bluuebunny/crossref_metadata_2025_split huggingface dataset:
MACE prediction using high-dimensional machine learning and mechanistic interpretation: A longitudinal cohort study in US veterans
Authors: Dhaubhadel Sayera , Kolade Beauty , Ribeiro Ruy M. , Ganguly Kumkum , Hengartner Nicolas W. , Bhattacharya Tanmoy , Cohn Judith D. , Agarwal Khushbu , Cho Kelly , Costa Lauren , Ho Yuk-Lam , Murata Allison E. , Murata Glen H. , Vassy Jason L. , Posner Daniel C. , Gaziano J. Michael , Sun Yan V. , Wilson Peter W. , Madduri Ravi , Justice Amy C. , Tsao Phil , O’Donnell Christopher J. , Damrauer Scott , McMahon Benjamin H. 
Published: November 2022

AbstractHigh dimensional predictive models of Major Adverse Cardiac Events (MACE), which includes heart attack (AMI), stroke, and death caused by cardiovascular disease (CVD), were built using four longitudinal cohorts of Veterans Administration (VA) patients created from VA medical records. We considered 247 variables / risk factors measured across 7.5 years for millions of patients in order to compare predictions for the first reported MACE event using six distinct modelling methodologies. The best-performing methodology varied across the four cohorts. Model coefficients related to disease pathophysiology and treatment were relatively constant across cohorts, while coefficients dependent upon the confounding variables of age and healthcare utilization varied considerably across cohorts. In particular, models trained on a retrospective case-control (Rcc) cohort (where controls are matched to cases by date of birth cohort and overall level of healthcare utilization) emphasize variables describing pathophysiology and treatment, while predictions based on the cohort of all active patients at the start of 2017 (C-17) rely much more on age and variables reflecting healthcare utilization. In consequence, directly using an Rcc-trained model to evaluate the C-17 cohort resulted in poor performance (C-statistic = 0.65). However, a simple reoptimization of model dependence on age, demographics, and five other variables improved the C-statistic to 0.74, nearly matching the 0.76 obtained on C-17 by a C-17-trained model. Dependence of MACE risk on biomarkers for hypertension, cholesterol, diabetes, body mass index, and renal function in our models was consistent with the literature. At the same time, including medications and procedures provided important indications of both disease severity and the level of treatment. More detailed study designs will be required to disentangle these effects.
Automated analysis of PD1 and PDL1 in lymph nodes and the microenvironment of transmissible tumors in Tasmanian devils
Authors: Russell Grace G , Palmieri Chiara , Darby Jocelyn , Morris Gary P. , Fountain-Jones Nicholas M. , Pye Ruth J. , Flies Andrew S. 
Published: November 2022

AbstractThe wild Tasmanian devil (Sarchophilus harrisii) population has suffered a devastating decline due to two clonal transmissible cancers. Devil facial tumor 1 (DFT1) was first observed in 1996, followed by a second genetically distinct transmissible tumor, devil facial tumor 2 (DFT2), in 2014. DFT1/2 frequently metastasize, with lymph nodes being common metastatic sites. Downregulation of MHC-I by DFT1 cells is a primary means of evading allograft immunity aimed at polymorphic MHC-I proteins. DFT2 cells constitutively express MHC-I, and MHC-I is upregulated on DFT1/2 cells by interferon gamma, suggesting other immune evasion mechanisms may contribute to overcoming allograft and anti-tumor immunity. Human clinical trials have demonstrated PD1/PDL1 blockade effectively treats patients showing increased expression of PD1 in tumor draining lymph nodes, and PDL1 on peritumoral immune cells and tumor cells. The effects of DFT1/2 on systemic immunity remain largely uncharacterized. This study applied the open-access software QuPath to develop a semiautomated pipeline for whole slide analysis of stained tissue sections to quantify PD1/PDL1 expression in devil lymph nodes. The QuPath protocol provided strong correlations to manual counting. PD-1 expression was approximately 10-fold higher than PD-L1 expression in lymph nodes and was primarily expressed in germinal centers, whereas PD-L1 expression was more widely distributed throughout the lymph nodes. The density of PD1 positive cells was increased in lymph nodes containing DFT2 metastases, compared to DFT1. This suggests PD1/PDL1 exploitation may contribute to the poorly immunogenic nature of transmissible tumors in some devils and could be targeted in therapeutic or prophylactic treatments.
Kinetic Model With Feedback Cycle for Age-Dependent Beta Amyloid Accumulation in Mice
Authors: Tyng Vivian , Kellman Michael E. 
Published: November 2022

