bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simple decision rules to predict local surges in COVID-19 hospitalizations during the winter and spring of 2022
Authors: Yaesoubi Reza , You Shiying , Xi Qin , Menzies Nicolas A. , Tuite Ashleigh , Grad Yonatan H. , Salomon Joshua A. 
Published: December 2021

AbstractLow rates of vaccination, emergence of novel variants of SARS-CoV-2, and increasing transmission relating to seasonal changes leave many U.S. communities at risk for surges of COVID-19 during the winter and spring of 2022 that might strain hospital capacity, as in previous waves. The trajectories of COVID-19 hospitalizations during this period are expected to differ across communities depending on their age distributions, vaccination coverage, cumulative incidence, and adoption of risk mitigating behaviors. Yet, existing predictive models of COVID-19 hospitalizations are almost exclusively focused on national- and state-level predictions. This leaves local policymakers in urgent need of tools that can provide early warnings about the possibility that COVID-19 hospitalizations may rise to levels that exceed local capacity. In this work, we develop simple decision rules to predict whether COVID-19 hospitalization will exceed the local hospitalization capacity within a 4- or 8-week period if no additional mitigating strategies are implemented during this time. These decision rules use real-time data related to hospital occupancy and new hospitalizations associated with COVID-19, and when available, genomic surveillance of SARS-CoV-2. We showed that these decision rules present reasonable accuracy, sensitivity, and specificity (all ≥80%) in predicting local surges in hospitalizations under numerous simulated scenarios, which capture substantial uncertainties over the future trajectories of COVID-19 during the winter and spring of 2022. Our proposed decision rules are simple, visual, and straightforward to use in practice by local decision makers without the need to perform numerical computations.Significance StatementIn many U.S. communities, the risk of exceeding local healthcare capacity during the winter and spring of 2022 remains substantial since COVID-19 hospitalizations may rise due to seasonal changes, low vaccination coverage, and the emergence of new variants of SARS-CoV-2, such as the omicron variant. Here, we provide simple and easy-to-communicate decision rules to predict whether local hospital occupancy is expected to exceed capacity within a 4- or 8-week period if no additional mitigating measures are implemented. These decision rules can serve as an alert system for local policymakers to respond proactively to mitigate future surges in the COVID-19 hospitalization and minimize risk of overwhelming local healthcare capacity.
Modifiable traits, healthy behaviours, and leucocyte telomere length
Authors: Bountziouka Vasiliki , Musicha Crispin , Allara Elias , Kaptoge Stephen , Wang Qingning , Di Angelantonio Emanuele , Butterworth Adam S , Thompson John R , Danesh John N , Wood Angela M , Nelson Christopher P , Codd Veryan , Samani Nilesh J 
Published: December 2021

AbstractBackgroundTelomere length is associated with risk of several age–related diseases and cancers. The extent to which telomere length may be modifiable through lifestyle and behaviour and whether this has any clinical consequences is unknown.MethodsIn up to 422,797 participants in UK Biobank, we investigated associations of leucocyte telomere length (LTL) with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating smoking, physical activity, diet, maintenance of a healthy body weight and alcohol intake. Associations were interpreted as age–related change in LTL by dividing the trait beta coefficients with the age–coefficient. We used Mendelian Randomisation (MR) to test causality of the observed associations of educational attainment and smoking behaviour with LTL. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease (CAD) may be mediated through LTL.Results71 traits showed significant associations with LTL but most were modest, equivalent to <1 year of age–related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age–related change in LTL), five traits – oily fish intake, educational attainment, general health status, walking pace and current smoking – remained significant. MR analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the healthiest behaviour having longer LTL equivalent to ∼3·5 years of age–related change in LTL when compared with those with the least heathy behaviours (P<0·001). However, healthy behaviours only explained <0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of CAD were substantially mediated through LTL.ConclusionsSeveral potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal. However, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy.
Quality Assurance Assessment of Intra-Acquisition Diffusion-Weighted and T2-Weighted Magnetic Resonance Imaging Registration and Contour Propagation for Head and Neck Cancer Radiotherapy
Authors: Naser Mohamed A. , Wahid Kareem A. , Ahmed Sara , Salama Vivian , Dede Cem , Edwards Benjamin W. , Lin Ruitao , McDonald Brigid , Salzillo Travis C. , He Renjie , Ding Yao , Abdelaal Moamen Abobakr , Thill Daniel , O’Connell Nicolette , Willcut Virgil , Christodouleas John P. , Lai Stephen Y , Fuller Clifton D. , Mohamed Abdallah S. R. 
Published: December 2021

