bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen Specific T Cells in People with Obesity at Five Months Following ChAdOx1 COVID-19 Vaccination
Authors: Wrigley Kelly Neil E. , De Barra Conor , Shaamile Ferrah , Holland Aisling , Shaw Liam , Mallon Patrick W.G. , O’Connell Jean , Hogan Andrew E. , O’Shea Donal 
Published: August 2022

AbstractBackground/ObjectivesPeople with obesity (PWO) face an increased risk of severe outcomes from COVID-19, including hospitalisation, ICU admission and death. Obesity has been seen to impair immune memory following vaccination against influenza, hepatitis B, tetanus, and rabies. Little is known regarding immune memory in PWO following COVID-19 adenovirus vector vaccination.Subjects/MethodsWe investigated SARS-CoV-2 specific T cell responses in 50 subjects, five months following a two-dose primary course of ChAdOx1 nCoV-19 (AZD1222) vaccination. We further divided our cohort into PWO (n=30) and matched controls (n=20). T cell (CD4+, CD8+) cytokine responses (IFNγ, TNFα) to SARS-CoV-2 spike peptide pools were determined using multicolour flow cytometry.ResultsCirculating T cells specific for SARS-CoV-2 were readily detected across our cohort, with robust responses to spike peptide stimulation across both T cell lines. PWO and controls had comparable levels of both CD4+and CD8+SARS-CoV-2 spike specific T cells. Polyfunctional T cells – associated with enhanced protection against viral infection – were detected at similar frequencies in both PWO and controls.ConclusionsThese data indicate that PWO who have completed a primary course of ChAdOx1 COVID-19 vaccination have robust, durable, and functional antigen specific T cell immunity that is comparable to that seen in people without obesity.
Significant increase of emergency department visits for heat-related emergency conditions in the United States from 2008 – 2019: a comprehensive nationwide study
Authors: Dring Penelope , Armstrong Megan , Alexander Robin , Xiang Henry 
Published: August 2022

AbstractIntroductionExposure to high temperatures is detrimental to human health. As climate change is expected to increase the frequency of extreme heat events, as well as raise ambient temperatures, an investigation into the burden of heat-related emergency department visits is necessary to assess the human health impact of this growing public health crisis.MethodsEmergency department visits were sourced from the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample. This dataset collects emergency department visit information from 989 facilities that represent a 20-percent stratified sample of United States hospital-owned emergency departments. Visits were included in this study if the medical diagnosis contained an ICD-9-CM or ICD-10-CM code specific to heat-related emergency conditions. Weighted heat-related emergency department visit counts were generated to estimate the total counts for heat-related emergency department visits across the United States. Visit year and month, hospital geographic region, patient age, and sex were recorded. Incidence rates per 100,000 US population, visit counts, and visit count percent change were analyzed on both a national scale and stratified by month, region, age, and sex.ResultsA total of 1,007,134 weighted heat-related emergency department visits between 2008 - 2019 were included in this study. The annual incidence rate per 100,000 US population increased by an average of 5.73% (95% CI: 8.64% – 20.1%) per year across the study period, rising from 20.56 in 2008 to 30.41 in 2019. For the twelve-year period, the burden of heat-related emergency department visits was greatest in the South (51.41%). Most cases occurred in July (29.56%), with visits increasing to the greatest degree in July (19.25%, 95% CI: 20.75% – 59.26%) and March (14.36%, 95% CI: 19.53% – 48.25%).ConclusionsThis study found a significant increase in emergency department visits for heat-related emergency conditions across the United States from the years 2008 to 2019.
Mitochondria morphology governs ATP production rate
Authors: Garcia Guadalupe C. , Gupta Kavya , Bartol Thomas M. , Sejnowski Terrence J. , Rangamani Padmini 
Published: August 2022

AbstractLife is based on energy conversion. In particular, in the nervous system significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand (Pekkurnaz and Wang, 2022). For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work (Pietrobon and Caplan, 1985; Magnus and Keizer, 1997; Metelkin et al., 2006; Garcia et al., 2019). The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.1.SummaryIn this work, Garcia et al present a thermodynamically consistent model for ATP production in mitochondria, in which reaction rate constants are set such that detailed balance is satisfied. Simulations revealed that ATP production, but not its export, is the limiting step, and simulations with 3D mitochondrial reconstructions linked the ATP production rate in the cytosol with the morphological features of the organelles.
Leveraging prior biological knowledge improves prediction of tocochromanols in maize grain
Authors: Tanaka Ryokei , Wu Di , Li Xiaowei , Tibbs-Cortes Laura E. , Wood Joshua C. , Magallanes-Lundback Maria , Bornowski Nolan , Hamilton John P. , Vaillancourt Brieanne , Li Xianran , Deason Nicholas T. , Schoenbaum Gregory R. , Buell C. Robin , DellaPenna Dean , Yu Jianming , Gore Michael A. 
Published: August 2022

