Miracle-dz/UniFAR-FTUs huggingface dataset:
Antigen spacing on protein nanoparticles influences antibody responses to vaccination

Immunogen design approaches aim to control the specificity and quality of antibody responses to enable the creation of next-generation vaccines with improved potency and breadth. However, our understanding of the relationship between immunogen structure and immunogenicity is limited. Here we use computational protein design to generate a self-assembling nanoparticle vaccine platform based on the head domain of influenza hemagglutinin (HA) that enables precise control of antigen conformation, flexibility, and spacing on the nanoparticle exterior. Domain-based HA head antigens were presented either as monomers or in a native-like closed trimeric conformation that prevents exposure of trimer interface epitopes. These antigens were connected to the underlying nanoparticle by a rigid linker that was modularly extended to precisely control antigen spacing. We found that nanoparticle immunogens with decreased spacing between closed trimeric head antigens elicited antibodies with improved hemagglutination inhibition (HAI) and neutralization potency as well as binding breadth across diverse HAs within a subtype. Our “trihead” nanoparticle immunogen platform thus enables new insights into anti-HA immunity, establishes antigen spacing as an important parameter in structure-based vaccine design, and embodies several design features that could be used to generate next-generation vaccines against influenza and other viruses. HIGHLIGHTS Computational design of a closed trimeric HA head (“trihead”) antigen platform. Design of a rigid, extendable linker between displayed antigen and underlying protein nanoparticle enables precise variation of antigen spacing. Decreased antigen spacing of triheads elicits antibodies with the highest HAI, neutralizing activity, and cross-reactivity. Changes to antigen spacing alter epitope specificities of vaccine-elicited antibodies.
Theoretical framework and experimental solution for the air−water interface adsorption problem in cryoEM

As cryogenic electron microscopy (cryoEM) gains traction in the structural biology community as a method of choice for determining atomic structures of biological complexes, it has been increasingly recognized that many complexes that behave well under conventional negative-stain electron microscopy tend to have preferential orientation, aggregate or simply mysteriously “disappear” on cryoEM grids, but the reasons for such misbehavior are not well understood, limiting systematic approaches to solving the problem. Here, we have developed a theoretical formulation that explains these observations. Our formulation predicts that all particles migrate to the air-water interface (AWI) to lower the total potential surface energy — rationalizing the use of surfactant, which is a direct solution to reducing the surface tension of the aqueous solution. By conducting cryogenic electron tomography (cryoET) with the widely-tested sample, GroEL, we demonstrate that, in a standard buffer solution, nearly all particles migrate to the AWI. Gradual reduction of the surface tension by introducing surfactants decreased the percentage of particles exposed to the surface. By conducting single-particle cryoEM, we confirm that applicable surfactants do not damage the biological complex, thus suggesting that they might offer a practical, simple, and general solution to the problem for high-resolution cryoEM. Application of this solution to a real-world AWI adsorption problem with a more challenging membrane protein, namely, the ClC-1 channel, has led to its first near-atomic structure using cryoEM.
A systemic approach allows to identify the pedoclimatic conditions most critical in the susceptibility of a grapevine cultivar to esca/Botryosphaeria dieback

