bluuebunny/crossref_metadata_2025_split huggingface dataset:
DnaJC7 specifically regulates tau seeding
Authors: Perez Valerie A. , Sanders David W. , Mendoza-Oliva Ayde , Stopschinski Barbara E. , Mullapudi Vishruth , White Charles L , Joachimiak Lukasz A. , Diamond Marc I. 
Published: March 2023

AbstractNeurodegenerative tauopathies are caused by accumulation of toxic tau protein assemblies. This appears to involve template-based seeding events, whereby tau monomer changes conformation and is recruited to a growing aggregate. Several large families of chaperone proteins, including Hsp70s and J domain proteins (JDPs) cooperate to regulate the folding of intracellular proteins such as tau, but the factors that coordinate this activity are not well known. The JDP DnaJC7 binds tau and reduces its intracellular aggregation. However, it is unknown whether this is specific to DnaJC7 or if other JDPs might be similarly involved. We used proteomics within a cell model to determine that DnaJC7 co-purified with insoluble tau and colocalized with intracellular aggregates. We individually knocked out every possible JDP and tested the effect on intracellular aggregation and seeding. DnaJC7 knockout decreased aggregate clearance and increased intracellular tau seeding. This depended on the ability of the J domain (JD) of DnaJC7 to bind to Hsp70, as JD mutations that block binding to Hsp70 abrogated the protective activity. Disease-associated mutations in the JD and substrate binding site of DnaJC7 also abrogated its protective activity. DnaJC7 thus specifically regulates tau aggregation in cooperation with Hsp70.
A general computational design strategy for stabilizing viral class I fusion proteins
Authors: Gonzalez Karen J. , Huang Jiachen , Criado Miria F. , Banerjee Avik , Tompkins Stephen , Mousa Jarrod J. , Strauch Eva-Maria 
Published: March 2023

AbstractMany pathogenic viruses, including influenza virus, Ebola virus, coronaviruses, and Pneumoviruses, rely on class I fusion proteins to fuse viral and cellular membranes. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more favorable and stable postfusion state. An increasing amount of evidence exists highlighting that antibodies targeting the prefusion conformation are the most potent. However, many mutations have to be evaluated before identifying prefusion-stabilizing substitutions. We therefore established a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. As a proof of concept, we applied this principle to the fusion protein of the RSV, hMPV, and SARS-CoV-2 viruses. For each protein, we tested less than a handful of designs to identify stable versions. Solved structures of designed proteins from the three different viruses evidenced the atomic accuracy of our approach. Furthermore, the immunological response of the RSV F design compared to a current clinical candidate in a mouse model. While the parallel design of two conformations allows identifying and selectively modifying energetically less optimized positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. We recaptured many approaches previously introduced manually for the stabilization of viral surface proteins, such as cavity-filling, optimization of polar interactions, as well as postfusion-disruptive strategies. Using our approach, it is possible to focus on the most impacting mutations and potentially preserve the immunogen as closely as possible to its native version. The latter is important as sequence re-design can cause perturbations to B and T cell epitopes. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.
LIPUS attenuates knee joint capsule fibrosis and athrogenic contracture through the TGF-β1/Smad signaling pathway
Authors: Zhou Ting , Wang Feng , Zhou Yun , Zhou Chen Xu , Zhang Quan Bing 
Published: March 2023