ABSTRACTWith an essential role in human health, tocochromanols are mostly obtained by consuming seed oils; however, the vitamin E content of the most abundant tocochromanols in maize grain is low. Several large-effect genes withcis-acting variants affecting mRNA expression are mostly responsible for tocochromanol variation in maize grain, with other relevant associated quantitative trait loci (QTL) yet to be fully resolved. Leveraging existing genomic and transcriptomic information for maize inbreds could improve prediction when selecting for higher vitamin E content. Here, we first evaluated a multikernel genomic best linear unbiased prediction (MK-GBLUP) approach for modeling known QTL in the prediction of nine tocochromanol grain phenotypes (12–21 QTL per trait) within and between two panels of 1,462 and 242 maize inbred lines. On average, MK-GBLUP models improved predictive abilities by 7.0 to 13.6% when compared to GBLUP. In a second approach with a subset of 545 lines from the larger panel, the highest average improvement in predictive ability relative to GBLUP was achieved with a multi-trait GBLUP model (15.4%) that had a tocochromanol phenotype and transcript abundances in developing grain for a few large-effect candidate causal genes (1–3 genes per trait) as multiple response variables. Taken together, our study illustrates the enhancement of prediction models when informed by existing biological knowledge pertaining to QTL and candidate causal genes.Core IdeasWith varying levels of vitamin E activity, tocochromanols found in maize grain are essential for human healthSelecting for higher vitamin E content in maize grain can be enhanced with genomic predictionPrediction models leveraging existing biological knowledge were evaluated in two panels of maize inbred linesMultikernel prediction models based on previously identified QTL improved predictive abilityA multi-trait prediction model that had transcript abundances of a few large-effect causal genes performed the best
Cryo-electron tomography and deep learning denoising reveal native chromatin landscapes of interphase nuclei
Authors: Fatmaoui Fadwa , Carrivain Pascal , Grewe Diana , Jakob Burkhard , Victor Jean-Marc , Leforestier Amélie , Eltsov Mikhail 
Published: August 2022

AbstractThe folding of nucleosome chains influences DNA availability for functional interactions necessary to the regulation of transcription, DNA replication and repair. Despite models based on in vitro studies, the nucleosome chain geometry within the crowded cell nucleus remains elusive. Using cryo-electron tomography and deep learning-based denoising, we directly observed the path of nucleosomal and linker DNA in situ in unstained flash-frozen Drosophila embryos. We quantified linker length and curvature characterizing a disordered zig-zag chromatin folding motif, with a low degree of linker bending. Additionally, nucleosome conformational variability with non-canonical structures and sub-nucleosomal particles were seen as individual objects, without structure averaging, highlighting the high structural heterogeneity of native chromatin.One-Sentence SummaryCryo-ET reveals local zig-zag motifs in interphase chromatin, a range of nucleosome conformations, and sub-nucleosomal particles.
The RSK-RPS6 Axis Controls the Preconditioning Effect and Induces Spinal Cord Regeneration
Authors: Decourt Charlotte , Schaeffer Julia , Blot Beatrice , Paccard Antoine , Excoffier Blandine , Pende Mario , Nawabi Homaira , Belin Stephane 
Published: August 2022

AbstractUnlike immature neurons and neurons from the peripheral nervous system (PNS), mature neurons from the central nervous system (CNS) cannot regenerate after injury. In the past 15 years, huge progress has been made to identify molecules and pathways necessary for neuroprotection and/or regeneration after CNS injury. In most regenerative models, phosphorylated ribosomal protein S6 (p-RPS6) is upregulated in neurons, which is often associated with an activation of the mTOR pathway. However, the exact contribution of post-translational modifications of this ribosomal protein in CNS regeneration remains elusive. In this study, we demonstrate that RPS6 phosphorylation is essential for PNS and CNS regeneration. We show that this phosphorylation is induced during the preconditioning effect in dorsal root ganglion (DRG) neurons, and that it is controlled by the p90S6 kinase RSK2. Our results reveal that RSK2 controls the preconditioning effect and that the RSK2-RPS6 axis is key for this process, as well as for PNS regeneration. Finally, we demonstrate that RSK2 promotes CNS regeneration in the dorsal column and allows functional recovery. Our data establish the critical role of RPS6 phosphorylation controlled by RSK2 in CNS regeneration and give new insights into the mechanism related to axon growth and circuit formation after traumatic lesion.
Reduced wound healing and angiogenesis in aged zebrafish and turquoise killifish
Authors: Örling Johanna , Kosonen Katri , Villman Jenna , Reichard Martin , Paatero Ilkka 
Published: August 2022