Esca and/or Botryosphaeria dieback (esca-BD) are two of the most destructive grapevine trunk diseases in the world, disease complex which remains poorly understood. As some vine cultivars show highly variable susceptibility to esca-BD, we designed a four-year experiment to identify which environmental factors influence the expression of the disease. We collected epidemiological and physiological data once a year for four consecutive years in 19 vineyard plots located in four wine-growing regions of Western Switzerland. We compared these data with climatic data obtained from weather stations for these same plots for four years and over the long term. We also estimated the soil water holding capacity of each plot. Confounding factors were minimal because all vineyards were planted in 2003 with the same cultivar and all plants grafted in the same nursery with genetically homogeneous grafting material. Principal component and regression analyses of combined epidemiological, biotic and pedoclimatic data identified a positive correlation between soil water retention capacity and plant mortality due to esca-BD. These analyses also showed that leaf disease symptoms and apoplexy are more frequent when cold, wet periods are followed - or alternate with - hot, dry periods, and that apoplexy occurs more frequently when weather conditions change abruptly (cold, wet May followed by a hot June) and deviate significantly from long-term climatic conditions. Regression analyses show that the soil water holding capacity impacts less the disease expression when the climate is warm and dry, both at the regional and at year-specific levels. Having identified the most important environmental factors towards expression of esca-BD, this study allows recommendations to be given to the winegrowers for the cultivar studied but can also be used as a model to identify the environmental factors that influence the expression of fungal diseases in other grapevine cultivars, other grapevine trunk diseases and even in other woody plants.
Triphasic production of IFNγ by innate and adaptive lymphocytes following influenza A virus infection

Interferon gamma (IFNγ) is a potent antiviral cytokine that can be produced by many innate and adaptive immune cells during infection. Currently, our understanding of which cells produce IFNγ and where they are located at different stages of an infection are limited. We have used reporter mice to investigate in vivo expression of IFNγ in the lung and secondary lymphoid organs during and following influenza A virus (IAV) infection. We observed a triphasic production of IFNγ expression. Unconventional T cells and innate lymphoid cells, particularly NK cells, were the dominant producers of early IFNγ, while CD4 and CD8 T cells were the main producers by day 10 post-infection. Following viral clearance, some memory CD4 and CD8 T cells continued to produce IFNγ in the lungs and draining lymph node. Interestingly, IFNγ production by lymph node Natural Killer (NK), NKT and innate lymphoid 1 cells also continued to be above naïve levels, suggesting memory-like phenotypes for these cells. Analysis of the localisation of IFNγ+ memory CD4 and CD8 T cells demonstrated that cytokine+ T cells were located near airways and in the lung parenchyma. Following a second IAV challenge, lung IAV specific CD8 T cells rapidly increased their expression of IFNγ while CD4 T cells in the draining lymph node increased their IFNγ response. Together, these data suggest that IFNγ production fluctuates based on cellular source and location, both of which could impact subsequent immune responses.
Pharmaceutical agent cetylpyridinium chloride inhibits immune mast cell function by interfering with calcium mobilization

Cetylpyridinium chloride (CPC) is an antimicrobial used in numerous personal care and janitorial products and food for human consumption at millimolar concentrations. Minimal information exists on the eukaryotic toxicology of CPC. We have investigated the effects of CPC on signal transduction of the immune cell type mast cells. Here, we show that CPC inhibits the mast cell function degranulation with antigen dose-dependence and at non-cytotoxic doses ∼1000-fold lower than concentrations in consumer products. Previously we showed that CPC disrupts phosphatidylinositol 4,5-bisphosphate, a signaling lipid critical for store-operated Ca2+ entry (SOCE), which mediates degranulation. Our results indicate that CPC inhibits antigen-stimulated SOCE: CPC restricts Ca2+ efflux from endoplasmic reticulum, reduces Ca2+ uptake into mitochondria, and dampens Ca2+ flow through plasma membrane channels. While inhibition of Ca2+ channel function can be caused by alteration of plasma membrane potential (PMP) and cytosolic pH, CPC does not affect PMP or pH. Inhibition of SOCE is known to depress microtubule polymerization, and here we show that CPC indeed dose-dependently shuts down formation of microtubule tracks. In vitro data reveal that CPC inhibition of microtubules is not due to direct CPC interference with tubulin. In summary, CPC is a signaling toxicant that targets Ca2+ mobilization.
Experimental evolution of hybrid populations to identify Dobzhansky-Muller incompatibility loci

