Miracle-dz/UniFAR-FTUs huggingface dataset:
Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor repertoires in 12,591 HIV-1 Envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.
Individual vocal signatures show reduced complexity following invasion

The manner in which vocal learning is used for social recognition may be sensitive to the social environment. Biological invaders capable of vocal learning are useful for testing this possibility, as invasion alters population size. If vocal learning is used for individual recognition, then individual identity should be encoded in frequency modulation patterns of acoustic signals. Furthermore, frequency modulation patterns should be more complex in larger social groups, reflecting greater selection for individual distinctiveness. We compared social group sizes and used supervised machine learning and frequency contours to compare contact call structure between native range monk parakeets (Myiopsitta monachus) in Uruguay and invasive range populations in the U.S. Invasive range sites exhibited fewer nests and simpler frequency modulation patterns. Beecher’s statistic revealed reduced individual identity content and fewer possible unique individual signatures in invasive range calls. Lower estimated social densities and simpler individual signatures are consistent with relaxed selection on the complexity of calls learned for individual recognition in smaller social groups. These findings run counter to the traditional view that vocal learning is used for imitation, and suggest that vocal learning can be employed to produce individual vocal signatures in a manner sensitive to local population size.
The ups and downs of amino acid co-evolution: evolutionary Stokes and anti-Stokes shifts

The most fundamental form of epistasis occurs between residues within a protein. Epistatic interactions can have significant consequences for evolutionary dynamics. For example, a substitution to a deleterious amino acid may be compensated for by replacements at other sites which increase its propensity (a function of its average fitness) over time - this is the evolutionary Stokes shift. We discovered that an opposite trend -the decrease in amino acid propensity with time-can also occur via the same epistatic dynamics. We define this novel and pervasive phenomenon as the evolutionary anti-Stokes shift. Our extensive simulations of three natural proteins show that evolutionary Stokes and anti-Stokes shifts occur with similar frequencies and magnitudes across the protein. This high-lights that decreasing amino acid propensities, on their own, are not conclusive evidence of adaptive responses to a changing environment. We find that stabilizing substitutions are often permissive (i.e., expand potential evolutionary paths) whereas destabilizing substitutions are restrictive. We show how these dynamics explain the variations in amino acid propensities associated with both evolutionary shifts in propensities.
In silico Drosophila Patient Model Reveals Optimal Combinatorial Therapies for Colorectal Cancer

In silico models of biomolecular regulation in cancer, annotated with patient-specific gene expression data can aid in the development of novel personalized cancer therapeutics strategies. Drosophila melanogaster is a well-established animal model that is increasingly being employed to evaluate preclinical personalized cancer therapies. Here, we report five Boolean network models of biomolecular regulation in cells lining the Drosophila midgut epithelium and annotate them with patient-specific mutation data to develop an in silico Drosophila Patient Model (DPM). The network models were validated against cell-type-specific RNA-seq gene expression data from the FlyGut-seq database and through three literature-based case studies on colorectal cancer. The results obtained from the study help elucidate cell fate evolution in colorectal tumorigenesis, validate cytotoxicity of nine FDA-approved cancer drugs, and devise optimal personalized drug treatment combinations. The proposed personalized therapeutics approach also helped identify synergistic combinations of chemotherapy (paclitaxel) with targeted therapies (pazopanib, or ruxolitinib) for treating colorectal cancer. In conclusion, this work provides a novel roadmap for decoding colorectal tumorigenesis and in the development of personalized cancer therapeutics through a DPM.
Polygenic Scores for Plasticity: A New Tool for Studying Gene-Environment Interplay

Outcomes of interest to demographers—fertility; health; education—are the product of both an individual’s genetic makeup and his or her social environment. Yet Gene × Environment research (GxE) currently deploys a limited toolkit on the genetic side to study gene-environment interplay: polygenic scores (PGS, or what we call mPGS) that reflect the influence of genetics on levels of an outcome. The purpose of the present paper is to develop a genetic summary measure better suited for GxE research. We develop what we call variance polygenic scores (vPGS), or polygenic scores that reflect genetic contributions to plasticity in outcomes. The first part of the analysis uses the UK Biobank (N ∼ 326,000 in the training set) and the Health and Retirement Study (HRS) (N = 10,524) to compare four approaches for constructing polygenic scores for plasticity. The results show that two widely-used methods for discovering which genetic variants affect outcome variability fail to serve as distinctive new tools for GxE. Then, using the polygenic scores that do capture distinctive genetic contributions to plasticity, we analyze heterogeneous effects of a UK education reform on health and educational attainment. The results show the properties of a new tool useful for population scientists studying the interplay of nature and nurture and for population-based studies that are releasing polygenic scores to applied researchers.
SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction

Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses. To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells. Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear. In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.
Ongoing evolution of KRAB zinc finger protein-coding genes in modern humans

Background Krüppel-associated box (KRAB) zinc finger proteins (KZFPs) constitute the largest and fastest evolving family of gene regulators encoded by the human genome. Recent data indicate that many KZFPs serve as repressors of transposable element-embedded regulatory sequences (TEeRS) and that the evolutionary turnover of KZFP genes is mainly attributable to the changing transposable element (TE) load of their hosts. However, how natural selection and genetic variation are shaping this process is still poorly defined. Methods Genetic information was collected from nine primate species and 138,500 human genomes. Gene-wide as well as functional amino acid position specific constraint was calculated across all human KZFPs. Results We found that the most conserved KZFPs, some of which go back close to 400 million years, have been subjected to marked negative selection in the evolutionarily recent past and are very homogeneous within the human population. In contrast, younger, largely primate-restricted family members present evidence of less negative selection than the rest of genome and lower levels of coding constraint, particularly within the sequences encoding the functional sites of their zinc finger (ZF) arrays. We defined 33 sets of KZFP paralogs, which pairwise displayed a broad range of coding constraints differentials, with more recently emerged paralogs usually displaying a higher frequency of putatively deleterious mutations and missense variants within the functional sites of their ZF arrays than their source gene. Finally, we identified three KZFP genes more constrained in the genomes of individuals of African ancestry than in Europeans, with their modes of expression or DNA targets pointing to possible links between these inter-populational genetic differences and regional differences in the prevalence of some diseases. Conclusions This work shows how the ongoing selection of KZFPs contributes to modern human genetic variation, in particular through the constraint of putatively deleterious- and missense variants in functional protein sites, and how ongoing interplays between environment and KZFP genes might be impacting the biology of modern humans.
Development of a copper-graphene nanocomposite based transparent coating with antiviral activity against influenza virus

Respiratory infections by RNA viruses are one of the major burdens upon global health and economy. Viruses like influenza or coronaviruses can be transmitted through respiratory droplets or contaminated surfaces. An effective antiviral coating can decrease the viability of the virus particles in the outside environment significantly, hence reducing their transmission rate. In this work, we have screened a series of nanoparticles and their composites for antiviral activity using Nano Luciferase based highly sensitive influenza A reporter virus. Using this screening system, we have identified copper-graphene (Cu-Gr) nanocomposite shows strong antiviral activity. Extensive material and biological characterization of the nanocomposite suggested a unique metal oxide embedded graphene sheet architecture that can inactivate the virion particles only within 30 minutes of pre-incubation and subsequently interferes with the entry of these virion particles into the host cell. This ultimately results in reduced viral gene expression, replication and production of progeny virus particles, slowing down the overall pace of progression of infection. Using PVA as a capping agent, we have been able to generate a Cu-Gr nanocomposite based highly transparent coating that retains its original antiviral activity in the solid form.
A Rarefaction-Based Extension of the LDM for Testing Presence-Absence Associations in the Microbiome

Background Many methods for testing association between the microbiome and covariates of interest (e.g., clinical outcomes, environmental factors) assume that these associations are driven by changes in the relative abundance of taxa. However, these associations may also result from changes in which taxa are present and which are absent. Analyses of such presence-absence associations face a unique challenge: confounding by library size (total sample read count), which occurs when library size is associated with covariates in the analysis. It is known that rarefaction (subsampling to a common library size) controls this bias, but at the potential cost of information loss as well as the introduction of a stochastic component into the analysis. Currently, there is a need for robust and efficient methods for testing presence-absence associations in the presence of such confounding, both at the community level and at the individual-taxon level, that avoid the drawbacks of rarefaction. Methods We have previously developed the linear decomposition model (LDM) that unifies the community-level and taxon-level tests into one framework. Here we present an extension of the LDM for testing presence-absence associations. The extended LDM is a non-stochastic approach that repeatedly applies the LDM to all rarefied taxa count tables, averages the residual sum-of-squares (RSS) terms over the rarefaction replicates, and then forms an F-statistic based on these average RSS terms. We show that this approach compares favorably to averaging the F-statistic from R rarefaction replicates, which can only be calculated stochastically. The flexible nature of the LDM allows discrete or continuous traits or interactions to be tested while allowing confounding covariates to be adjusted for. Results Our simulations indicate that our proposed method is robust to any systematic differences in library size and has better power than alternative approaches. We illustrate our method using an analysis of data on inflammatory bowel disease (IBD) in which case samples have systematically smaller library sizes than controls. Conclusions The rarefaction-based extension of the LDM performs well for testing presenceabsence associations and should be adopted even when there is no obvious systematic variation in library size.
Myristate can be used as a carbon and energy source for the asymbiotic growth of arbuscular mycorrhizal fungi