AbstractAmyloid beta (Aβ) is believed to play a key role in Alzheimer’s disease (AD), whose causes, progression, diagnosis, and treatment nonetheless remain poorly understood despite decades of research. Recent studies suggest that Aβ in its various forms participates in multiple mutual feedback loops (“vicious cycles”) including tauopathy, oxidative stress, inflammation, calcium dysregulation, excitotoxicity, and probably many others, eventually leading to neurodegeneration and cognitive decline. Here, we explore a simple kinetic model of a coupled feedback vicious cycle for Aβ buildup based on literature data for Tg2576 mice. The model is used to examine the efficacy of various hypothetical therapeutic approaches, either singly or in combination, to mitigate Aβ buildup. While our computational results support the possible efficacy of combination interventions, they also suggest caution, inasmuch as clear synergy is not found. This kinetic approach highlights the essential importance of a vicious cycle of positive feedbacks in a quantitative model.
Network analysis uncovers associations in the turnover of C1 molecules in a winter lake
Authors: Mondav Rhiannon , Martin Gaëtan , Peura Sari , Garcia Sarahi L 
Published: November 2022

AbstractThe generation and consumption of single carbon molecules (CO2and CH4) by aquatic microbial communities is an essential aspect of the global carbon budget. Organic carbon flow (warm sunlit regimes) is depicted as beginning at the surface with autochthonous fixation followed by biomass settling to sediments, CO2 respiration to the atmosphere, and outflow. We sought to broaden understanding of C1 cycling and consortia by examining the microbial community of a below-ice lake water column in which both input and output are likely disrupted due to ice cover. By analysing the microbial community composition and co-occurrence network of an ice-covered lake timeseries, we were able to identify potential consortia involved in C1 cycling. The network confirmed known associations supporting the efficacy of such analyses but also pointed to previously unknown potential associations. Further and contrary to typical organic carbon flow under warm sunlit regimes, we found support for upward flow of recently fixed carbon in cold low-light conditions under-ice in winter.
Targeting AAV vectors to the CNS viade novoengineered capsid-receptor interactions
Authors: Huang Qin , Chen Albert T. , Chan Ken Y. , Sorensen Hikari , Barry Andrew J. , Azari Bahar , Beddow Thomas , Zheng Qingxia , Zhao Binhui , Tobey Isabelle G. , Eid Fatma-Elzahraa , Chan Yujia A. , Deverman Benjamin E. 
Published: November 2022

AbstractViruses have evolved the ability to bind and enter cells through interactions with a wide variety of host cell macromolecules. Here, we screened for AAV capsids that bind two host cell proteins expressed on the mouse blood-brain barrier, LY6A or the related protein LY6C1. Introducing interactions with either protein target generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms. In contrast to the AAV-PHP.B capsid family, which interacts with LY6A and only exhibits its enhanced CNS tropism in a subset of mouse strains, the capsids that engage LY6C1 maintain their CNS tropism in BALB/cJ mice. Compared to conventionalin vivoscreens for CNS cell transducing capsids, a single round of protein target binding screening recovered significantly more capsids with enhanced performance that were validated in subsequentin vivoscreens. Moreover, the initial screening round generated reproducible and quantitative target binding data that enabled the efficient machine learning-guided generation of more diverse targetspecific capsids. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.
Polyploidy impacts population growth and competition with diploids: multigenerational experiments reveal key life history tradeoffs
Authors: Anneberg Thomas J. , O’Neill Elizabeth M. , Ashman Tia-Lynn , Turcotte Martin M. 
Published: November 2022