Epistatic interactions between loci that reduce fitness in inter-species hybrids, Dobzhansky-Muller incompatibilities (DMIs), contribute genetically to the inviability and infertility within hybrid populations. It remains a challenge, however, to identify the loci that contribute to DMIs as causes of reproductive isolation between species. Here, we assess through forward simulation the power of evolve and resequence experimental evolution of hybrid populations to map DMI loci. We document conditions under which such a mapping strategy may be most feasible and demonstrate how mapping power is sensitive to biologically relevant parameters such as one-way versus two-way incompatibility type, selection strength, recombination rate, and dominance interactions. We also assess the influence of parameters under direct control of an experimenter, including duration of experimental evolution and number of replicate populations. We conclude that an evolve and re-sequence strategy for mapping DMI loci, and other cases of epistasis, can be a viable option under some circumstances for study systems with short generation times like Caenorhabditis nematodes.
Phylogenetic and spatial determinants of leaf endophyte microbiomes in the flowering plant genus Heuchera (Saxifragaceae)

Premise: Endophytic plant-microbe interactions range from mutualistic relationships that confer important ecological and agricultural traits to neutral or quasi-parasitic relationships. In contrast to root-associated endophytes, the role of environmental and host-related factors for acquiring leaf endophyte communities remains relatively unexplored. Here we assess leaf endophyte diversity to test the hypothesis that membership of these microbial communities is driven primarily by abiotic environment and host phylogeny. Methods: We used a broad geographic coverage of North America in the genus, Heuchera (Saxifragaceae). Bacterial and fungal communities were characterized with 16S and ITS amplicon sequencing, using QIIME2 to call operational taxonomic units and calculate species richness, Shannon diversity, and phylogenetic diversity. We assembled environmental predictors for microbial diversity at collection sites including latitude, elevation, temperature, precipitation, and soil parameters. Results: We find differing assembly patterns for bacterial and fungal endophytes; we found that only host phylogeny is significantly associated with bacteria, while geographic distance alone was the best predictor of fungal community composition. Species richness and phylogenetic diversity are very similar across sites and species, with only fungi showing a response to aridity and precipitation for some metrics. Unlike what has been observed with root-associated microbial communities, in this system microbes show no relationship with pH or other soil factors. Conclusions: Host phylogeny and geographic distance independently influence different microbial communities, while aridity and precipitation determine fungal diversity within leaves of Heuchera. Our results indicate the importance of detailed clade-based investigation of microbiomes and the complexity of microbiome assembly within specific plant organs.
A programmed response precedes cell lysis and death in a mat-forming cyanobacterium

Cyanobacteria form dense multicellular communities that experience transient conditions in terms of access to light and oxygen. These systems are productive but also undergo substantial biomass turnover, supplementing heightened heterotrophic respiration and oxygen drawdown. Here we use metagenomics and metaproteomics to survey the cellular response of a mat-forming cyanobacterium undergoing mass cell lysis after exposure to dark and anoxic conditions. A lack of evidence for visral, bacterial, or eukaryotic antagonism contradicts commonly held beliefs on the causative agent for cyanobacterial death during dense growth. Instead, proteogenomics data indicated that lysis resulted from a genetically programmed response triggered by a failure to maintain osmotic pressure in the wake of severe energy limitation. Cyanobacterial DNA was rapidly degraded, yet cyanobacterial proteins remained abundant. A subset of proteins, including enzymes involved in amino acid metabolism, peptidases, toxin-antitoxin systems, and a potentially self-targeting CRISPR-Cas system, were upregulated upon lysis, indicating involvement in the programmed cell death response. We propose this natural form of programmed cell death could provide new pathways for controlling harmful algal blooms and for sustainable bioproduct production.
Using activity theory to understand contradictions in the safe sex practices of married people in a rural area of the Eastern Cape, South Africa

