bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health Care Access and COVID-19 Vaccination in the United States
Authors: De Guzman Charles , Thomas Chloe A. , Wiwanto Lynn , Hu Dier , Henriquez-Rivera Jose , Gage Lily , Perreault Jaclyn C. , Harris Emily , Rastas Charlotte , McCormick Danny , Gaffney Adam 
Published: May 2024

Background:
Although federal legislation made COVID-19 vaccines free, inequities in access to medical care may affect vaccine uptake.

Objective:
To assess whether health care access was associated with uptake and timeliness of COVID-19 vaccination in the United States.

Design:
A cross-sectional study.

Setting:
2021 National Health Interview Survey (Q2-Q4).

Subjects:
In all, 21,532 adults aged≥18 were included in the study.

Measures:
Exposures included 4 metrics of health care access: health insurance, having an established place for medical care, having a physician visit within the past year, and medical care affordability. Outcomes included receipt of 1 or more COVID-19 vaccines and receipt of a first vaccine within 6 months of vaccine availability. We examined the association between each health care access metric and outcome using logistic regression, unadjusted and adjusted for demographic, geographic, and socioeconomic covariates.

Results:
In unadjusted analyses, each metric of health care access was associated with the uptake of COVID-19 vaccination and (among those vaccinated) early vaccination. In adjusted analyses, having health coverage (adjusted odds ratio [AOR] 1.60; 95% CI: 1.39, 1.84), a usual place of care (AOR 1.58; 95% CI: 1.42, 1.75), and a doctor visit within the past year (AOR 1.45, 95% CI: 1.31, 1.62) remained associated with higher rates of COVID-19 vaccination. Only having a usual place of care was associated with early vaccine uptake in adjusted analyses.

Limitations:
Receipt of COVID-19 vaccination was self-reported.

Conclusions:
Several metrics of health care access are associated with the uptake of COVID-19 vaccines. Policies that achieve universal coverage, and facilitate long-term relationships with trusted providers, may be an important component of pandemic responses.
Modulation ofIdeonella sakaiensisPETase active site flexibility and activity on morphologically distinct substrates by surface charge engineering
Authors: Ding Ke , Levitskaya Zarina , Sana Barindra , Pasula Rupali Reddy , Kannan Srinivasaraghavan , Adam Abdurrahman , Sundaravadanam Vishnu Vadanan , Verma Chandra , Lim Sierin , Ghadessy John F. 
Published: May 2024

ABSTRACTEnzymatic hydrolysis of polyethylene terephthalate (PET) waste is a compelling strategy for environmentally friendly recycling of a major pollutant. Here, we investigate the effects of surface charge point mutations both proximal and distal to the active site of the mesophilic PET-degrading enzyme fromIdeonella sakaienses(IsPETase) and an engineered thermostable variant with superior activity, STAR PETase. The vicinal K95A mutation significantly inhibitedIsPETase activity on mechanically processed PET powder. Conversely, this mutation significantly increased hydrolysis of PET powder in the STAR PETase background. Activity of both enzymes on PET film was inhibited by the K95A mutation, highlighting complex interplay between mutation context and substrate morphology. Further installing the distal R132N and R280A surface charge mutations potentiated activity of STAR on all substrates tested. This variant afforded 100% degradation of bottle-grade PET powder in 3 days at 40°C reaction temperature, a 3-fold improvement overIsPETase. Molecular dynamics simulations reveal modulation of active site flexibility in mutants, which differentially impacts both hydrolysis of morphologically distinct PET substrates and the concentration-dependent inhibition phenomenon observed for PETase.
Brassinosteroids function as the plant male and female reproductive hormone coordinating gene expression
Authors: Matsuura-Tokita Kumi , Suzuki Takamasa , Kimata Yusuke , Takebayashi Yumiko , Ueda Minako , Nakano Takeshi , Sakakibara Hitoshi , Nakano Akihiko , Higashiyama Tetsuya 
Published: May 2024

