bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic Prediction of Cellular Immune Responses to Mumps Vaccine
Authors: Coombes Brandon J. , Ovsyannikova Inna G. , Schaid Daniel J. , Warner Nathaniel D. , Poland Gregory A. , Kennedy Richard B. 
Published: February 2024

AbstractIn this report, we provide a follow-up analysis of a previously published genome-wide association study of host genetic variants associated with inter-individual variations in cellular immune responses to mumps vaccine. Here we report the results of a polygenic score (PGS) analysis showing how common variants can predict mumps vaccine response. We found higher PGS for IFNγ, IL-2, and TNFα were predictive of higher post-vaccine IFNγ (p-value = 2e-6), IL-2 (p = 2e-7), and TNFα (p = 0.004) levels, respectively. Control of immune responses after vaccination is complex and polygenic in nature. Our results suggest that the PGS-based approach enables better capture of the combined genetic effects that contribute to mumps vaccine-induced immunity, potentially offering a more comprehensive understanding than traditional single-variant GWAS. This approach will likely have broad utility in studying genetic control of immune responses to other vaccines and to infectious diseases.
FATAL: A Forensic AuTopsy Annotation tooL for digital recording of autopsy findings
Authors: Petersen Mikkel V. , Thomsen Asser H. , Hansen Kasper 
Published: February 2024

AbstractThe findings from forensic autopsies, where cause of death must be established and reported to legal authorities, are reported in paper-based formats. Practitioners are required to map 3D injury findings to 2D space. Here, we design and describe a digital Forensic AuTopsy Annotation tooL (FATAL), that can be used by practitioners to record systematically detailed autopsy findings onto an interactive 3D body model.We employ a user-centred design process involving an expert forensic medicine team. We describe the iteration process and the final functionality determined, based on in-depth analyses of forensic clinical workflows, and feedback on the types of complex cases confronting practitioners.FATAL functions include freehand drawing, a layer system for injury categorisation, trajectory plotting, surface area markings, and point-of-interest marking. Relevant external images, such as investigative report or autopsy photographs, can be loaded into the FATAL tool and assigned to individual annotations. The application streamlines workflows, supports template-driven documentation, and collates all forensic data into a single interface. Findings from the digital tool can be exported to a 2D report (PDF).We highlight the advancements in accuracy, efficiency, and reproducibility afforded by a digital tool for forensic autopsy documentation. Potential applications in forensic medical examinations beyond autopsies are described, along with specific areas for extension, such as supporting touch screen and pen inputs, export for 3D printing models and extending the tool’s compatibility with custom 3D body models.HighlightsFATAL is a digital platform for systematised detailed documentation of autopsy findingsThe platform enables accurate annotation of injuries onto a 3D body modelAllows the forensic pathologist to move from traditional paper-based body diagrams to interactive 3D visualisationsThe platform can export annotations to 2D body diagrams and embed them directly in custom PDF templates
Changes in injecting versus smoking heroin, fentanyl, and methamphetamine among people who inject drugs in San Diego, California, 2020 to 2023
Authors: Eger William H. , Abramovitz Daniela , Bazzi Angela R. , Bórquez Annick , Vera Carlos F. , Harvey-Vera Alicia , Friedman Joseph R. , Strathdee Steffanie A. 
Published: February 2024

AbstractBackgroundAmidst a rapidly evolving drug supply in North America, people who inject drugs may be transitioning to smoking them. We aimed to assess changes in injecting and smoking heroin, fentanyl and methamphetamine among a cohort of people who injected drugs at baseline from San Diego, California.MethodsOver five six-month periods spanning October 2020–April 2023, we assessed prevalence of injecting and smoking opioids or methamphetamine and whether participants used these drugs more frequently by smoking than injecting. Multivariable Poisson regression via Generalized Estimating Equations was used to examine time trends.ResultsOf 362 participants, median age was 40 years; most were male (72%), non-Hispanic (55%), and unhoused (67%). Among this cohort, of whom 100% injected (or injected and smoked) at baseline, by period five (two years later), 34% reported only smoking, while 59% injected and smoked, and 7% only injected. By period five, the adjusted relative risk (aRR) of injecting opioids was 0.41 (95% Confidence Interval [CI]: 0.33, 0.51) compared to period one, and the aRR for injecting methamphetamine was 0.50 (95% CI: 0.39, 0.63). Compared to period one, risks for smoking fentanyl rose significantly during period three (aRR=1.44, 95% CI: 1.06, 1.94), four (aRR=1.65, 95% CI: 1.24, 2.20) and five (aRR=1.90, 95% CI: 1.43, 2.53). Risks for smoking heroin and methamphetamine more frequently than injecting these drugs increased across all periods.ConclusionsOpioid and methamphetamine injection declined precipitously, with notable increases in smoking these drugs. Research is urgently needed to understand the health consequences of these trends.
Mechanical confinement induces ferroptosis through mitochondrial dysfunction
Authors: Zhou Fang , Ju Robert J. , Kang Chenlu , Li Jiayi , Yang Ao , Libert Alexandre , Sun Yujie , Liang Ling , Hu Xiaoqing , Stehbens Samantha J. , Wu Congying 
Published: February 2024