Significance The origins of arbuscular mycorrhizal (AM) fungi, which form symbiotic associations with land plants, date back >460 Mya. During evolution, these fungi acquired an obligate symbiotic lifestyle, and thus depend on their host for essential nutrients. In particular, fatty acids are regarded as crucial nutrients for the survival of AM fungi, owing to the absence of genes involved in de novo fatty acid biosynthesis in the AM fungal genomes that have been sequenced so far. Here we show that myristate initiates AM fungal growth under asymbiotic conditions. These findings will advance the pure culture of AM fungi. Arbuscular mycorrhizal (AM) fungi, forming symbiotic associations with land plants, are obligate symbionts that cannot complete their natural life cycle without a host. The fatty acid auxotrophy of AM fungi is supported by recent studies showing that lipids synthesized by the host plants are transferred to the fungi, and that the latter lack genes encoding cytosolic fatty acid synthases. Therefore, to establish an asymbiotic cultivation system for AM fungi, we tried to identify the fatty acids that could promote biomass production. To determine whether AM fungi can grow on medium supplied with fatty acids or lipids under asymbiotic conditions, we tested eight saturated or unsaturated fatty acids (C12 to C18) and two β-monoacylglycerols. Only myristate (C14:0) led to an increase in the biomass of Rhizophagus irregularis, inducing extensive hyphal growth and formation of infection-competent secondary spores. However, such spores were smaller than those generated symbiotically. Furthermore, we demonstrated that R. irregularis can take up fatty acids in its branched hyphae and use myristate as a carbon and energy source. Myristate also promoted the growth of Rhizophagus clarus and Gigaspora margarita. Finally, mixtures of myristate and palmitate accelerated fungal growth and induced a substantial change in fatty acid composition of triacylglycerol compared with single myristate application, although palmitate was not used as a carbon source for cell wall biosynthesis in this culture system. Our findings demonstrate that myristate boosts the asymbiotic growth of AM fungi and can also serve as a carbon and energy source.
Mangrove Flora of the World

The species composition and characteristics of mangrove flora in the world were reviewed and discussed. The results suggested that the world's mangrove plants have 84 species (including 12 varieties) in 24 genera and 16 families. Of which, true mangrove plants have 70 species (including 12 varieties) in 16 genera and 11 families, and semi_mangrove plants 14 species in eight genera and five families. The Eastern Group has 74 species (including 12 varieties) in 18 genera and 14 families, characterized by the genera Aegiceras , Osbornia , Aegialitis , Bruguiera , Ceriops , Kandelia , Scyphiphora and Nypa etc. The Western Group has only 10 species in six genera and five families, characterized by the endemic one_species family, Pelliceraceae, and the genus Laguncularia . The mangrove flora of China is composed of 26 species (including one variety) in 15 genera and 12 families, four of which are endemic. Hainan is most rich in mangrove species, making up about 96.2% of the Chinese total; Guangdong ranks second, making up about 42.3%. It has been demonstrated that Rhizophora stylosa was mistaken for R. mucronata in Taiwan by previous authors.
Responses of three Zoysiagrass species to salt stress

The effects of salt(NaCl)on the antioxidant system and soluble protein content during growth of Zoysia macrostachys,Z.matrellaand Z.japonica was investigated.The biomass and the soluble protein contents of all three grasses reduced gradually with increasing salt concentration and duration of exposure,while leaf relative conductance and malondialdehyde(MDA)content increased.Under lower salt concentration(0.2%-0.4%),leaf relative conductance and MDA increased slightly,but both peaked at 0.8% salt.The proline content peaked 10 days after treatment application but subsequently declined.Under lower salt concentrations the activities of catalase and superoxide dismutase in all three grasses reduced gradually,while under0.6%-0.8% salt,they initially increased,declined and then increased again.Z.macrostachys had the lowest leaf relative conductance and the lowest MDA,but the highest protective enzyme activity and soluble protein content.Consequently Z.macrostachys demonstrated greater salt resistance than Z.matrellaand Z.japonica.
Histopathologic Observations of Eyes in Exenterated Orbits After Neoadjuvant Intra-Arterial Cytoreductive Chemotherapy for Adenoid Cystic Carcinoma of the Lacrimal Gland.

