA showed stronger connectivity to primary visual cortex and to the rest of the cortex in the alpha frequency range (8-13 Hz) but there were no differences in local oscillatory alpha power. The pre-stimulus connectivity metrics predicted the accuracy of post-stimulus decoding and the delay associated with rivalry disambiguation suggesting that perceptual content is shaped by ongoing neural network states.
Stress-induced cross-feeding of internal metabolites provides a dynamic mechanism of microbial cooperation

Despite the ubiquity of microbial diversity observed across environments, mechanisms of cooperativity that enable species coexistence beyond the classical limit of one-species-per-niche have been elusive. Here we report the observation of a transient but substantial cross-feeding of internal metabolites between two marine bacterial species under acid stress, and further establish through quantitative physiological characterization of the individual strains that this cross-feeding is central to the survival and coexistence of these species in growth-dilution cycles. The coculture self-organizes into a limit cycle in which acid-stressed producers excrete various internal metabolites upon entering growth arrest, enabling the cross-feeders to grow, restore medium pH, and protect the producers from death. These results establish a rare, mechanistic example of inter-species cooperation under stress, as anticipated long ago by the stress gradient hypothesis. As the accumulation of acetate and other fermentation products occurs ubiquitously in habitats ranging from the gut to wastewater, and the excretion of internal metabolites is an obligatory physiological response by bacteria under weak acid stress, stress-induced cross-feeding provides a general physiological basis for the extensive sharing of metabolic resources to promote the coexistence of diverse species in microbial communities.
Mutations in PIKFYVE cause autosomal dominant congenital cataract

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.
Prophages in the infant gut are largely induced, and may be functionally relevant to their hosts

Background Bacteriophages are the most abundant biological entity on the planet, and are key components of any ecosystem they are present in. The gut virome is increasingly being implicated in disease states although these studies largely focus on lytic phages in adults. Here we identify prophages from a large infant cohort and investigate their potential functions. Results We identified 10645 vOTUs from 662 metagenomes. No core virome was found: the most prevalent vOTU was identified in 70% of the samples. The most abundant and prevalent group of phages are a novel group closely related to Bacteroides phage Hanky p00’. Functional annotation of this group revealed the presence of genes in the dDTP-L-rhamnose pathway, possibly involved in the production of capsular polysaccharides. We also found an abundance of diversity generating retroelements in the phages. Additionally, paired virome data allowed us to show that the majority of prophages are induced in at least one sample and that this is not affected by the use of antibiotics in the 4 weeks prior to sampling. Conclusions Prophages in the infant gut are largely unique to the individual and not shared. Most of them appear to be induced and so may be key drivers in shaping the bacterial microbiome. The most abundant group of phages are novel, and possess elements that may allow them to maintain differentially susceptible subpopulations of their host bacterium; whilst also containing diversity generating retroelements that could expand their host range. Prophages are important components of the infant gut that may have far reaching influences on the composition and function of the microbiome.
Post-exercise Hypotension Following a Single Bout of High Intensity Interval Exercise vs. a Single Bout of Moderate Intensity Continuous Exercise in Adults With or Without Hypertension: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Background: Post-exercise hypotension (PEH) is an important tool in the daily management of patients with hypertension. Varying the exercise parameters is likely to change the blood pressure (BP) response following a bout of exercise. In recent years, high-intensity interval exercise (HIIE) has gained significant popularity in exercise-based prevention and rehabilitation of clinical populations. Yet, to date, it is not known whether a single session of HIIE maximizes PEH more than a bout of moderate-intensity continuous exercise (MICE). Objective: To compare the effect of HIIE vs. MICE on PEH by means of a systematic review and meta-analysis. Methods: A systematic search in the electronic databases MEDLINE, Embase, and SPORTDiscus was conducted from the earliest date available until February 24, 2020. Randomized clinical trials comparing the transient effect of a single bout of HIIE to MICE on office and/or ambulatory BP in humans (≥18 years) were included. Data were pooled using random effects models with summary data reported as weighted means and 95% confidence interval (CIs). Results: Data from 14 trials were included, involving 18 comparisons between HIIE and MICE and 276 (193 males) participants. The immediate effects, measured as office BP at 30- and 60-min post-exercise, was similar for a bout of HIIE and MICE (p > 0.05 for systolic and diastolic BP). However, HIIE elicited a more pronounced BP reduction than MICE [(−5.3 mmHg (−7.3 to −3.3)/ −1.63 mmHg (−3.00 to −0.26)] during the subsequent hours of ambulatory daytime monitoring. No differences were observed for ambulatory nighttime BP (p > 0.05). Conclusion: HIIE promoted a larger PEH than MICE on ambulatory daytime BP. However, the number of studies was low, patients were mostly young to middle-aged individuals, and only a few studies included patients with hypertension. Therefore, there is a need for studies that involve older individuals with hypertension and use ambulatory BP monitoring to confirm HIIE's superiority as a safe BP lowering intervention in today's clinical practice. Systematic Review Registration: PROSPERO (registration number: CRD42020171640).
Macro-Nutrient Stoichiometry of Glacier Algae From the Southwestern Margin of the Greenland Ice Sheet