AbstractCells exist in highly crowded environments where they are exposed to fluctuating mechanical forces arising from surrounding cells and the extracellular matrix microenvironment. In these settings, external forces are transmitted to intracellular organelles including the nucleus. While cells can survive confinement, extended duration of confinement or confinement in settings where cells are unable to escape, can result in cell death. How cells sense and respond to prolonged confinement to trigger cell death remains unclear. Here, we demonstrate that nuclear deformation generated by axial confinement triggers the programmed cell death pathway – ferroptosis. We show that axial confinement results in Drp1-dependent mitochondrial fragmentation and cPLA2 translocation to mitochondria, where Drp1 undergoes acute phase separation. Ensuing mitochondrial ROS accumulation and arachidonic acid production concertedly leads to lipid peroxidation evoking ferroptosis. Finally, of clinical relevance, we find that in human osteoarthritis tissue cPLA2 exhibits mitochondrial localization and high ROS levels. Together, our findings unveil a pivotal role for Drp1 and cPLA2 in linking mechanical confinement with mitochondrial dysfunction resulting in ferroptosis, which sheds new light on a mechanical mechanism of pathophysiology in osteoarthritis.
Thymidine Phosphorylase Mediates SARS-CoV-2 Spike Protein Enhanced Thrombosis in K18-hACE2TGMice
Authors: Roytenberg Renat , Yue Hong , DeHart Autumn , Kim Eugene , Bai Fang , Kim Yongick , Denning Krista , Kwei Alec , Zhang Quan , Liu Jiang , Zheng X. Long , Li Wei 
Published: February 2024

AbstractCOVID-19, caused by SARS-CoV-2, is associated with arterial and venous thrombosis, thereby increasing mortality. SARS-CoV-2 spike protein (SP), a viral envelope structural protein, is implicated in COVID-19-associated thrombosis. However, the underlying mechanisms remain unknown. Thymidine phosphorylase (TYMP), a newly identified prothrombotic protein, is upregulated in the plasma, platelets, and lungs of patients with COVID-19 but its role in COVID-19-associated thrombosis is not defined. In this study, we found that wild-type SARS-CoV-2 SP significantly promoted arterial thrombosis in K18-hACE2TGmice. SP-accelerated thrombosis was attenuated by inhibition or genetic ablation of TYMP. SP increased the expression of TYMP, resulting in the activation of signal transducer and activator of transcription 3 (STAT3) in BEAS-2B cells, a human bronchial epithelial cell line. A siRNA-mediated knockdown of TYMP inhibited SP-enhanced activation of STAT3. Platelets derived from SP-treated K18-hACE2TGmice also showed increased STAT3 activation, which was reduced by TYMP deficiency. Activated STAT3 is known to potentiate glycoprotein VI signaling in platelets. While SP did not influence ADP- or collagen-induced platelet aggregation, it significantly shortened activated partial thromboplastin time and this change was reversed by TYMP knockout. Additionally, platelet factor 4 (PF4) interacts with SP, which also complexes with TYMP. TYMP enhanced the formation of the SP/PF4 complex, which may potentially augment the prothrombotic and procoagulant effects of PF4. We conclude that SP upregulates TYMP expression, and TYMP inhibition or knockout mitigates SP-enhanced thrombosis. These findings indicate that inhibition of TYMP may be a novel therapeutic strategy for COVID-19-associated thrombosis.Key PointsSARS-CoV-2 spike protein, thymidine phosphorylase, and platelet factor 4 form a complex that may promote clot formation.Inhibiting thymidine phosphorylase attenuates SARS-CoV-2 spike protein-enhanced thrombosis, platelet activation, and coagulation.
Optimizing contrast in automated 4D-STEM cryo-tomography
Authors: Seifer Shahar , Kirchweger Peter , Edel Karlina Maria , Elbaum Michael 
Published: February 2024