HIV/AIDS is a significant public health issue in South Africa. Drawing upon activity theory, this study investigated the prevailing contradictions, tensions and dilemmas related to safe sex practices in the sexual activity systems of heterosexual married people in a rural area of the Eastern Cape in South Africa. This study used secondary data obtained from a National Research Foundation (NRF) funded qualitative project on responses to HIV/AIDS. Nine individual semi-structured interviews (5 women and 4 men) and two focus group discussions (one with women and one with men) were analysed. The findings identify primary and secondary contradictions within two sexual activity systems (that of the married woman, and that of the married man). Tertiary level contradictions between the object of each activity system (specifically sexual pleasure versus safe sex practice) are exacerbated by contradictions between the division of labour components of the two activity systems. These tertiary contradictions are enabled because of the primary contradiction within the married women’s sexual activity system, specifically within the division of labour component. This is a contradiction between being responsible for sexual safety, but submissive in the negotiation of sexual activity. A significant finding of this study is that these contradictions within and between the activity systems are at an early start of maturity, as they have not yet lead to a crisis in, and collapse of, the systems. This analysis contributes to understanding the lack of change in behaviour related to safe sex practices.
What are the Needs and Experiences of Family Caregivers with Regard to Primary Care? Findings from a Qualitative Interview Study

Family caregivers face a variety of challenges. Family physicians (FPs) are in an excellent position to provide support and a stabilising influence in addressing the needs and expectations on support in this group. This study was intended to shed light on the attitudes, desires, and experience of family caregivers regarding support from primary care.
The Association of VMAT2 Gene Polymorphisms With the Development of Schizophrenia

Objective: To investigate the association between common single nucleotide polymorphisms (SNPs) in the vesicular monoamine transporter type 2 ( VMAT2 ) gene and a diagnosis of schizophrenia in the US population. Methods: 968 individuals with a diagnosis of schizophrenia were ancestry-matched to healthy controls to create a final cohort of 1,936 individuals. Diagnosis criteria was determined from Electronic Health Records provided by the AllofUs Research Program. Additive and dominant logistic regression analyses were done for the promoter SNPs rs363324 and rs363371. Additional stratified analyses were performed using sex and ancestry variables. Results: No significant results were observed for rs363324 and rs363371 using the additive model. The dominant model suggested a protective effect for rs363324 for the entire cohort ( p = 0 . 007; OR = 0 . 75[0 . 61 , 0 . 92]) and within the African ancestral group ( p = 0 . 028; OR = 0 . 76[0 . 56 , 0 . 97]). Stratification by sex did not give significant results for either genotype model, nor did stratification by ancestry+sex. Conclusion: Premature mortality rates and the need for targeted treatments in schizophrenia make it an important disease to study for public health. This study found that ’GA’ and ’AA’ genotypes have an equal protective effect from the development of schizophrenia for rs363324. Unlike previous studies, the results for rs363371 were not significant. Future studies should use a larger sample size and include variables concerning environmental factors.
Numerical and experimental investigation of natural flow-induced vibrations of flexible hydrofoils

The objective of this work is to present combined numerical and experimental studies of natural flow-induced vibrations of flexible hydrofoils. The focus is on identifying the dependence of the foil’s vibration frequencies and damping characteristics on the inflow velocity, angle of attack, and solid-to-fluid added mass ratio. Experimental results are shown for a cantilevered polyacetate (POM) hydrofoil tested in the cavitation tunnel at the French Naval Academy Research Institute (IRENav). The foil is observed to primarily behave as a chordwise rigid body and undergoes spanwise bending and twisting deformations, and the flow is observed to be effectively two-dimensional (2D) because of the strong lift retention at the free tip caused by a small gap with a thickness less than the wall boundary layer. Hence, the viscous fluid-structure interaction (FSI) model is formulated by coupling a 2D unsteady Reynolds-averaged Navier-Stokes (URANS) model with a two degree-of-freedom (2-DOF) model representing the spanwise tip bending and twisting deformations. Good agreements were observed between viscous FSI predictions and experimental measurements of natural flow-induced vibrations in fully turbulent and attached flow conditions. The foil vibrations were found to be dominated by the natural frequencies in absence of large scale vortex shedding due to flow separation. The natural frequencies and fluid damping coefficients were found to vary with velocity, angle of attack, and solid-to-fluid added mass ratio. In addition, the numerical results showed that the in-water to in-air natural frequency ratios decreased rapidly, and the fluid damping coefficients increased rapidly, as the solid-to-fluid added mass ratio decreases. Uncoupled mode (UM) linear potential theory was found to significantly over-predict the fluid damping for cases of lightweight flexible hydrofoils, and this over-prediction increased with higher velocity and lower solid-to-fluid added mass ratio.
Effect of hafnium doping on density of states in dual-target magnetron co-sputtering HfZnSnO thin film transistors