Glacier algae residing within the surface ice of glaciers and ice sheets play globally significant roles in biogeochemical cycling, albedo feedbacks, and melt of the world’s cryosphere. Here, we present an assessment of the macro-nutrient stoichiometry of glacier algal assemblages from the southwestern Greenland Ice Sheet (GrIS) margin, where widespread glacier algal blooms proliferate during summer melt seasons. Samples taken during the mid-2019 ablation season revealed overall lower cellular carbon (C), nitrogen (N), and phosphorus (P) content than predicted by standard microalgal cellular content:biovolume relationships, and elevated C:N and C:P ratios in all cases, with an overall estimated C:N:P of 1,997:73:1. We interpret lower cellular macro-nutrient content and elevated C:N and C:P ratios to reflect adaptation of glacier algal assemblages to their characteristic oligotrophic surface ice environment. Such lower macro-nutrient requirements would aid the proliferation of blooms across the nutrient poor cryosphere in a warming world. Up-scaling of our observations indicated the potential for glacier algal assemblages to accumulate ∼ 29 kg C km2 and ∼ 1.2 kg N km2 within our marginal surface ice location by the mid-ablation period (early August), confirming previous modeling estimates. While the long-term fate of glacier algal autochthonous production within surface ice remains unconstrained, data presented here provide insight into the possible quality of dissolved organic matter that may be released by assemblages into the surface ice environment.
Effect of Heat Stimulation on Circulating Irisin in Humans

High temperatures lead to oxidative stress. The aim of the study was to determine whether heat stimulation-induced hyperthermia can increase the level of circulating irisin. Twenty-one healthy female subjects (age, 26.3 ± 2.71 years; height, 162.1 ± 3.15 cm; weight, 54.2 ± 3.86 kg; and body surface area, 1.57 ± 0.11 m2) not taking contraceptives participated in this study. All experiments were performed individually for each participant when they were in the early proliferative menstrual phase. In an automated climate chamber (25 ± 0.5°C), the heat load was applied via half-body immersion into a hot water bath (42 ± 0.5°C). Five-minutes break was provided every after 5 min of immersion and the total passive heating time was 30 min. Tympanic temperature (Tty) and skin temperature (Ts) were measured. Mean body temperature (mTb) was calculated. Blood samples were collected before and immediately after immersion. Levels of irisin, cortisol, creatine kinase (CK), and lactate dehydrogenase (LDH) were analyzed. Tty, mTb and serum irisin levels increased after hot water immersion. The blood levels of cortisol, CK, and LDH were also elevated after hot water immersion. Heat stimulation might increase the levels of circulating irisin in humans in response to oxidative stress.
Systems Immunology Analysis Reveals the Contribution of Pulmonary and Extrapulmonary Tissues to the Immunopathogenesis of Severe COVID-19 Patients

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.
White Matter Hyperintensities Are Associated With Severity of Essential Tremor in the Elderly

Background: Essential tremor (ET) occurs with steeply increasing prevalence in the elderly, and apart from disease duration, age is independently associated with an increase of tremor amplitude and a decrease of frequency. White matter hyperintensities (WMHs) are a common finding in the elderly, and their role in the pathophysiology of ET is unknown. The aims of this study were to examine whether ET patients differ in their total or region-specific WMH volumes from healthy controls and to determine the impact of WMH on tremor characteristics. Methods: A total of 47 elderly ET patients with a mean age of 72 years and 39 age-matched healthy controls underwent a thorough clinical assessment and 3T MRI. Total WMH volumes were derived from T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Additionally, region of interest-based WMH volumes for the Johns Hopkins University (JHU) white matter tracts and labels were calculated, and WMHs were assessed semiquantitatively using the Fazekas scale. Results: Essential tremor patients and healthy controls did not differ in their total or tract-specific WMH volumes or Fazekas scores. However, WMH volume was significantly positively correlated with tremor severity on the TETRAS scale, and there was a significant negative correlation with the mean accelerometric tremor frequency. In a multiple linear regression model including disease duration, age, and age-adjusted total WMH volume, only the WMH volume significantly predicted tremor severity, while age and disease duration were not significant. Conclusion: We found evidence for a direct association between WMH volume and tremor severity. If confirmed by larger studies, our findings could explain the well-known relation between age and tremor severity.
Mutational Landscape of Pirin and Elucidation of the Impact of Most Detrimental Missense Variants That Accelerate the Breast Cancer Pathways: A Computational Modelling Study

Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD) simulation that demonstrated the role of the mutation in protein structure destability and affecting its internal dynamics. The findings of this study are believed to open doors to investigate the biological relevance of the mutations and drugability potential of the protein.