SummaryEcological theory predicts that early generation polyploids (“neopolyploids”) should quickly go extinct owing to the disadvantages of rarity and competition with their diploid progenitors. However, polyploids persist in natural habitats globally. This paradox has been addressed theoretically by recognizing that reproductive assurance of neopolyploids and niche differentiation can promote establishment. Despite this, the direct effects of polyploidy at the population level remain largely untested even though establishment is an intrinsically population-level process.We conducted population-level experiments where investment in current and future growth was tracked in four lineage pairs of diploids and synthetic neopolyploids of the aquatic plantSpirodela polyrhiza. Population growth was evaluated with and without competition between diploids and neopolyploids across a range of nutrient treatments.Although neopolyploid populations produce more biomass, they reach lower population sizes, and have reduced carrying capacities when growing alone or in competition across all nutrient treatments. Thus, contrary to individual-level studies, our population-level data suggest that neopolyploids are competitively inferior to diploids. Conversely, neopolyploid populations have greater investment in dormant propagule production than diploids.Our results show that neopolyploid populations should not persist based on current growth dynamics, but high potential future growth may allow polyploids to establish in subsequent growing seasons.
Hereditary Fusion Genes Are Associated with the Inheritance of Acute Myeloid Leukemia
Authors: Ling Fei , Zhuo Degen 
Published: November 2022

ABSTRACTFusion genes are thought to be somatic and cause cancer, including acute myeloid leukemia (AML). Validating highly-recurrent fusion genes in healthy samples compelled us to systematically study hereditary fusion genes (HFGs). Here, we used curated HFGs to analyze AML fusion genes, and we identified 243 HFGs associated with AML inheritance from 926 potential HFGs. Many HFGs were one-to-many and many-to-one fusions that augmented signals from environmental and genomic alterations and seemed to support the “two-hit” hypothesis. The most highly-recurrent HFGs were also observed in multiple myeloma and monozygotic twin datasets, suggesting that AML is a complex genetic disease. HFGs, as cancer genetic biomarkers, are the most basic foundations for future genetic and genomic studies.
Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox
Authors: Siepe Dirk H. , Picton Lora K. , Garcia K. Christopher 
Published: November 2022

ABSTRACTIn recent years, targeted protein degradation (TPD) of plasma membrane proteins by hijacking the ubiquitin proteasome system (UPS) or the lysosomal pathway have emerged as novel therapeutic avenues in drug development to address and inhibit canonically difficult targets. While TPD strategies have been successful to target cell surface receptors, these approaches are limited by the availability of suitable binders to generate heterobifunctional molecules. Here, we present the development of a nanobody (VHH) based degradation toolbox termed REULR (Receptor Elimination by E3 Ubiquitin Ligase Recruitment). We generated human and mouse cross-reactive nanobodies against 5 transmembrane PA-TM-RING type E3 Ubiquitin Ligases (RNF218, RNF130, RNF167, RNF43, ZNRF3) covering a broad range and selectivity of tissue expression with which we characterized expression in human and mouse cell lines and immune cells (PBMCs). We demonstrate that heterobifunctional REULR molecules can enforce transmembrane E3 ligase interaction with a variety of disease relevant target receptors (EGFR, EPOR, PD-1) by induced proximity resulting in effective membrane clearance of the target receptor at varying levels. In addition, we designed E3 Ligase self-degrading molecules, ‘fratricide’ REULRs (RNF128, RNF130, RENF167, RNF43, ZNRF3), that allow downregulation of one or several E3 Ligases from the cell surface and consequently modulate receptor signaling strength. REULR molecules represent a VHH-based, modular and versatile “mix and match” targeting strategy for facile modulation of cell surface proteins by induced proximity to transmembrane PA-TM-RING E3 ligases.
The evolution of antibiotic resistance is associated with collateral drug phenotypes inMycobacterium tuberculosis
Authors: Waller Natalie J.E. , Cheung Chen-Yi , Cook Gregory M. , McNeil Matthew B. 
Published: November 2022