AbstractBrassinosteroids (BRs) are steroid hormones identified in plants. Besides promoting cell elongation and division, BRs facilitate the development of both male and female reproductive tissues. In animals, reproductive steroid hormones play an essential role in reproductive tissue development by regulating gene expression. Here, we focused on the function of BRs during fertilization. We measured the content of biologically active BRs, brassinolide (BL) and castasterone (CS), in the reproductive tissues ofArabidopsis thaliana. Both BL and CS accumulated abundantly in pollen grains and in larger amounts in pistils than in leaves. To evaluate BL function during fertilization, we used anin vitroguidance assay with exogenously applied BL. Although pollen tubes need to be elongated through the pistils for efficient capacitation, BL treatment promoted pollen tube capacitation and improved attraction to ovulesin vitro. Transcriptome analysis demonstrated that BL treatment induced the expression of half of the genes expressed in pollen tubes that elongated through the pistils. These results indicated that BL supplied from pistils is a key factor for pollen tube capacitation. However, using thebri1mutant for the guidance assay resulted in reduced pollen tube capacitation, suggesting that BRI1-signaling in pistils is also important. Furthermore, BRs act on ovules. Exogenous BL application to ovules maintained guidance capacity by promoting the expression of small secreted proteins involved in pollen tube attraction and gamete fusion. Overall, BRs play a significant role as male and female reproductive hormones throughout the plant fertilization process.
Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory
Authors: Tseng Pei-Li , Sun Weiwei , Salem Ahmed , Macfarlane Sarah , Gad Annica K. B. , Collins Mark O. , Erdmann Kai S. 
Published: May 2024

SUMMARYCells sense and respond to mechanical cues from their environment. Mechanical cues are important for many biological processes, including embryonic development, ageing, cellular homeostasis, and diseases. Cells translate mechanical cues into cellular biochemical signals that govern cellular behaviour, like cell proliferation or migration, via a process called mechanotransduction. However, this process and the proteins involved remain incompletely understood. Here, we present an unbiased and large-scale approach to identify proteins involved in mechanotransduction. The screen revealed that the splicing factor PTBP1 is a novel mechanotransducer. We show that the nuclear localisation of PTBP1 depends on extracellular matrix stiffness, cell density, and the actomyosin-based contractility of the cell. Furthermore, we demonstrate that PTBP1 promotes the mechanosensitive splicing of the adapter protein Numb and that alternative splicing of Numb is crucial for matrix stiffness-induced cell proliferation and mechanomemory. Our results support the idea that changes in alternative splicing are an integral part of mechanotransduction and provide a mechanism by which matrix stiffness regulates cell proliferation and the formation of a mechanomemory in cells.
Accurate single domain scaffolding of three non-overlapping protein epitopes using deep learning
Authors: Castro Karla M. , Watson Joseph L. , Wang Jue , Southern Joshua , Ayardulabi Reyhaneh , Georgeon Sandrine , Rosset Stéphane , Baker David , Correia Bruno E. 
Published: May 2024

AbstractDe novoprotein design has seen major success in scaffolding single functional motifs, however, in nature most proteins present multiple functional sites. Here we describe an approach to simultaneously scaffold multiple functional sites in a single domain protein using deep learning. We designed small single domain immunogens, under 130 residues, that simultaneously present three distinct and irregular motifs from respiratory syncytial virus. These motifs together comprise nearly half of the designed proteins, and hence the overall folds are quite unusual with little global similarity to proteins in the PDB. Despite this, X-ray crystal structures confirm the accuracy of presentation of each of the motifs, and the multi-epitope design yields improved cross-reactive titers and neutralizing response compared to a single-epitope immunogen. The successful presentation of three distinct binding surfaces in a small single domain protein highlights the power of generative deep learning methods to solve complex protein design problems.
High-resolution disease phenotyping reveals distinct resistance strategies of wild tomato crop wild relatives againstSclerotinia sclerotiorum
Authors: Einspanier Severin , Tominello-Ramirez Christopher , Hasler Mario , Barbacci Adelin , Raffaele Sylvain , Stam Remco 
Published: May 2024