AbstractAs one of main causes of athrogenic contracture, joint capsule fibrosis which is described as a condition with excessive deposition of collagen components and extracellular matrix (ECM) in joint capsule, is a response to long-time immobilization. The purpose of this study was to explore the effect and the underlying mechanism of low-intensity pulsed ultrasound (LIPUS) in treating knee joint capsule fibrosis. A rabbit model of knee joint capsule fibrosis induced by 6w-immobilization was employed in this study. The degree of knee joint capsule fibrosis was assessed by measurement of arthrogenic contracture and Masson-staining. Furthermore, malondialdehyde (MDA) and superoxide dismutase (SOD) were measured to assess the level of reactive oxygen species (ROS). Apart from these, the activation of TGF-β1/Smad signaling pathway was determined through western blot analysis contained TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3 and Smad4, and immunohistochemical staining for p-Smad2/3 positive cells. After 6 wk-immobilization, the degree of arthrogenic contracture and the collagen density were increased. Moreover, the activity of MDA was upregulated and the content of SOD was downregulated. Correspondingly, the TGF-β1/Smad signaling pathway was significantly activated. After 2 wk-LIPUS treatment, the degree of arthrogenic contracture and the collagen density were lower than 2 wk-remobilizaiton. Relatively, the activity of MDA was decresed and the content of SOD was increased compared with 2 wk-remobilizaiton. Importantly,the TGF-β1/Smad signaling pathway was significantly inhibited compared with 2 wk-remobilizaiton. Our findings thus conclude that high level ROS and hyperactive TGF-β1/Smad signaling pathway might be one of the causes of knee joint capsule fibrosis induced by immobilization and LIPUS attenuated the severity of immobilization-induced knee joint capsule fibrosis through inhibition of the production of ROS and the activation of TGF-β1/Smad signaling pathway. Our findings might provide a theoretical basis for knee joint capsule fibrosis after immobilization and provide the potential therapeutic target.
The role of airborne particles in the epidemiology of clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus in commercial poultry production units
Authors: James Joe , Warren Caroline J. , De Silva Dilhani , Lewis Thomas , Grace Katherine , Reid Scott M. , Falchieri Marco , Brown Ian H. , Banyard Ashley C 
Published: March 2023

ABSTRACTSince October 2021, Europe has experienced the largest avian influenza virus (AIV) epizootic, caused by clade 2.3.4.4b H5N1 high pathogenicity AIV (HPAIV), with over 320 poultry and captive bird infected premises (IPs) and 2480 dead H5N1 positive wild birds detected in Great Britain alone. Many IPs have been detected as geographical clusters, raising questions around potential lateral spread between premises by airborne particles. Airborne transmission over short distances has been reported for some AIVs strains. However, the risk of airborne spread of this strain remains to be elucidated. We conducted extensive sampling from IPs where clade 2.3.4.4b H5N1 HPAIVs was confirmed during the 2022/23 epizootic, each representing a major poultry species (ducks, turkeys, and chickens). A range of environmental samples were collected inside and outside houses, including deposited dust, feathers, and other potential fomites. Viral RNA (vRNA) and infectious virus were detected in air samples collected from inside and outside, but in close proximity, of infected houses, with vRNA alone being detected greater distances (>10m) outside. Some dust samples collected outside of the affected houses contained infectious virus, while feathers from the affected houses, located up to 60m away, only contained vRNA. Together, these data suggest that airborne particles harbouring infectious HPAIV can be translocated short distances (<10m) through the air, while particles containing vRNA might travel further (<50m). Therefore, the potential for airborne transmission of clade 2.3.4.4b H5N1 HPAIV between premises is considered low. Other factors, including indirect contact with wild birds, fomite spread and the efficiency of biosecurity represent greater importance in disease incursion.IMPORTANCEUnderstanding the routes of avian influenza virus incursion into poultry premises is critical to ensure the implementation of effective preventative measures, reducing the risk of spread of the virus. Extensive environmental sampling across three infected premises, representing the major global commercial poultry species, detected viral RNA and infectious virus in air samples, dust, and other fomites inside of the houses containing infected poultry, as well as within the immediate proximity of infected houses. This suggests that particles harbouring infectious virus may travel short distances outside of affected houses, which may potentially contribute to house-to-house transmission on the same premises, but not at distances likely to contribute to the transmission to another poultry premises. Consequently, control efforts should be focused on traditional, robust biosecurity measures at key barriers on poultry houses. Human behaviour in and around poultry houses as factors contributing to biosecurity risks should be considered.
Drift of neural ensembles driven by slow fluctuations of intrinsic excitability
Authors: Delamare Geoffroy , Zaki Yosif , Cai Denise J , Clopath Claudia 
Published: March 2023