This study investigates the effect of hafnium doping on the density of states (DOSs) in HfZnSnO thin film transistors fabricated by dual-target magnetron co-sputtering system. The DOSs is extracted by temperature-dependent field-effect measurements, and they decrease from 1.1 × 1017 to 4.6 × 1016 eV/cm3 with increasing the hafnium concentrations. The behavior of DOSs for the increasing hafnium concentration HfZnSnO thin film transistors can be confirmed by both the reduction of ΔVT under bias stress and the trapping charges calculated by capacitance voltage measurements. It suggests that the reduction in DOSs due to the hafnium doping is closely related with the bias stability and thermal stability.
Exploring the Moderating Effect of Positive and Negative Word-of-Mouth on the Relationship between Health Belief Model and the Willingness to Receive COVID-19 Vaccine

This study indicates that the positive and negative effects of word-of-mouth (WOM) have an impact and moderating effect on vaccine uptake willingness, which is important to exploring the factors that affect vaccine uptake. We further analyzed the differences in the impact relationship between variables through questionnaire research. Based on the Health Belief Model (HBM) widely used to explore global health issues, this study focuses on Taiwanese residents and uses a questionnaire survey method. Furthermore, this study investigates the impact of various factors in the HBM on the willingness to receive the COVID-19 vaccine when faced with positive and negative word-of-mouth evaluations from the perspective of vaccine recipients, as well as whether WOM evaluations have an interference effect, along with the differences between variables. Practical recommendations are provided based on the research results, which can serve as a reference for future vaccine promotion programs and health promotion. By improving the national vaccination rate and achieving herd immunity, we aim to increase the persuasiveness of word-of-mouth on public healthcare decision-making. We also hope to provide a basis for health promotion and encourage people to make informed decisions about vaccination.
Mixed Copolymer Micelles for Nanomedicine

Mixed micelles from copolymers in aqueous media have emerged as a valuable tool for producing functional polymer nanostructures with applications in nanomedicine, including drug delivery and bioimaging. In this review, we discuss the basics of mixed copolymer micelles’ design, structure, and physicochemical properties. We also focus on their utilization in biomedical applications using examples from recent literature.
Inducible Knockout of 14-3-3β Attenuates Proliferation and Spheroid Formation in a Human Glioblastoma Cell Line U87MG

Glioblastomas (GBs) are the most common and malignant brain tumors in adults. A protein encoded by the gene YWHAB, 14-3-3β, is commonly found to be upregulated throughout the initiation and progression of GB. The 14-3-3β has oncogenic roles in several different types of cancer cells through interactions with proteins such as Bad, FBI1, Raf-1, Cdc25b, and others. Previous RNA interference studies have shown that 14-3-3β promotes proliferation, cell cycle progression, and migration and invasion of GB cells. However, despite the many oncogenic functions of 14-3-3β, a CRISPR/Cas9 knockout model of 14-3-3β has not been investigated. This study confirmed previous findings and showed that siRNA inhibition of 14-3-3β results in reduced cellular proliferation in a human glioblastoma cell line, U87MG. We also used a YWHAB Tet-On CRISPR/Cas9 U87MG cell line that, upon doxycycline induction, leads to robust Cas9 expression and subsequent knockout of 14-3-3β. Using this model, we show that loss of 14-3-3β significantly reduces cellular proliferation and spheroid formation of U87MG cells.