AbstractImpaired wound healing is associated with aging and has significant effects on human health on an individual level, but also the whole health care sector. Deficient angiogenesis appears to be involved in the process, but the underlying biology is still poorly understood. This is at least partially being explained by complexity and costs in using mammalian aging models.To understand aging-related vascular biology of impaired wound healing, we have utilized zebrafish and turquoise killifish fin regeneration models. The regeneration of caudal fin after resection was significantly reduced in old individuals in both species. Age-related changes in angiogenesis, vascular density and expression levels of angiogenesis biomarker VEGF-A were observed. Furthermore, anti-angiogenic drug, vascular endothelial growth factor receptor blocking inhibitor SU5416 reduced regeneration indicating a key role for angiogenesis in the regeneration of aging caudal fin despite aging-related changes in vasculature.Taken together, our data indicates that these fish models are suitable for studying aging-related decline in wound healing and associated alterations in aging vasculature.
Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress
Authors: Do Brian T. , Hsu Peggy P. , Vermeulen Sidney Y. , Wang Zhishan , Hirz Taghreed , Abbott Keene L. , Aziz Najihah , Replogle Joseph M. , Bjelosevic Stefan , Paolino Jonathan , Nelson Samantha , Block Samuel , Darnell Alicia M. , Ferreira Raphael , Zhang Hanyu , Milosevic Jelena , Schmidt Daniel R. , Chidley Christopher , Harris Isaac S. , Weissman Jonathan S. , Pikman Yana , Stegmaier Kimberly , Cheloufi Sihem , Su Xiaofeng A. , Sykes David B. , Vander Heiden Matthew G. 
Published: August 2022

ABSTRACTControl of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that modulating aspects of metabolism could alter cell state along differentiation trajectories. Here we find that nucleotide depletion and DNA replication stress are common drivers of cell state progression across a variety of normal and transformed hematopoietic systems. DNA replication stress-induced cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress leads to increased activity at primed regulatory loci and expression of lineage-appropriate maturation genes while progenitor TF activity is still present. Altering the baseline cell state by manipulating the cohort of transcription factors expressed redirects the effect of replication stress towards induction of a different set of lineage-specific genes. The ability of replication stress to selectively activate primed maturation programs across different cellular contexts suggests a general mechanism by which metabolism can promote lineage-appropriate and potentially therapeutically relevant cell state transitions.
Effectors enabling adaptation to mitochondrial complex I loss in Hürthle cell carcinoma
Authors: Gopal Raj K. , Vantaku Venkata R. , Panda Apekshya , Reimer Bryn , Rath Sneha , To Tsz-Leung , Fisch Adam S. , Cetinbas Murat , Livneh Maia , Calcaterra Michael J. , Gigliotti Benjamin J. , Pierce Kerry , Clish Clary B. , Dias-Santagata Dora , Sadow Peter M. , Wirth Lori J. , Daniels Gilbert H. , Sadreyev Ruslan I. , Calvo Sarah E. , Parangi Sareh , Mootha Vamsi K. 
Published: August 2022

SummaryOncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging, a safeguard against ferroptosis, to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.SignificanceOncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is a unique tumor with a remarkable accumulation of mitochondria. HCC harbors unique genetic alterations, including mitochondrial DNA (mtDNA) mutations in complex I genes and widespread loss-of-heterozygosity in the nuclear DNA. With less favorable clinical outcomes, new therapies for HCC are needed, especially since these tumors show intrinsic resistance to radioactive iodine, which is one of the main treatments for metastatic well-differentiated thyroid cancer. An absence of authentic HCC cell lines and animal models has hindered the mechanistic understanding of this disease and slowed therapeutic progress. In this study, we describe the transcriptomic and metabolomic landscape of HCC and present new HCC models that recapitulate key mtDNA and nuclear DNA alterations. A targeted CRISPR-Cas9 knockout screen in an HCC cell line highlights the molecular programs nominated by our -omics profiling that are required for cell fitness. This screen suggests that lipid peroxide scavenging, a defense system against an iron-dependent form of cell death known as ferroptosis, is a vulnerability in HCC that is coupled to complex I loss, and that targeting this pathway may help patients with HCC.
MitoTNT: Mitochondrial Temporal Network Tracking for 4D live-cell fluorescence microscopy data
Authors: Wang Zichen , Natekar Parth , Tea Challana , Tamir Sharon , Hakozaki Hiroyuki , Schöneberg Johannes 
Published: August 2022