AbstractRepresentational drift refers to the dynamic nature of neural representations in the brain despite the behavior being seemingly stable. Although drift has been observed in many different brain regions, the mechanisms underlying it are not known. Since intrinsic neural excitability is suggested to play a key role in regulating memory allocation, fluctuations of excitability could bias the reactivation of previously stored memory ensembles and therefore act as a motor for drift. Here, we propose a rate-based plastic recurrent neural network with slow fluctuations of intrinsic excitability. We first show that subsequent reactivations of a neural ensemble can lead to drift of this ensemble. The model predicts that drift is induced by co-activation of previously active neurons along with neurons with high excitability which leads to remodeling of the recurrent weights. Consistent with previous experimental works, the drifting ensemble is informative about its temporal history. Crucially, we show that the gradual nature of the drift is necessary for decoding temporal information from the activity of the ensemble. Finally, we show that the memory is preserved and can be decoded by an output neuron having plastic synapses with the main region.
A Machine Learning approach to study plant functional trait divergence
Authors: Majumder Sambadi , Mason Chase M. 
Published: March 2023

ABSTRACTPremise of the studyPlant functional traits are often used to describe spectra of ecological strategies among species. Here we demonstrate a machine learning approach for identifying the traits that contribute most to interspecific phenotypic divergence in multivariate trait space.MethodsDescriptive and predictive machine learning approaches were applied to trait data for the genusHelianthus, including Random Forest and Gradient Boosting Machine classifiers, Recursive Feature Elimination, and the Boruta algorithm. These approaches were applied at the genus level as well as within each of the three major clades within the genus to examine the variability in major axes of trait divergence in three independent species radiations.Key ResultsMachine learning models were able to predict species identity from functional traits with high accuracy, and differences in functional trait importance were observed between the genus level and clade levels indicating different axes of phenotypic divergence.ConclusionsApplying machine-learning approaches to identify divergent traits can provide insights into the predictability or repeatability of evolution through comparison of parallel diversification of clades within a genus. These approaches can be implemented in a range of contexts across basic and applied plant science from interspecific divergence to intraspecific variation across time, space, and environmental conditions.
Proximity interaction analysis of thePlasmodium falciparumputative ubiquitin ligasePfRNF1 reveals a role in RNA regulation
Authors: Farrukh Afia , Musabyimana Jean Pierre , Distler Ute , Tenzer Stefan , Pradel Gabriele , Ngwa Che Julius 
Published: March 2023

AbstractSome proteins have acquired both ubiquitin ligase activity and RNA-binding properties and are therefore known as RNA-binding Ubiquitin ligases (RBULs). These proteins provide a link between the RNA metabolism and the ubiquitin proteasome system (UPS). The UPS is a crucial protein surveillance system of eukaryotes primarily involved in the selective proteolysis of proteins which are covalently marked with ubiquitin through a series of steps involving ubiquitin E1 activating, E2 conjugating and E3 ligating enzymes. The UPS also regulates other key cellular processes such as cell cycle, proliferation, cell differentiation, transcription and signal transduction. While RBULs have been characterized in other organisms, little is known about their role inPlasmodium falciparum, the causative agent of the deadliest human malaria, malaria tropica. In this study, we characterized a previously identified putativeP. falciparumRING finger E3 ligasePfRNF1. We show that the protein is highly expressed in sexual stage parasites and mainly present in immature male gametocytes. Using proximity interaction studies with parasite lines expressingPfRNF1 tagged with the Biotin ligase BirA, we identified an interaction network ofPfRNF1 in both the asexual blood stages and gametocytes composed mainly of ribosomal proteins, RNA-binding proteins including translational repressors such DOZI, CITH, PUF1 and members of the CCR4-NOT complex, as well as proteins of the UPS such as RPN11, RPT1 and RPT6. Our interaction network analysis revealsPfRNF1 as a potential RNA-binding E3 ligase which links RNA dependent processes with protein ubiquitination to regulate gene expression.ImportanceRBULs provide a link between RNA-mediated processes with the ubiquitin system. Only a few RBULs have been identified and none has been characterized in the malaria parasiteP. falciparum. In this study, we unveiled the interactome of the putativeP. falciparumE3 ligasePfRNF1. We show thatPfRNF1 interacts with both proteins of the ubiquitin system as well as RNA-binding proteins therefore indicating that it is a putative RBUL which links RNA regulation with the ubiquitin system inP. falciparum.
Prevalence and predictors of HIV testing among young men in Papua New Guinea: a cross-sectional analysis of a nationally representative sample
Authors: Maviso McKenzie 
Published: March 2023