Abstract4D-STEM is an emerging approach to electron microscopy. While it has been developed principally for high resolution studies in materials science, the possibility to collect the entire transmitted flux makes it attractive for cryo-microscopy in application to life science and radiation-sensitive materials where dose efficiency is of utmost importance. We present a workflow to acquire tomographic tilt series of 4D-STEM datasets using a segmented diode and an ultra-fast pixelated detector, demonstrating the methods using a specimen of T4 bacteriophage. Full integration with the SerialEM platform conveniently provides all the tools for grid navigation and automation of the data collection. Scripts are provided to convert the raw data to mrc format files, and further to generate a variety of modes representing both scattering and phase contrast, including incoherent and annular bright field, integrated center of mass (iCOM), and parallax decomposition of a simulated integrated differential phase contrast (iDPC). Principal component analysis of virtual annular detectors proves particularly useful, and axial contrast is improved by 3D deconvolution with an optimized point spread function. Contrast optimization enables visualization of irregular features such as DNA strands and thin filaments of the phage tails, which would be lost upon averaging or imposition of an inappropriate symmetry.
Proteomics-based characterization of ribosome heterogeneity in adult mouse organs
Authors: Brunchault Marie R , Hesse Anne-Marie , Schaeffer Julia , Decourt Charlotte , Combes Florence , Nawabi Homaira , Couté Yohann , Belin Stephane 
Published: February 2024

ABSTRACTWhile long thought to be invariable in all cellular organisms, evidence has emerged that the translation process,i.e.protein assembly from mRNA sequence decoding, is regulated by variable features of the translation machinery. Notably, ribosomes, the functional units of protein synthesis, display variations in their composition, depending on the developmental stage, cell type or physiopathological context, thus providing a new level of actionable regulation of gene expression. Yet, a comprehensive map of the heterogeneity of ribosome composition in ribosomal proteins (RPs) in different organs and tissues is not available. In this work, we explored tissue-specific ribosome heterogeneity using mass spectrometry-based quantitative proteomic characterization of ribosomal fractions purified from 14 adult mouse organs and tissues. We performed crossed clustering and statistical analyses of RP composition to highlight stable, variable and tissue-specific RPs across organs and tissues. Focusing on specific RPs, we validated their relative abundance with a targeted proteomic approach, which gave further insight into the tissue-specific ribosome RP signature. Finally, we investigated the origin of RP variations in ribosome fraction of the different tissues, by comparing RP relative abundances in our proteomic dataset and in three independent transcriptomic datasets. Interestingly, we found that, in some tissues, the RP abundance in purified ribosomes does not always correlate with the corresponding RP transcript level, arguing for a translational regulation of RP expression, and/or a regulated incorporation of RPs into ribosomes. Altogether, our data support the notion of a tissue-specific RP signature of ribosomes, which opens avenues to study how specific ribosomal composition provides an additional level of regulation to control gene expression in different tissues and organs.
Induction of expansion of ex vivo NK cells using a new feeder cell built in Brazil. An extended flow cytometry evaluation of K562.mbIL21.4BBL
Authors: Watanabe Caroline Mitiká , Ishihama Suzuki Caroline , Marins dos Santos Alessandro , Aloia Thiago Pinheiro Arrais , Lee Grace , Wald David , Okamoto Oswaldo Keith , Azevedo Julia T. Cottas de , Godoy Juliana Aparecida Preto de , Santos Fabio P. S. , Weinlich Ricardo , Kerbauy Lucila N. , Kutner Jose Mauro , Paiva Raquel de Melo Alves , Hamerschlak Nelson 
Published: February 2024

