bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Diagnostic Potential of Combined Photoplethysmography and Ankle-Brachial Index in Peripheral Arterial Obstructive Disease: A Comparative Analysis with Doppler Ultrasound
Authors: Huang Han-Luen , Chang Chia-Hsiu , Lo Men-Tzung , Lin Chen 
Published: February 2024

AbstractBackground and aimsWhile ankle-brachial index (ABI) and photoplethysmography (PPG) have also shown adequate sensitivity in detecting PAOD, their accuracies can be compromised in detecting milder cases. We aim to evaluate the diagnostic value of combining ABI and PPG in detecting PAOD for subjects with high atherosclerotic cardiovascular risks compared to duplex sonography.Methods130 participants underwent ABI, PPG, and duplex sonography during the evaluation process. Two parameters were derived from the PPG-PPG amplitude ratio of the lower-to-upper extremities (PPGratio) and the PPG amplitude of the lower extremity (PPGamp). Sensitivity, specificity, accuracy, and the area under receiver operative curve (AUC) were calculated for PPG parameters and ABI, and the combination of both methods. Multivariate analysis was performed for adjusting other relevant risk factors.Results65 participants were diagnosed with PAOD based on duplex sonography. The ROC analysis revealed optimal cut-off values in diagnosing PAOD were 0.417 for PPGratioand 58 for PPGamp. Both PPGratioand PPGampdemonstrated significantly higher sensitivities, 78.4% and 75.7%, in comparison to 55.9% of ABI<0.9 (p<0.05). Lower PPGratioand PPGampremained independently associated with PAOD even after adjusting for confounding factors. The AUC of combination models, including model 1 (ABI and PPGratio), model 2 (ABI and PPGamp), and model 3 (ABI, PPGratio, and PPGamp), exhibited improved performance with AUCs of 0.922, 0.922, and 0.931 (all p<0.01) compared to that of ABI alone (AUC:0.822).ConclusionsThe combination of ABI and PPG increases the sensitivity and accuracy prominently in diagnosing PAOD compared to ABI or PPG alone.
DexDesign: A new OSPREY-based algorithm for designingde novoD-peptide inhibitors
Authors: Guerin Nathan , Childs Henry , Zhou Pei , Donald Bruce R. 
Published: February 2024

AbstractWith over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designingde novoD-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan, which enable exponential reductions in the size of the peptide sequence search space. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a new framework for analyzingde novopeptides—evaluation along a replication/restitution axis—and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets’ endogenous ligands, validating the peptides’ potential as lead therapeutic candidates. We provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.
Advanced Surface Passivation for High-Sensitivity Studies of Biomolecular Condensates
Authors: Yao Run-Wen , Rosen Michael K. 
Published: February 2024

AbstractBiomolecular condensates are cellular compartments that concentrate biomolecules without an encapsulating membrane. In recent years, significant advances have been made in the understanding of condensates through biochemical reconstitution and microscopic detection of these structures. Quantitative visualization and biochemical assays of biomolecular condensates rely on surface passivation to minimize background and artifacts due to condensate adhesion. However, the challenge of undesired interactions between condensates and glass surfaces, which can alter material properties and impair observational accuracy, remains a critical hurdle. Here, we introduce an efficient, generically applicable, and simple passivation method employing self-assembly of the surfactant Pluronic F127 (PF127). The method greatly reduces nonspecific binding across a range of condensates systems for both phase-separated droplets and biomolecules in dilute phase. Additionally, by integrating PF127 passivation with the Biotin-NeutrAvidin system, we achieve controlled multi-point attachment of condensates to surfaces. This not only preserves condensate properties but also facilitates long-time FRAP imaging and high-precision single-molecule analyses. Using this method, we have explored the dynamics of polySIM molecules within polySUMO/polySIM condensates at the single-molecule level. Our observations suggest a potential heterogeneity in the distribution of available polySIM-binding sites within the condensates.Significance StatementThe understanding of biomolecular condensates has significantly benefited from biochemical reconstitution with microscopy detection. Here, we present a novel surface passivation method utilizing self-assembly of Pluronic F127 on hydrophobic surfaces. This approach not only effectively minimizes non-specific binding without altering the physical properties of the condensates but also offers universal passivation across a variety of condensate systems. It demonstrates high resistance to different treatments and enables condensate immobilization through controlled anchor points. This allows for highly sensitive analytical techniques, including single-molecule imaging. The simplicity and high-performance of this method, coupled with time and cost efficiencies, could facilitate robustness and throughput of experiments, and could broaden the accessibility of biochemical phase separation studies to a wider scientific community.
The genomic landscape of Acute Respiratory Distress Syndrome: a meta-analysis by information content of genome-wide studies of the host response
Authors: Millar Jonathan E , Clohisey-Hendry Sara , McMannus Megan , Zechner Marie , Wang Bo , Parkinson Nick , Jungnickel Melissa , Zaki Nureen Mohamad , Pairo-Castineira Erola , Rawlik Konrad , Rogers Joshua , Russell Clark D , Bos Lieuwe DJ , Meyer Nuala J , Calfee Carolyn , McAuley Daniel F , Shankar-Hari Manu , Baillie J Kenneth 
Published: February 2024