AbstractBackgroundHIV testing is an important component of HIV prevention and serves as a gateway to other HIV-related services. However, the uptake remains suboptimal among young people, particularly in highly prevalent settings such as Papua New Guinea (PNG). This study used nationally representative data to assess the prevalence and determine predictors of HIV testing uptake among young men aged 15–24 years in PNG.MethodsThe 2016–2018 PNG Demographic and Health Survey (PNGDHS) data was used. A total of 1,275 young men aged 15–24 years were included in the final analysis. Descriptive, bivariate, and multivariable logistic regression analyses were performed to determine independent predictors of HIV testing. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were reported. All analyses were adjusted using survey weights to account for unequal sampling probabilities.ResultsThe overall prevalence of HIV testing among young men was 17.2% (95% CI: 15–19). Of those who were tested for HIV, most lived in rural areas (73%), about one-third had a sexual debut at age <15 years (32.9%), and 33.9% inconsistently used condoms during sex. In multivariable analysis, men aged 20–24 years (AOR 1.18, 95% CI: 1.00–2.31), who own mobile phones (AOR 1.43, 95% CI: 1.00– 2.55), who were aware that consistent condom use during sex can reduce HIV risk (AOR 2.18, 95% CI: 1.18–4.04), who had paid for sex (AOR 1.75, 95% CI: 1.01–5.83), and who had two or more sexual partners (AOR 1.37, 95% CI: 1.01–3.14) had increased odds of HIV testing. However, decreased odds of HIV testing were found among men who were never married (AOR 0.51, 95% CI: 0.29–0.88), lived in rural areas (AOR 0.54, 95% CI: 0.32–0.92), and consistently used condoms during sex (AOR 0.59, 95% CI: 0.34–1.01).ConclusionThe findings show that HIV testing is low among young men in PNG. To increase HIV testing uptake among young men, it is crucial to implement comprehensive youth-friendly HIV/STI education and tailored sensitization programs and enable more accessible and affordable HIV testing services. Also, outreach and community-based testing programs for young men in prioritized areas requiring urgent prevention intervention are feasible options in PNG.
Delivering maternal and child health interventions through the private sector in LMIC: a scoping review of strategies and effective approaches
Authors: Awor Phyllis 
Published: March 2023

ABSTRACTDespite growing evidence on the role of private health providers, the global public health response to date has primarily focused on the provision of public sector health services for women and children in low and middle income countries (LMIC). Limitations of this approach are well documented and include: shortage of human resources, inefficient institutional frameworks and inadequate quality especially in rural areas. In order to achieve Universal Health Coverage, it is important to strengthen both the public and private sector. The objective was to determine effective strategies for engagement with private health providers for maternal and child health in LMIC.A scoping review of both published and grey literature from 2000 – 2022 was undertaken, using including all types of papers reporting on: either population level data on the extent of utilization of the private sector for maternal and child health services in more than one country; or interventions for service provision in the private sector using population level results in one or more country; Or both of the above. Aggregate results were extracted, and content analysis was used to identify engagement strategies/themes.The results confirm that the private sector is the dominant provider of outpatient care for women and children in LMIC, and a significant provider of reproductive and maternal health services including for inpatient care. Effective strategies and recommendations for engagement with private health providers are presented across challenges of private health provider engagement.
Protection against symptomatic SARS-CoV-2 BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original (ancestral) monovalent vaccines – a matched cohort study in France
Authors: Auvigne Vincent , Tamandjou Cynthia , Schaeffer Justine , Vaux Sophie , Parent du Chatelet Isabelle 
Published: March 2023