AbstractMitochondria form a network in the cell that rapidly changes through fission, fusion, and motility. This four-dimensional (4D, x,y,z,time) temporal network has only recently been made accessible through advanced imaging methods such as lattice light-sheet microscopy. Quantitative analysis tools for the resulting datasets however have been lacking. Here we present MitoTNT, the first-in-class software forMitochondrialTemporalNetworkTracking in 4D live-cell fluorescence microscopy data. MitoTNT uses spatial proximity and network topology to compute an optimal tracking. Tracking is >90% accurate in dynamic spatial mitochondria simulations and are in agreement with published motility results in vitro. Using MitoTNT, we reveal correlated mitochondrial movement patterns, local fission and fusion fingerprints, asymmetric fission and fusion dynamics, cross-network transport patterns, and network-level responses to pharmacological manipulations. MitoTNT is implemented in python with a JupyterLab interface. The extendable and user-friendly design aims at making temporal network tracking accessible to the wider mitochondria community.
Genome size variation and evolution during invasive range expansion in an introduced plant
Authors: Cang F. Alice , Welles Shana R. , Wong Jenny , Ziaee Maia , Dlugosch Katrina M. 
Published: August 2022

AbstractPlants demonstrate some of the greatest variation in genome size among eukaryotes, and their genome sizes can vary dramatically across individuals and populations within species. This genetic variation can have consequences for traits and fitness, but few studies have been able to attribute genome size differentiation to ecological and evolutionary processes. Biological invasions present particularly useful natural laboratories to infer selective agents that might drive genome size shifts across environments and population histories. Here, we test hypotheses for the evolutionary causes of genome size variation across 14 invading populations of yellow starthistle,Centaurea solstitialis, in California, USA. We use a survey of genome sizes and trait variation to ask: (1) Is variation in genome size associated with developmental trait variation? (2) Are genome sizes smaller toward the leading edge of the expansion, consistent with selection for ‘colonizer’ traits? Or alternatively, does genome size increase toward the leading edge of the expansion, consistent with predicted consequences of founder effects and drift? (3) Finally, are genome sizes smaller at higher elevations, consistent with selection for shorter development times? We found that 2C DNA content varied 1.21-fold among all samples, and was associated with flowering time variation, such that plants with larger genomes reproduced later, with lower lifetime capitula production. Genome sizes increased toward the leading edge of the invasion, but tended to decrease at higher elevations, consistent with genetic drift during range expansion but potentially strong selection for smaller genomes and faster development time at higher elevations.
A local sequence signature defines a subset of heterochromatin-associated CpGs with minimal loss of methylation in healthy tissues but extensive loss in cancer
Authors: Bar Dror , Fishman Lior , Zheng Yueyuan , Unterman Irene , Schlesinger Devorah , Eden Amir , Lin De-Chen , Berman Benjamin P. 
Published: August 2022

AbstractGlobal loss of DNA methylation in mammalian genomes occurs during aging and cancer, primarily in heterochromatin-associated Partially Methylated Domains (PMDs). It has previously been shown that local sequence context (100bp) has a strong influence on the rate of demethylation of individual CpG dinucleotides within PMDs. Here, we train a deep learning model to capture this sequence dependence, finding that methylation loss in healthy tissues and cancer can be predicted with high accuracy based on the 150bp surrounding a CpG. We use a published whole-genome map of the re-methylation rate of newly synthesized DNA during mitosis to show that CpGs with a “slow-loss” sequence context are efficiently re-methylated, while CpGs with a “fast-loss” sequence context are inefficiently re-methylated. Intriguingly, we find that the 10% most slow-loss CpGs lose almost no DNA methylation in healthy cell types, but lose significant DNA methylation in many cancer types. This finding suggests that loss of DNA methylation at slow-loss CpGs could underlie some cancer-specific transcriptional deregulation that has been linked to DNA hypomethylation, including the derepression of cancer antigens and transposable elements.