AbstractAcute respiratory distress syndrome (ARDS) is a clinically defined syndrome of acute hypoxaemic respiratory failure secondary to non-cardiogenic pulmonary oedema. It arises from a diverse set of triggers and encompasses marked biological heterogeneity, complicating efforts to develop effective therapies. An extensive body of recent work (including transcriptomics, proteomics, and genome-wide association studies) has sought to identify proteins/genes implicated in ARDS pathogenesis. These diverse studies have not been systematically collated and interpreted.To solve this, we performed a systematic review and computational integration of existing omics data implicating host response pathways in ARDS pathogenesis. We identified 40 unbiased studies reporting associations, correlations, and other links with genes and single nucleotide polymorphisms (SNPs), from 6,856 ARDS patients.We used meta-analysis by information content (MAIC) to integrate and evaluate these data, ranking over 7,000 genes and SNPs and weighting cumulative evidence for association. Functional enrichment of strongly-supported genes revealed cholesterol metabolism, endothelial dysfunction, innate immune activation and neutrophil degranulation as key processes. We identify 51 hub genes, most of which are potential therapeutic targets. To explore biological heterogeneity, we conducted a separate analysis of ARDS severity/outcomes, revealing distinct gene associations and tissue specificity. Our large-scale integration of existing omics data in ARDS enhances understanding of the genomic landscape by synthesising decades of data from diverse sources. The findings will help researchers refine hypotheses, select candidate genes for functional validation, and identify potential therapeutic targets and repurposing opportunities. Our study and the publicly available computational framework represent an open, evolving platform for interpretation of ARDS genomic data.
Simulating desegregation through affordable housing development: an environmental health impact assessment of Connecticut zoning law
Authors: Prasanth Saira , Oloyede Nire , Zhang Xuezhixing , Chen Kai , Carrión Daniel 
Published: February 2024

AbstractResidential segregation shapes access to health-promoting resources and drives health inequities in the United States. Connecticut’s Section 8-30g incentivizes municipalities to develop a housing stock that is at least 10% affordable housing. We used this implicit target to project the impact of increasing affordable housing across all 169 Connecticut municipalities on all-cause mortality among low-income residents. We modeled six ambient environmental exposures: fine particulate matter (PM2.5), ozone (O3), nitrogen dioxide (NO2), summertime daily maximum heat index, greenness, and road traffic noise. We allocated new affordable housing to reach the 10% target in each town and simulated random movement of low-income households into new units using an inverse distance weighting penalty. We then quantified exposure changes and used established exposure-response functions to estimate deaths averted stratified by four ethnoracial groups: Asian, Hispanic or Latino, non-Hispanic Black, and non-Hispanic White. We quantified racialized segregation by computing a multi-group index of dissimilarity at baseline and post-simulation. Across 1,000 simulations, in one year (2019) we found on average 169 (95% CI: 84, 255) deaths averted from changes in greenness, 71 (95% CI: 49, 94) deaths averted from NO2, 9 (95% CI: 4, 14) deaths averted from noise, and marginal impacts from other exposures, with the highest rates of deaths averted observed among non-Hispanic Black and non-Hispanic White residents. Multi-group index of dissimilarity declined on average in all eight Connecticut counties post-simulation. Sensitivity analyses simulating a different population movement strategy and modeling a different year (2018) yielded consistent results. Strengthening desegregation policy may reduce deaths from environmental exposures among low-income residents. Further research should explore non-mortality impacts and additional mechanisms by which desegregation may advance health equity.
Mapping Evidence on Road Safety Information Management Systems in Sub-Saharan Africa: Scoping Review Protocol
Authors: Amme Shemsedin , Seid Sheka Shemsi , Bogale Mekonen , Amdisa Demuma , Husen Abdusemed , Tilahun Getachew , Jibat Nega , Mamo Getachew 
Published: February 2024