AbstractThis cohort study aimed to evaluate the protection against symptomatic SARS-CoV-2 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to mRNA Original (ancestral) monovalent vaccines. Individuals of ≥60 years old who received a booster dose between 03/10/2022 and 06/11/2022, when both the bivalent and monovalent vaccines were used in France, were included. Individuals who received a booster dose with (1) a monovalent Original mRNA vaccine (Pfizer- BioNTech or Moderna) or (2) the bivalent Pfizer-BioNTech Original/BA.4-5 vaccine were matched. The outcome of interest was a positive SARS-CoV-2 RT-PCR or antigenic test associated to self-reported symptoms, at least seven days after receiving the booster dose. Data were analysed with a Cox Proportional-Hazards model adjusted for the presence of previous infection, age, sex, and the presence of medium risk comorbidities. A total of 136,852 individuals were included and followed for a median period of 77 days. The bivalent vaccine conferred an additional protection of 8% [95% CI: 0% - 16%, p=0.045] against symptomatic SARS-CoV-2 infection compared to the monovalent vaccines.
Using natural language processing to study homelessness longitudinally with electronic health record data subject to irregular observations
Authors: Chapman Alec B. , Scharfstein Daniel O. , Montgomery Ann Elizabeth , Byrne Thomas , Suo Ying , Effiong Atim , Velasquez Tania , Pettey Warren , Nelson Richard E. 
Published: March 2023

AbstractThe Electronic Health Record (EHR) contains information about social determinants of health (SDoH) such as homelessness. Much of this information is contained in clinical notes and can be extracted using natural language processing (NLP). This data can provide valuable information for researchers and policymakers studying long-term housing outcomes for individuals with a history of homelessness. However, studying homelessness longitudinally in the EHR is challenging due to irregular observation times. In this work, we applied an NLP system to extract housing status for a cohort of patients in the US Department of Veterans Affairs (VA) over a three-year period. We then applied inverse intensity weighting to adjust for the irregularity of observations, which was used generalized estimating equations to estimate the probability of unstable housing each day after entering a VA housing assistance program. Our methods generate unique insights into the long-term outcomes of individuals with a history of homelessness and demonstrate the potential for using EHR data for research and policymaking.
Time-resolved molecular measurements reveal changes in astronauts during spaceflight
Authors: Zheng Minzhang , Charvat Jacqueline , Zwart Sara R. , Mehta Satish , Crucian Brian E. , Smith Scott M. , He Jin , Piermarocchi Carlo , Mias George I. 
Published: March 2023

AbstractFrom the early days of spaceflight to current missions, astronauts continue to be exposed to multiple hazards that affect human health, including low gravity, high radiation, isolation during long-duration missions, a closed environment and distance from Earth. Their effects can lead to adverse physiological changes and necessitate countermeasure development and/or longitudinal monitoring. A time-resolved analysis of biological signals can detect and better characterize potential adverse events during spaceflight, ideally preventing them and maintaining astronauts’ wellness. Here we provide a time-resolved assessment of the impact of spaceflight on multiple astronauts (n=27) by studying multiple biochemical and immune measurements before, during, and after long-duration orbital spaceflight. We reveal space-associated changes of astronauts’ physiology on both the individual level and across astronauts, including associations with bone resorption and kidney function, as well as immune-system dysregulation.