AbstractThe increasing incidence of drug resistance inMycobacterium tuberculosishas diminished the efficacy of almost all available antibiotics, complicating efforts to combat the spread of this global health burden. Alongside the development of new drugs, optimised drug combinations are needed to improve treatment success and prevent the further spread of antibiotic resistance. Typically, antibiotic resistance leads to reduced sensitivity, yet in some cases the evolution of drug resistance can lead to enhanced sensitivity to unrelated drugs. This phenomenon of collateral sensitivity is largely unexplored inM. tuberculosisbut has the potential to identify alternative therapeutic strategies to combat drug-resistant strains that are unresponsive to current treatments. To investigate the collateral impacts of drug resistance inM. tuberculosis, we generated an isogenic collection of mono-resistant strains in a PC2-approved avirulent background ofM. tuberculosisagainst 23 structurally and functionally diverse antibiotics. Through drug susceptibility profiling, genomics, and evolutionary studies we provide evidence for the existence of collateral drug sensitivity inM. tuberculosis. In proof-of-concept studies, we demonstrate how collateral drug phenotypes can be targeted to select against and prevent the emergence of drug-resistant strains ofM. tuberculosis. This study highlights that the evolution of drug resistance inM. tuberculosisleads to collateral drug responses that can be exploited to design improved drug regimens.
A CRISPRi-based genetic resource to study essentialStaphylococcus aureusgenes
Authors: Reed Patricia , Sorg Moritz , Alwardt Dominik , Serra Lúcia , Veiga Helena , Schäper Simon , Pinho Mariana G. 
Published: November 2022

AbstractWe have optimized a CRISPR interference system to facilitate gene knockdown in the gram-positive bacterial pathogenStaphylococcus aureus.Our approach used a CRISPRi system derived fromStreptococcus pyogenes,which involves the co-expression of thedcas9gene encoding a catalytically inactive Cas9 protein and a customizable single guide RNA (sgRNA). In our system,dcas9is expressed from a single copy in the chromosome of methicillin resistantS. aureus(MRSA) strains COL or JE2, under the control of a tightly regulated promoter, inducible by anhydrotetracycline. The sgRNAs are expressed from a replicative plasmid under the control of a constitutively active promoter. This system enables efficient, inducible, knockdown of both essential and non-essential genes. Using this approach, we constructed the Lisbon CRISPRi Mutant Library (LCML) comprising 261 strains, in the JE2 background, containing sgRNAs targeting 200 essential genes/operons. This library facilitates the study of the function of essentialS. aureusgenes and is complementary to the Nebraska Transposon Mutant Library which consists of nearly 2000 strains, each carrying a transposon insertion within a non-essential gene. The availability of these two libraries will facilitate the study ofS. aureuspathogenesis and biology.Abstract ImportanceStaphylococcus aureusis an important clinical pathogen that causes a high number of antibiotic resistant infections. The study ofS. aureusbiology, and particularly of the function of essential proteins, is of particular importance to develop new approaches to combat this pathogen. We have optimized a CRISPRi system that allows efficient targeting of essentialS. aureusgenes. Furthermore, we have used that system to construct a library of 261 strains which allow the depletion of essential proteins encoded in 200 genes/operons. This library, which we have named Lisbon CRISPRi Mutant Library (LCML), should facilitate the study ofS. aureuspathogenesis and biology.
Identification of the EH CRISPR-Cas9 system on a metagenome and its application to genome engineering
Authors: Esquerra-Ruvira Belen , Baquedano Ignacio , Ruiz Raul , Fernandez Almudena , Montoliu Lluis , Mojica Francisco JM 
Published: November 2022

AbstractNon-coding RNAs (crRNAs) produced from clustered regularly interspaced short palindromic repeats (CRISPR) loci, and CRISPR associated (Cas) proteins of the prokaryotic CRISPR-Cas systems, form complexes that interfere with the spread of transmissible genetic elements through Cas-catalysed cleavage of foreign genetic material matching the guide crRNA sequences. The easily programmable targeting of nucleic acids enabled by these ribonucleoproteins has facilitated the implementation of CRISPR-based molecular biology tools forin vivoandin vitromodification of DNA and RNA targets. Despite the diversity of DNA-targeting Cas nucleases so far identified, native and engineered derivatives of theStreptococcus pyogenesSpCas9 are the most used for genome engineering, at least in part due to its catalytic robustness and the requirement of an exceptionally short motif (5’-NGG-3’ PAM) flanking the target sequence. However, the large size of the SpCas9 variants impairs the delivery of the tool to eukaryotic cells and smaller alternatives are demanded. Here we identify in a metagenome a new CRISPR-Cas9 system associated with a smaller Cas9 protein (EHCas9) that targets DNA sequences flanked by 5’-NGG-3’ PAMs. We develop a simplified EHCas9 tool that specifically cleaves DNA targets and is functional for genome editing applications in prokaryotes and eukaryotic cells.
Propagation-based phase-contrast breast computed tomography: a visual grading assessment of the performance of photon-counting and flat-panel X-ray detectors
Authors: Giannotti Nicola , Taba Seyedamir Tavakoli , Gureyev Timur , Lewis Sarah , Brombal Luca , Longo Renata , Donato Sandro , Tromba Giuliana , Pena Lucia Arana , Hausermann Daniel , Hall Chris , Maksimenko Anton , Arhatari Benedicta , Nesterets Yakov , Brennan Patrick 
Published: November 2022