AbstractBackground/PurposeAdequate image registration of anatomic and functional MRI scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images.Materials/MethodsWe compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same imaging session in twenty immobilized HNC patients. In addition, we used the non-registered images (None) as a control comparator. Ground truth segmentations of radiotherapy structures (tumor and organs at risk) were generated by a physician expert on both image sequences. For each registration approach, structures were propagated from T2W to DWI images. These propagated structures were then compared with ground truth DWI structures using the Dice similarity coefficient and mean surface distance.Results19 left submandibular glands, 18 right submandibular glands, 20 left parotid glands, 20 right parotid glands, 20 spinal cords, and 12 tumors were delineated. Most DIR methods took < 30 seconds to execute per case, with the exception of Elastix 23 which took ∼458 seconds to execute per case. ADMIRE and Elastix 23 demonstrated improved performance over None for all metrics and structures (Bonferroni-corrected p < 0.05), while the other methods did not. Moreover, ADMIRE and Elastix 23 significantly improved performance in individual and pooled analysis compared to all other methods.ConclusionsThe ADMIRE DIR method offers improved geometric performance with reasonable execution time so should be favored for registering T2W and DWI images acquired during the same scan session in HNC patients. These results are important to ensure the appropriate selection of registration strategies for MR-guided radiotherapy.
Ferritin trajectories over repeated whole blood donations: results from the FIND+ study
Authors: Moazzen Sara , Sweegers Maike G , Janssen Mart , Hogema Boris M , Hoekstra Trynke , van den Hurk Katja 
Published: December 2021

AbstractBackgroundWhole blood donors lose approximately 200-250 mg of iron per donation. Depending on post-donation erythropoiesis, available iron stores, and iron absorption rates, optimal donation intervals may differ between donors. This project aims to define subpopulations of donors with different ferritin trajectories over repeated donations.MethodsFerritin levels of 300 new whole blood donors were measured from stored (lookback) samples from each donation over a two-year period in an observational cohort study. Latent classes of ferritin level trajectories were investigated using growth mixture models for male and female donors, separately. Associations of ferritin levels with subsequent iron deficiency and/or low haemoglobin were assessed with generalized linear mixed models.ResultsIn both genders two groups of donors were identified using group-based trajectory modelling. Ferritin levels showed rather linear reductions among 42.9% of male donors and 87.7% of female donors. For the remaining groups of donors, steeper declines in ferritin levels were observed. Ferritin levels at baseline and the end of follow-up varied greatly between groups.ConclusionRepeated ferritin measurements show depleting iron stores in all new whole blood donors, the level at which mainly depends on baseline ferritin levels. Tailored, less intensive donation strategies might help to prevent low iron in donors, and could be supported with ferritin monitoring and/or iron supplementation.
The salivary microbiome shows a high prevalence of core bacterial members yet variability across human populations
Authors: Ruan Xinwei , Luo Jiaqiang , Zhang Pangzhen , Howell Kate 
Published: December 2021

AbstractHuman saliva contains diverse bacterial communities, reflecting human health status, dietary patterns and contributing to variability in the sensory perception of food. Many descriptions of salivary microbiome diversity compare commonalities and differences with reference to a diseased state, but the composition of healthy saliva has not been described. Here, we use a meta-analysis approach to define and explore the core membership of the human salivary microbial community by collecting and re-analysing raw 16S rRNA amplicon sequencing data from 47 studies with 2206 saliva samples. We found 68 core bacterial taxa that were consistently detected. Differences induced by various host intrinsic and behaviour factors, including gender, age, geographic location, tobacco usage, and alcohol consumption, were evident. The core of the salivary microbiome was verified by collecting and analysing saliva in an independent study. These results suggest that the methods used can effectively define a core microbial community in human saliva with high prevalence. The core salivary microbiome demonstrated both stability and variability among populations. Geographic location was identified as the host factor with the largest effect in shaping salivary microbiota. The independent analysis underlined that the impact of geographic variation is likely due to diet.
Landscape dynamics promoted the evolution of mega-diversity in South American freshwater fishes
Authors: Cassemiro Fernanda A. S. , Albert James S. , Antonelli Alexandre , Menegotto André , Wüest Rafael O. , Coelho Marco Túlio P. , Bailly Dayani , da Silva Valéria F. B. , Frota Augusto , da Graça Weferson J. , Ré Reginaldo , Ramos Telton , de Oliveira Anielly Galego , Dias Murilo S. , Colwell Robert K. , Rangel Thiago F. , Graham Catherine H. 
Published: December 2021