AbstractBackgroundRoad safety information management systems (RSIMS) play a vital role in improving road safety in sub-Saharan Africa (SSA) by providing reliable and timely data and information for evidence-based decision making. However, little is known about RSIMS in SSA.ObjectiveThe objective of this scoping review is to map the extent and type of evidence on RSIMS in Sub-Saharan Africa.Inclusion criteriaThis review will include sources that report on the application of RSIMS in SSA. The source of information that have considered the use of electronic data systems or software related to any aspects of the road safety management will be included irrespective of their designs or methods. Sources that focused on other populations, concepts, or context will be excluded.MethodsA comprehensive search of published studies in electronic databases such as Scopus, PubMed, Embase, PubMed, RSKC, ARSO, Lens, and in the sources of grey literature will be carried out to identify relevant sources of information reported in English from 2019 onwards. A scoping review will be performed based on the JBI frameworks using Parsifal platform. Reviewers will independently screen the sources for eligibility, extract data using a JBI-adapted tool, analyze data using descriptive statistics and thematic analysis. The results will be presented in tables, figures, diagrams, and a narrative summary.Registration detailsThis protocol for this scoping review has been registered on OSF,https://osf.io/6e2mx/.
Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure
Authors: Peterson Tess E , Hahn Virginia S , Moaddel Ruin , Zhu Min , Haberlen Sabina A , Palella Frank J , Plankey Michael , Bader Joel S , Lima Joao AC , Gerszten Robert E , Rotter Jerome I , Rich Stephen S , Heckbert Susan R , Kirk Gregory D , Piggott Damani A , Ferrucci Luigi , Margolick Joseph B , Brown Todd T , Wu Katherine C , Post Wendy S 
Published: February 2024

ABSTRACTBackgroundPeople living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH.MethodsWe performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression.ResultsAmong 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m2. Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up).ConclusionProteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.
Phosphorylation code of human nucleophosmin includes four cryptic sites for hierarchical binding of 14-3-3 proteins
Authors: Kapitonova Anna A. , Perfilova Kristina V. , Cooley Richard B. , Sluchanko Nikolai N. 
Published: February 2024

AbstractNucleophosmin (NPM1) is the 46th most abundant human protein with many functions whose dysregulation leads to various cancers. Pentameric NPM1 resides in the nucleolus but can also shuttle to the cytosol. NPM1 is regulated by multisite phosphorylation, yet molecular consequences of site-specific NPM1 phosphorylation remain elusive. Here we identify four 14-3-3 protein binding sites in NPM1 concealed within its oligomerization and α-helical C-terminal domains that are found phosphorylatedin vivo. By combining mutagenesis, in-cell phosphorylation and PermaPhos technology for site-directed incorporation of a non-hydrolyzable phosphoserine mimic, we show how phosphorylation promotes NPM1 monomerization and partial unfolding, to recruit 14-3-3 dimers with low-micromolar affinity. Using fluorescence anisotropy we quantified pairwise interactions of all seven human 14-3-3 isoforms with four recombinant NPM1 phosphopeptides and assessed their druggability by fusicoccin. This revealed a complex hierarchy of 14-3-3 affinities toward the primary (S48, S293) and secondary (S106, S260) sites, differentially modulated by the small molecule. As three of these 14-3-3 binding phospho-sites in NPM1 reside within signal sequences, this work highlights a key mechanism of NPM1 regulation by which NPM1 phosphorylation promotes 14-3-3 binding to control nucleocytoplasmic shuttling. It also provides further evidence that phosphorylation-induced structural rearrangements of globular proteins serve to expose otherwise cryptic 14-3-3-binding sites that are important for cellular function.
The RNA-binding activity of the TRIM-NHL protein NHL-2 is essential for miRNA-mediated gene regulation
Authors: Saadat Nasim , Colson Rhys N. , Grimme Acadia L. , Seroussi Uri , Anderson Joshua W. , Claycomb Julie M. , Wilce Matthew C. J. , McJunkin Katherine , Wilce Jacqueline A. , Boag Peter R. 
Published: February 2024