AbstractRationale and objectivesBreast cancer represents the leading cause of death from cancer in women worldwide. Early detection of breast tumours improves the prognosis and survival rate. Propagation-based phase-contrast computed tomography (PB-CT) is a technique that uses refraction and absorption of the X-ray to produce images for clinical applications. This study compared the performance of photon-counting and flat-panel X-ray detectors in PB-CT breast imaging using synchrotron radiation.Materials and methodsMastectomy specimens underwent PB-CT imaging using the Hamamatsu C10900D Flat Panel and PIXIRAD-8 CdTe single-photon-counting detectors. PB-CT images generated at different imaging conditions were compared to absorption-based CT (AB-CT) reference images acquired with the same detectors to investigate the image quality improvement delivered by PB-CT relative to AB-CT. The image quality of the different image sets was assessed by eleven readers in a visual grading characteristics (VGC) study.ResultsThe intraclass correlation coefficient showed a moderate/good interobserver agreement for the image set analysed (ICC = 0.626, p = <0.001). The area under the curve showed that the image quality improvement in PB-CT images obtained by the PIXIRAD-8 CdTe single-photon-counting detector were consistently higher than the one for flat-panel Hamamatsu detector. The level of improvement in image quality was more substantial at lower radiation doses.ConclusionIn this study, the PIXIRAD-8 photon-counting detector was associated with higher image quality scores at all tested radiation dose levels, which was likely a result of the combined effect of the absence of dark current noise and better spatial resolution, compared to the flat-panel detector.
Moderate to Vigorous Intensity Locomotor Training After Stroke: A Systematic Review and Meta-Analysis of Mean Effects and Individual Response Variability
Authors: Boyne Pierce , Miller Allison , Kubalak Owen , Mink Caroline , Reisman Darcy S. , Fulk George 
Published: November 2022

ABSTRACTBackground and PurposeThis meta-analysis quantified mean effects of moderate-to-vigorous intensity locomotor training (LTmv) on walking outcomes in subacute and chronic stroke, and the magnitude of individual variability in LTmvresponse.MethodsDatabases were searched for randomized trials comparing LTmvwith no intervention, non-gait intervention or low-intensity gait training. Comfortable gait speed (CGS), fastest gait speed (FGS), 6-minute walk distance (6MWT), walking activity (steps/day) and adverse effect/event (AE) data were extracted. Pooled estimates were calculated for mean changes within and between groups, the relative risk of different AEs, and the standard deviation of individual response (SDIR) to LTmvversus control groups, stratified by study chronicity where possible.ResultsThere were 19 eligible studies (total N=1,096); 14 in chronic stroke (N=839) and 5 in subacute stroke (N=257). Compared with control interventions, LTmvyielded significantly greater increases in CGS, FGS and 6MWT in both subacute and chronic stroke, with subacute studies showing significantly greater effect sizes for CGS, FGS and nearly 6MWT (p=0.054). In 4 studies reporting steps/day data, LTmvwas not significantly different from control interventions. In 14 studies reporting on AEs, there were no treatment-related serious AEs among 398 LTmvparticipants. SDIRestimates indicated significant individual response variability for CGS, nearly FGS (p=0.0501) and 6MWT.Discussion and ConclusionsLTmvimproves mean walking capacity outcomes in subacute and chronic stroke and does not appear to have high risk of serious harm, but response magnitude varies between chronicity subgroups and individuals, and few studies have tested effects on daily walking activity or non-serious AEs.