AbstractLandscape dynamics and river network rearrangements are widely thought to shape the diversity of Neotropical freshwater fishes, the most species-rich continental vertebrate fauna on Earth. Yet the effects of hydrogeographic changes on fish dispersal and diversification remain poorly understood. Here we integrate an unprecedented occurrence dataset of 4,967 South American freshwater fish species with a species-dense phylogeny to track the evolutionary processes associated with hydrogeographic events over 100 Ma. Net lineage diversification was heterogeneous through time, across space, and among clades. Three abrupt shifts in diversification rates occurred during the Paleogene (between 63 and 23 Ma) in association with major landscape evolution events, and net diversification accelerated from the Miocene to the Recent (c. 20 – 0 Ma). The Western Amazon exhibited the highest rates of in situ diversification and was also the most important source of species dispersing to other regions. All regional biotic interchanges were associated with documented hydrogeographic events and the formation of biogeographic corridors, including Early Miocene (c. 20 Ma) uplift of the Serra do Mar, and Late Miocene (c. 10 Ma) uplift of the Northern Andes and formation of the modern transcontinental Amazon River. Reciprocal mass dispersal of fishes between the Western and Eastern Amazon coincided with this phase of Andean uplift. The Western Amazon has the highest contemporary levels of species richness and phylogenetic endemism. Our results support the hypothesis that landscape dynamics were constrained by the history of drainage basin connections, strongly affecting the assembly and diversification of basin-wide fish faunas.Significance StatementDespite progress in mapping geographic distributions and genealogical relationships, scientists have few clear answers about the origins of South American freshwater fishes, the most diverse vertebrate fauna on Earth. Here we used the most complete dataset of geographic distributions and evolutionary relationships of South American fishes to track how the geological history of river dynamics influenced the origin, extinction, and interchange of species over the past 100 Ma. We found abrupt increases of species origination between 66 and 23 Ma, coinciding with repeated uplifts of the Andes. The Western Amazon region served as source of freshwater fishes to other regions, as a place where species tended to persist over longer historical periods, and where species originations occurred with higher frequency.
Combining δ13C and δ15N from bone and dentine in marine mammal palaeoecological research: insights from toothed whales
Authors: Rey-Iglesia Alba , Wilson Tess , Routledge Jennifer , Skovrind Mikkel , Garde Eva , Heide-Jørgensen Mads Peter , Szpak Paul , Lorenzen Eline D. 
Published: December 2021

AbstractStable carbon (δ13C) and nitrogen (δ15N) isotope compositions of bone and dentine collagen extracted from museum specimens have been widely used to study the paleoecology of past populations. Due to possible systematic differences in stable isotope values between bone and dentine, dentine values need to be transformed into bone-collagen equivalent using a correction factor to allow comparisons between the two collagen sources. Here, we provide correction factors to transform dentine δ13C and δ15N values into bone-collagen equivalent for two toothed whales: narwhal and beluga.We sampled bone and tooth dentine from the skulls of 11 narwhals and 26 belugas. In narwhals, dentine was sampled from tusk and embedded tooth; in beluga, dentine was sampled from tooth. δ13C and δ15N were measured and intraindividual bone and dentine isotopic compositions were used to calculate correction factors for each species.We detected differences in δ13C and δ15N. In narwhals, we found (i) lower average δ13C and δ15N in bone compared with dentine; (ii) no difference in dentine δ13C between tusk and embedded tooth. For belugas, we also detected lower δ13C and δ15N in bone compared with tooth dentine. The correction factors provided by the study enable the combined analysis of stable isotope data from bone and dentine in these species.
Mechanistic insights of radiation-induced endothelial senescence impelling glioblastoma genomic instability at relapse
Authors: Degorre Charlotte , Renoult Ophélie , Parplys Ann Christin , Awada Hala , Clavreul Anne , Pietri Manon , Oliver Lisa , Joalland Noemie , Ricoul Michelle , Gratas Catherine , Vallette François , Borgmann Kirsten , Sabatier Laure , Pecqueur Claire , Paris François 
Published: December 2021