AbstractBesides the well-understood qualitative disease resistance, plants possess a more complex quantitative form of resistance: quantitative disease resistance (QDR). QDR is commonly defined as a partial but more durable form of resistance and, therefore, might display a valuable target for resistance breeding. The characterization of QDR phenotypes, especially of wild crop relatives, displays a major bottleneck in deciphering QDR’s genomic and regulatory background. Moreover, the relationship between QDR parameters, such as infection frequency, lag phase duration, and lesion growth rate, remains elusive. High hurdles for applying modern phenotyping technology, such as the low availability of phenotyping facilities or complex data analysis, further dampen progress in understanding QDR. Here, we applied a low-cost phenotyping system to measure lesion growth dynamics of wild tomato species (e.g.,S. pennelliiorS. pimpinellifolium). We provide insight into QDR diversity of wild populations and derive specific QDR strategies and their crosstalk. We show how temporally continuous observations are required to dissect end-point severity into functional resistance strategies. The results of our study show how QDR can be maintained by facilitating different defense strategies during host-parasite interaction and that the capacity of the QDR toolbox highly depends on the host’s genetic context. We anticipate that the present findings display a valuable resource for more targeted functional characterization of the processes involved in QDR. Moreover, we show how modest phenotyping technology can be leveraged to help answer highly relevant biological questions.
Clinicogenomic characterization of inflammatory breast cancer
Authors: Priedigkeit Nolan , Harrison Beth , Shue Robert , Hughes Melissa , Li Yvonne , Kirkner Gregory J. , Spurr Liam F. , Remolano Marie Claire , Strauss Sarah , Files Janet , Feeney Anne-Marie , Grant Libby , Mohammed-Abreu Ayesha , Garrido-Castro Ana , Sousa Romualdo Barroso , Bychkovsky Brittany , Nakhlis Faina , Bellon Jennifer R. , King Tari A. , Winer Eric P. , Lindeman Neal , Johnson Bruce E. , Sholl Lynette , Dillon Deborah , Overmoyer Beth , Tolaney Sara M. , Cherniack Andrew , Lin Nancy U. , Lynce Filipa 
Published: May 2024

ABSTRACTBackgroundInflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined—partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts.Patients and MethodsA retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases.ResultsClinicopathologic differences between IBC and non-IBC cases were consistent with prior reports—including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involvedTP53(72%),ERBB2(32%),PIK3CA(24%),CCND1(12%),MYC(9%),FGFR1(8%) andGATA3(8%). A multivariate logistic regression analysis revealed a significant enrichment inTP53SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease.ConclusionTaken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency ofTP53mutations and a potential enrichment in NOTCH pathway activation—but overall; a lack of major genomic differences. These results both reinforce the importance ofTP53alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.
Amyloid β Induces Hormetic-Like Effects Through Major Stress Pathways in aC. elegansModel of Alzheimer’s Disease
Authors: Lichty James D. , San Miguel Adriana 
Published: May 2024

AbstractAmyloid β (Aβ) is a peptide known for its characteristic aggregates in Alzheimer’s Disease and its ability to induce a wide range of detrimental effects in various model systems. However, Aβ has also been shown to induce some beneficial effects, such as antimicrobial properties against pathogens. In this work, we explore the influence of Aβ in stress resistance in aC. elegansmodel of Alzheimer’s Disease. We found thatC. elegansthat express human Aβ exhibit increased resistance to heat and hypoxia, but not to oxidative stress. This beneficial effect of Aβ was driven from Aβ in neurons but not muscles, and the abundance of Aβ in neurons correlated with stress resistance levels. Transcriptomic analysis revealed that this selective stress resistance was mediated by the Heat Shock Protein (HSPs) family of genes. Furthermore, neuropeptide signaling was necessary for Aβ to induce stress resistance, suggesting neuroendocrine signaling plays a major role in activating organismal stress response pathways. These results highlight the potential beneficial role of Aβ in cellular function, as well as its complex effects on cellular and organismal physiology that must be considered when usingC. elegansas a model for Alzheimer’s Disease.
Enhancing Whole Slide Image Classification with Discriminative and Contrastive Learning
Authors: Liang Peixian , Zheng Hao , Li Hongming , Gong Yuxin , Fan Yong 
Published: May 2024