AbstractThe conserved TRIM-NHL protein, NHL-2, plays a key role in small RNA pathways inCaenorhabditis elegans. NHL-2 has been shown to interact with U-rich RNA through its NHL domain, but the importance to its biological function is unknown. We defined the crystal structure of the NHL domain to 1.4 Å resolution and identified residues that affect affinity for U-rich RNA. Functional analysis of an NHL-2 RNA-binding loss-of-function mutant demonstrated defects in the heterochronic pathway, suggesting that RNA binding is essential for its role in this miRNA pathway. Processing bodies were enlarged in the NHL-2 RNA-binding mutant, suggesting a defect in mRNA decay. We also identified the eIF4E binding protein IFET-1 as a strong synthetic interactor with NHL-2 and the DEAD box RNA helicase CGH-1 (DDX6), linking NHL-2 function to translation repression. We demonstrated that in the absence of NHL-2, there was an enrichment of miRNA transcripts associated with the miRNA pathway Argonaute proteins ALG-2 and ALG-2. We demonstrate that NHL-2 RNA-binding activity is essential forlet-7family miRNA-mediated translational repression. We conclude that the NHL-2, CGH-1, and IFET-1 regulatory axes work with the core miRISC components to form an effector complex that is required for some, but not all, miRNAs.
Bacteria use spatial sensing to direct chemotaxis on surfaces
Authors: Wheeler James H. R. , Foster Kevin R. , Durham William M. 
Published: February 2024

AbstractPlanktonic bacteria navigate chemical gradients using temporal sensing to detect changes in concentration over time as they swim. Here we show that surface-attached bacteria use a fundamentally different mode of sensing during chemotaxis. We combined microfluidic experiments, massively parallel cell tracking, and fluorescent reporters to study howPseudomonas aeruginosasenses chemical gradients during pili-based “twitching” chemotaxis on surfaces. First, we asked whether surface-attached cells use temporal sensing by exposing them to temporal chemical gradients generated via Taylor-Aris dispersion. However, we find that temporal changes in concentration do not induce changes in motility, indicating that twitching cells do not sense chemical gradients like swimming bacteria do. We, therefore, designed experiments to test whether cells can detect chemical gradients across the length of their bodies. In these experiments, we follow the localisation of a fluorescent protein fusion to quantify the chemotactic behaviour of stationary cells in an alternating chemical gradient. We find thatP. aeruginosacells can directly sense differences in concentration across the lengths of their bodies, even in the presence of strong temporal fluctuations. Our work reveals thatP. aeruginosacells are capable of spatial sensing, thus overturning the widely held notion that bacterial cells are too small to directly sense chemical gradients in space.
The cellular representation of temperature across the somatosensory thalamus
Authors: Leva Tobias , Whitmire Clarissa J. , Sauve Ilaria , Bokiniec Phillip , Memler Charlene , Horn Bibiana M. , Vestergaard Mikkel , Carta Mario , Poulet James F.A. 
Published: February 2024

AbstractAlthough distinct thalamic nuclei encode sensory information for almost all sensory modalities, the existence of a thalamic representation of temperature with a role in thermal perception remains unclear. To address this, we performed high-density electrophysiological recordings across the entire forelimb somatosensory thalamus in awake mice, and identified an anterior and a posterior representation of temperature that spans three thalamic nuclei. We found that these parallel representations show fundamental differences in the cellular encoding of temperature which reflects their cortical output targets. While the anterior representation encodes cool only and the posterior both cool and warm; in both representations cool was more densely represented and showed shorter latency, more transient responses as compared to warm. Moreover, thalamic inactivation showed a major role in thermal perception. Our comprehensive dataset identifies the thalamus as a key structure in thermal processing and highlights a novel posterior pathway in the thalamic representation of warm and cool.
Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity
Authors: Liu Jiahui , Zaidi Ali , Pike Christian J. 
Published: February 2024

AbstractObesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer’s disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglial TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglial TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.