AbstractDespite aggressive clinical protocol, all glioblastoma (GBM) recur at the initial site within the irradiated peritumoral microenvironment. Whereas irradiated microenvironment has been recently proposed to accelerate GBM relapse, molecular and cellular mechanisms remain unknown. Here, using relevant in vitro and in vivo models, we decipher how radiation-induced endothelial senescence drives the emergence of aggressive GBM cells. Secretome (SASP) of radiation-induced senescent (RIS) endothelium enhances genomic instability and intratumoral heterogeneity in irradiated GBM cells. In-depth molecular studies revealed that CXCL5 and CXCL8, from the SASP, activate CXCR2 receptor on tumor cells leading to increased DNA hyper-replication, micronuclei formation and aneuploidy. Importantly, through CXCL5/8-CXCR2 axis activation, this SASP increases GBM aggressiveness in vivo. Both chemokines were detected in relapsing, but not primary, GBM biopsies and positively correlated with worst patient outcome. In conclusion, we identify new molecular and preclinical insights of relapsing GBM aggressiveness where RIS vascular niches fuel aggressive tumor emergence.
CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation
Authors: Carrasco Kendall , Montersino Camille , Derviaux Carine , Saez-Ayala Magali , Hoffer Laurent , Restouin Audrey , Castellano Rémy , Casassa Justine , Roche Philippe , Pasquier Eddy , Combes Sébastien , Morelli Xavier , Collette Yves , Betzi Stéphane 
Published: December 2021

ABSTRACTDifferentially screening the Fr-PPIChem chemical library on the BET BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the BD cavity and its potential as starting scaffold for the development of potent and selective bromodomain inhibitors.
BRG1 defines a genomic subset of inflammatory genes transcriptionally controlled by the glucocorticoid receptor
Authors: Mechtidou Aikaterini , Greulich Franziska , Strickland Benjamin A. , Jouffe Céline , Cernilogar Filippo M. , Schotta Gunnar , Uhlenhaut N. Henriette 
Published: December 2021

ABSTRACTGlucocorticoids (such as Dexamethasone) are commonly used immunomodulatory drugs with potent anti-inflammatory effects, whose mechanisms of action remain incompletely understood. They bind to the Glucocorticoid Receptor (GR), a nuclear hormone receptor that acts as a transcription factor to directly control the expression of inflammatory genes. To elucidate the complex molecular mechanisms employed by GR during the suppression of innate immune responses, we have performed proteomics, ChIP-seq, ATAC-seq, RNA-seq and bioinformatics together with genetic and pharmacological loss of function studies in primary mouse macrophages. We found that GR interacts with the ATP-dependent SWI/SNF chromatin remodeling complex to regulate a specific subset of target genes. Here we show that the central catalytic subunit BRG1 is required not only for the transcriptional activation of classical GR target genes such as Fkbp5 or Klf9, but also for the transcriptional repression of cytokines and chemokines such as Ccl2, Cxcl10 or Il1a. We demonstrate that loss of BRG1 activity leads to reduced histone deacetylase (HDAC) function, and consequently increased histone acetylation, at these repressive GR binding sites. Altogether, our findings suggest that GR interacts with BRG1 to assemble a functional co-repressor complex at a defined fraction of macrophage cis-regulatory elements. These results may indicate additional non-classical, remodeling-independent functions of the SWI/SNF complex and may have implications for the development of future immunomodulatory therapies.GRAPHICAL ABSTRACTGraphical Abstract.In macrophages (mΦ) responding to bacterial LPS and Dexamethasone, the Glucocorticoid Receptor (GR) activates target genes like Klf9 or Fkbp5 via interaction with the BRG1-containing SWI/SNF complex, chromatin remodeling and Mediator recruitment. At the same time, GR represses the expression of inflammatory cytokines and chemokines such as Ccl2, Cxcl10, Il1a etc. by assembling a BRG1-containing co-repressor complex and de-acetylating surrounding histone tails. Loss of BRG1 activity affects both the transcriptional activation and repression of a subset of myeloid GR target genes via distinct mechanisms. (iTF: inflammatory transcription factor; Ac: histone acetylation) (Created with BioRender.com.)
2.7 Å cryo-EM structure of ex vivo RML prion fibrils
Authors: Manka Szymon W. , Zhang Wenjuan , Wenborn Adam , Betts Jemma , Joiner Susan , Saibil Helen R. , Collinge John , Wadsworth Jonathan D.F. 
Published: December 2021

AbstractMammalian prions are lethal infectious agents that propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP), often referred to as prion rods. The structural features that define infectious prion rods and the molecular determinants of prion strain diversity are poorly understood. Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94-225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP primary sequence and/or represent distinguishing features of the distinct prion strains. These conformational changes impact the overall geometry of the fibrils and may also impact fibril pairing, one or both of which may critically influence PrP glycoform selection that occurs during strain-specific prion propagation.