AbstractWhole slide image (WSI) classification plays a crucial role in digital pathology data analysis. However, the immense size of WSIs and the absence of fine-grained sub-region labels, such as patches, pose significant challenges for accurate WSI classification. Typical classification-driven deep learning methods often struggle to generate compact image representations, which can compromise the robustness of WSI classification. In this study, we address this challenge by incorporating both discriminative and contrastive learning techniques for WSI classification. Different from the extant contrastive learning methods for WSI classification that primarily assign pseudo labels to patches based on the WSI-level labels, our approach takes a different route to directly focus on constructing positive and negative samples at the WSI-level. Specifically, we select a subset of representative and informative patches to represent WSIs and create positive and negative samples at the WSI-level, allowing us to better capture WSI-level information and increase the likelihood of effectively learning informative features. Experimental results on two datasets and ablation studies have demonstrated that our method significantly improved the WSI classification performance compared to state-of-the-art deep learning methods and enabled learning of informative features that promoted robustness of the WSI classification.
Single particle cryo-electron microscopy with an enhanced 200 kV cryo-TEM configuration achieves near-atomic resolution
Authors: Jia Lijia , Ruben Eliza A. , Suarez Humberto J. , Olsen Shaun K. , Wasmuth Elizabeth V. 
Published: May 2024

AbstractSingle particle cryogenic electron microscopy (cryo-EM) as a structural biology methodology has become increasingly attractive and accessible to investigators in both academia and industry as this ever-advancing technology enables successful structural determination of a wide range of protein and nucleic acid targets. Although data for many high resolution cryo-EM structures are still obtained using a 300 kV cryogenic transmission electron microscope (cryo-TEM), a modern 200 kV cryo-TEM equipped with an advanced direct electron detector and energy filter is a cost-effective choice for most single particle applications, routinely achieving sub 3 angstrom (Å) resolution. Here, we systematically evaluate performance of one such high-end configuration - a 200 kV Glacios microscope coupled with a Falcon 4 direct electron detector and Selectris energy filter (Glacios-F4-S). First, we evaluated data quality on the standard benchmarking sample, rabbit muscle aldolase, using three of the most frequently used cryo-EM data collection software: SerialEM, Leginon and EPU, and found that – despite sample heterogeneity – all final reconstructions yield same overall resolutions of 2.6 Å and map quality when using either of the three software. Furthermore, comparison between Glacios-F4-S and a 300 kV cryo-TEM (Titan Krios with Falcon 4) revealed nominal resolution differences in overall reconstructions of a reconstituted human nucleosome core particle, achieving 2.8 and 2.5 Å, respectively. Finally, we performed comparative data analysis on the human RAD51 paralog complex, BCDX2, a four-protein complex of approximately 150 kilodaltons, and found that a small dataset (≤1,000 micrographs) was sufficient to generate a 3.3 Å reconstruction, with sufficient detail to resolve co-bound ligands, AMP-PNP and Mg+2. In summary, this study provides evidence that the Glacios-F4-S operates equally well with all standard data collection software, and is sufficient to obtain high resolution structural information of novel macromolecular complexes, readily acquiring single particle data rivaling that of 300 kV cryo-TEMs.
Spatial Transcriptomic Sequencing of a DIPG-infiltrated Brainstem reveals Key Invasion Markers and Novel Ligand-Receptor Pairs contributing to Tumour to TME Crosstalk
Authors: Kordowski Anja , Mulay Onkar , Tan Xiao , Vo Tuan , Baumgartner Ulrich , Maybury Mellissa K. , Hassall Timothy E. G. , Wainwright Brandon J. , Harris Lachlan , Nguyen Quan , Day Bryan W. 
Published: May 2024