ABSTRACTBackgroundNatural killer (NK) cells are lymphocytes from the innate immune system capable of promoting an antitumor response through activation and inhibition receptors. NK cells can better mediate cell engraftment after hematopoietic stem cell transplantation (HSCT), decreasing relapse rates and preventing viral diseases after HSCT. These characteristics make NK cells eligible for application in cell therapy by increasing the frequency of NK cells in peripheral blood. Manufacturing and using feeder cells is necessary to expand NK cells while keeping their cytotoxic characteristics.AimsWe aimed to develop feeder cells from a K562 leukemic cell line capable of promoting clonal expansion of NK cells ex vivo while preserving its antitumor potential.Methods and resultsFeeder cells, named K562.clone1, were produced by transduction of mbIL-21 and 4-1BBL proteins. Next, peripheral blood NK cells were co-cultivated with K562.clone1 and expanded more than 100 folds compared to NK cells co-cultivated with K562-WT (less than 10 folds). On the first day of cultivation, the average frequency of NK cells (CD3-CD56+CD16+/−) was 5.95% ± 3.92%, increasing to 83.97% ± 8.19% on the fourteenth day after co-cultivation with K562.Clone1, while the percentage of NK cells raised to 75.15% ± 7.57% when co-cultivated with control. In addition, NK cells expanded with the feeder K562.Clone1 were potentially cytotoxic against acute myeloid leukemia (AML) blast, tumor cell lines of leukemia and glial origin.ConclusionWe successfully built a national feeder cell, named K562.Clone1. The co-culture with K562.Clone1 feeder cell, preserving their primordial functions such as missing-self, important to distinguish health and defective cell, and natural cytotoxicity against tumoral cells, and increasing the natural cytotoxicity.
Y chromosome sequencing data suggests dual paths of haplogroup N1a1 into Finland
Authors: Preussner Annina , Leinonen Jaakko , Riikonen Juha , Pirinen Matti , Tukiainen Taru 
Published: February 2024

ABSTRACTThe paternally inherited Y chromosome is highly informative of genetic ancestry, therefore making it useful in studies of population history. In Finland, two Y- chromosomal haplogroups reveal the major substructure of the population: N1a1 (TAT) enriched in the northeast and I1a (M253) in the southwest, suggested to reflect eastern and western ancestry contributions to the population. Yet, beyond these major Y-chromosomal lineages, the distribution of finer-scale Y- chromosomal variation has not been assessed in Finland. Here we provide the most comprehensive Y-chromosomal study among the Finns up to date, exploiting full sequences for 1,802 geographically mapped Finnish Y chromosomes from the FINRISK project. We assessed the distribution of common Y-chromosomal haplogroups (frequency ≥ 1%) throughout 19 Finnish regions, and further compared the autosomal genetic backgrounds of the Y-chromosomal haplogroups. With such high-resolution data, we identified novel sublineages and geographical enrichment patterns among the major Finnish haplogroups N1a1 (64%), I1a (25%), R1a (4.3%), and R1b (4.8%). Most notably, we discovered that haplogroup N1a1 splits into three major lineages within the country. While two of the sublineages followed a northeastern enrichment pattern observed for N1a1 in general, the sublineage N1a1a1a1a1a (CTS2929) (22% of all samples) displayed an enrichment in the southwest. Further, the carriers of this haplogroup showed a high proportion of southwestern autosomal ancestry unlike the other N1a1 sublineages. Collectively, these results point to distinct demographics within haplogroup N1a1, possibly induced by two distinct arrival routes into Finland. Overall, our study suggests a more complex genetic population history for Finns than previously proposed.
Laboratory application of the Aquascope approach of automated imaging and classification for long-term plankton monitoring
Authors: Merkli Stefanie , Reyes Marta , Pomati Francesco 
Published: February 2024