PURPOSE To assess whether exenteration specimens obtained after neoadjuvant intra-arterial cytoreductive chemotherapy (IACC) for adenoid cystic carcinoma of the lacrimal gland demonstrate significant ocular histopathologic alterations that might preclude future pursuit of globe-preserving therapy. METHODS Retrospective histopathologic analysis of globes in IACC-treated exenteration specimens among the same cohort of patients whose survival outcomes have been reported. RESULTS Twenty patients had specimens available. Nineteen globes revealed no abnormalities of the iris, ciliary body, lens, retinal pigment epithelium, choroid, or chorioretinal vasculature. Eighteen globes showed no optic nerve abnormalities. One globe from a patient who refused exenteration until adenoid cystic carcinoma recurrence supervened demonstrated optic nerve edema with a peripapillary hemorrhage and cotton wool spot, as well as hemorrhage and necrosis within an extraocular muscle. Eighteen globes showed no retinal abnormalities attributable to intra-arterial chemotherapy. Three globes showed incidental retinal findings: 2 globes contained 1 to 2 small peripheral retinal hemorrhages and 1 had a pigmented retinal hole. Seven demonstrated mild, chronic extraocular muscle inflammation, and 13 had unremarkable musculature. The single patient who received IACC via the internal carotid rather than the external carotid artery developed ophthalmic artery occlusion with orbital apex syndrome prior to exenteration, and diffuse necrosis and hemorrhage were evident histopathologically. CONCLUSIONS Neoadjuvant IACC does not cause significant histopathologic damage to key ocular structures or compromise visual function in patients receiving intra-arterial chemotherapy through the external carotid artery. However, delivering chemotherapy through the internal carotid artery may result in visually significant thrombotic vascular events. The generally benign histopathological findings in these exenteration specimens support the concept of IACC delivery through the external carotid system as the cornerstone of a future globe-preserving strategy for lacrimal gland adenoid cystic carcinoma.
Effectiveness of HIIE versus MICT in Improving Cardiometabolic Risk Factors in Health and Disease: A Meta-analysis.

PURPOSE We aimed to investigate differences between high-intensity interval exercise [HIIE; included high-intensity interval training (HIIT) and sprint interval training (SIT)] and moderate-intensity continuous training (MICT) on physical fitness, body composition, blood pressure, blood lipids, insulin and glucose metabolism, inflammation, and endothelial function. METHODS Differences between HIIE and MICT were summarized using a random-effects meta-analysis on the effect size (Cohen's d). A meta-regression was conducted using subgroups: population, age, training duration, men ratio, exercise type, baseline values (clinical relevant ranges), and type of HIIE. Studies were included if at least one of the following outcomes were reported: maximal oxygen uptake (V[Combining Dot Above]O2max), flow-mediated dilation (FMD), body mass index (BMI), body mass, % body fat, systolic and diastolic blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, total cholesterol, C-reactive protein (CRP), fasting glucose and insulin, glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR). A total of 55 studies were included. RESULTS Overall, HIIE was superior to MICT in improving V[Combining Dot Above]O2max (d=0.40, p<0.001), and FMD (d=0.54, p<0.05). Oppositely, MICT was superior to HIIE in improving HbA1c (d=-0.27, p<0.05). No differences were observed in BMI (d=-0.02), body mass (d=-0.05), % body fat (d=0.04), systolic (d=-0.04) and diastolic blood pressure (d=0.03), HDL (d=-0.05), LDL (d=0.08), triglycerides (d=0.03), total cholesterol (d=0.14), CRP (d=-0.11), fasting insulin (d=0.02), fasting glucose (d=0.02), and HOMA-IR (d=-0.04). Moderator analyses indicated the difference between HIIE and MICT was affected by different subgroups. CONCLUSION Overall, HIIE showed to be more effective in improving cardiovascular health and cardiorespiratory fitness, while MICT was superior in improving long-term glucose metabolism. In the process of personalized training counseling, health-enhancing effects of exercise training may be improved by considering the individual risk profiles.