ABSTRACTEmerging spatially-resolved sequencing technologies offer unprecedented possibilities to study cellular functionality and organisation, transforming our understanding of health and disease. The necessity to understand healthy and diseased tissues in its entirety becomes even more evident for the human brain, the most complex organ in the body. The brain’s cellular architecture and corresponding functions are tightly regulated. However, when intercellular communications are altered by pathologies, such as brain cancer, these microenvironmental interactions are disrupted.DIPG is a brainstem high-grade glioma arising in young children and is universally fatal. Major disease obstacles include intratumoural genetic and cellular heterogeneity as well as a highly invasive phenotype. Recent breakthrough studies have highlighted the vital oncogenic capacity of brain cancer cells to functionally interact with the central nervous system (CNS). This CNS-crosstalk crucially contributes to tumour cell invasion and disease progression. Ongoing worldwide efforts seek to better understand these cancer-promoting CNS interactions to develop more effective DIPG anti-cancer therapies.In this study, we performed spatial transcriptomic analysis of a complete tumour-infiltrated brainstem from a single DIPG patient. Gene signatures from ten sequential tumour regions were analysed to assess disease progression and to study DIPG cell interactions with the tumour microenvironment (TME). We leveraged this unique DIPG dataset to evaluate genes significantly correlated with invasive tumour distal regions versus the proximal tumour initiation site. Furthermore, we assessed novel ligand-receptor pairs that actively promote DIPG tumour progression via crosstalk with endothelial, neuronal and immune cell communities, which can be utilised to support future research efforts in this area of high unmet need.
A new method and application of PacBio sequencing for low copy and difficulty preparation plasmids
Authors: Ma Xiaoshu , Wang Yusha , Jia Ruikai , Ye Hua 
Published: May 2024

AbstractThe Single Molecule Real Time (SMRT) system developed by Pacific Biosciences applies the principle of synthesis while sequencing and uses the SMRT chip as the sequencing carrier. The high starting amount and good integrity of DNA required by PacBio library construction has always been a headache. Generally, the total loading volume of PacBio sequencing is 10μg, and the concentration is not less than 200ng/μL, which is a huge challenge for low-copy plasmids. Tight plasmid means that when the bacterial chromosome replicates once, the plasmid replicates once, and each bacterium only contains 1 to 2 plasmids. The replicon of the plasmid determines the copy number of the plasmid. Low copy plasmids should produce 0.2-1 μg DNA per ml of LB culture. Low-copy plasmids play a key role in gene synthesis. When vectors are used for expression or other purposes, low-copy plasmids are used to reduce resource consumption caused by plasmid expansion. Low-copy plasmids are also used when plasmids have lethal gene clones. In order to solve the problem of low copy plasmid library database construction in PacBio, we used Phi29 polymerase to perform multiple substitution amplification of low copy plasmid, so as to obtain a large number of high molecular weight DNA to meet the computer requirements of PacBio. In addition, this study also established a PacBio sequencing method for bacterial fluids without the need for plasmid extraction steps, thereby reducing time and money costs.
FAPM: Functional Annotation of Proteins using Multi-Modal Models Beyond Structural Modeling
Authors: Xiang Wenkai , Xiong Zhaoping , Chen Huan , Xiong Jiacheng , Zhang Wei , Fu Zunyun , Zheng Mingyue , Liu Bing , Shi Qian 
Published: May 2024

AbstractAssigning accurate property labels to proteins, like functional terms and catalytic activity, is challenging, especially for proteins without homologs and “tail labels” with few known examples. Unlike previous methods that mainly focused on protein sequence features, we use a pretrained large natural language model to understand the semantic meaning of protein labels. Specifically, we introduce FAPM, a contrastive multi-modal model that links natural language with protein sequence language. This model combines a pretrained protein sequence model with a pretrained large language model to generate labels, such as Gene Ontology (GO) functional terms and catalytic activity predictions, in natural language. Our results show that FAPM excels in understanding protein properties, outperforming models based solely on protein sequences or structures. It achieves state-of-the-art performance on public benchmarks and in-house experimentally annotated phage proteins, which often have few known homologs. Additionally, FAPM’s flexibility allows it to incorporate extra text prompts, like taxonomy information, enhancing both its predictive performance and explainability. This novel approach offers a promising alternative to current methods that rely on multiple sequence alignment for protein annotation. The online demo is at:https://huggingface.co/spaces/wenkai/FAPM_demo.