AbstractAnthropogenic changes such as climate change and pollution have strong effects on plankton and its ecosystem services. In freshwater, phytoplankton forms the basis of the food web and plays a key role in water quality. It is therefore important to monitor the plankton community. In Switzerland, lake plankton has been monitored for decades by cantonal authorities. But in the future, there will be a limitation in the availability of trained taxonomists that are able to count plankton samples under the microscope as well as time and budget constraints. New technologies will be needed to fulfil the federal requirements on the monitoring of lakes in the future. Here we focus on two such instruments, both based on plankton automated imaging: the FlowCam and the Aquascope. The first is a commercially available instrument, the second is custom made. They are the only automated imaging instruments that can track freshwater plankton across the desired size range (phytoplankton and zooplankton). Their design makes them the state of the art technologies to make quantitative observations of plankton. While the FlowCam is a laboratory instrument, the Aquascope is originally designed for field deployment. In this report, we focus the empirical work on the laboratory application of the Aquascope approach of automated imaging and classification for long term plankton monitoring. We find that there are major advantages of the Aquascope approach but the application as a laboratory instrument still needs further development. The major advantages of the Aquascope approach compared to traditional, human-supervised, microscopy methods are the automation and the speed of the data processing, the availability of individual level traits and the management of the data generated. One of the major drawbacks is the lack of taxonomic resolution (mostly at the genus level). Nevertheless, we show that with a larger benchmarking project, it might be possible to continue the long term time series on a coarse taxonomic level as usually reported by cantonal authorities to the general public. We discuss advantages and limitations of Aquascope relative to traditional microscopy and FlowCam, and propose ways forward for future development and application of this approach.
Enterovirus A71 adaptation to heparan sulfate comes with capsid stability tradeoff
Authors: Tee Han Kang , Mathez Gregory , Cagno Valeria , Antanasijevic Aleksandar , Clément Sophie , Tapparel Caroline 
Published: February 2024

SummaryBecause of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as model and demonstrated that unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. We experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. We then extended these findings to another HS-dependent strain, suggesting that adaptation to HS generally modifies capsid stability and alters entry mechanism. Our data show EV-A71 pH-independent entry for the first time and, more importantly, highlight the intricate interplay between HS-binding, capsid stability, and viral fitness, wherein enhanced multiplication in cell lines leads to attenuation in hostilein vivoenvironments such as the gastrointestinal tract.
m6A landscape is more pervasive whenTrypanosoma bruceiexits the cell cycle
Authors: Serra Lúcia , Pereira Sara Silva , Viegas Idálio J. , Machado Henrique , López-Escobar Lara , Figueiredo Luisa M 
Published: February 2024

AbstractN6-methyladenosine (m6A) is a mRNA modification with important roles in gene expression. In African trypanosomes, this post-transcriptional modification is detected in hundreds of transcripts and it affects the stability of the variant surface glycoprotein (VSG) transcript in the proliferating blood stream form. However, how m6A landscape varies across the life cycle remains poorly defined. Using full-length, non-fragmented RNA, we immunoprecipitated and sequenced m6A-modified transcripts across three life cycle stages ofTrypanosoma brucei– slender (proliferative), stumpy (quiescent), and procyclic forms (proliferative). We found that 1037 transcripts are methylated in at least one of these three life cycle stages. While 21% of methylated transcripts are common in the three stages of the life cycle, globally each stage has a distinct methylome. Interestingly, 47% of methylated transcripts are detected in the quiescent stumpy form only, suggesting a critical role for m6A when parasites exit the cell cycle and prepare for transmission by the Tsetse fly. In this stage, we found that a significant proportion of methylated transcripts encodes for proteins involved in RNA metabolism, which is consistent with their reduced transcription and translation. Moreover, we found that not all major surface proteins are regulated by m6A, as procyclins are not methylated, and that, within the VSG repertoire, not all VSG transcripts are demethylated upon parasite differentiation to procyclic form. This study reveals that the m6A regulatory landscape is specific to each life cycle stage, becoming more pervasive asT. bruceiexits the cell cycle.SummaryAfrican trypanosome parasites adapt to mammalian and insect hosts by adjusting gene expression, morphology, and metabolism. In this study, we focus on how N6-methyladenosine (m6A), a post-transcriptional modification, affects the parasite’s transcriptome throughout its differentiation from the mammalian host to the fly. We found that methylation is differentially regulated as the life cycle progresses, being particularly prevalent in the non-proliferative stumpy form, as more methylated transcripts are found at this insect-infective stage than in slender and procyclic forms. We further show that the not all parasite surface proteins are regulated by m6A and that the previously identified link between m6A methylation and the expression level of the major surface protein of bloodstream forms applies to the active variant surface glycoprotein, but not always to silent genes, suggesting two distinct regulatory mechanisms of (de)methylation.