bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing Temporal Sensitivity of Omics Association Studies with Epigenome-Wide Distributed Lag Models
Authors: Parikh Milan N , Manning Erika Rasnick , Niu Liang , Ruehlmann Anna Kotsakis , Folger Alonzo T , Brunst Kelly J , Brokamp Cole 
Published: September 2024

Abstract
Current methods for identifying temporal windows of effect for time-varying exposures in omics settings can control false discovery rates at the biomarker-level but cannot efficiently screen for timing-specific effects in high dimensions. Current approaches leverage separate models for site screening and identification of susceptible time windows, which miss associations that vary over time. We introduce the epigenome-wide distributed lag model (EWDLM), a novel approach that combines traditional false discovery rate methods with the distributed lag model (DLM) to screen for timing-specific effects in high dimensional settings. This is accomplished by marginalizing DLM effect estimates over time and correcting for multiple comparisons. In a simulation investigating timing-specific effects of ambient air pollution during pregnancy on DNA methylation across the epigenome at age 12 years, EWDLM achieved an increased sensitivity for associations limited to specific periods of time compared to traditional two-stage approaches. In a real-world EWDLM analysis, 353 CpG sites at which DNAm measured at age 12 was significantly associated with PM2.5 exposure during pregnancy were identified. EWDLM is a novel method that provides an efficient and sensitive way to screen epigenomic datasets for associations with exposures localized to specific time periods.
Hard Choices and Ultimate Ends
Authors: Costella Annalisa 
Published: September 2024

Abstract
I propose a novel view on hard choices. It broadens the concept to include not only ‘classic’ hard choices but also transformative and aspirational choices. I argue that a choice is hard when an individual does not have an all-things-considered reason to choose one option over another and the objects of choice are ultimate ends. Construing hard choices in this way supports and explains the widely held assumption that, when faced with hard choices, it is impermissible to choose arbitrarily. More specifically, it shows that it is impermissible to choose arbitrarily by plumping, and yet legitimate to do so by picking. Understanding hard choices in the way I propose sheds light on the fact that there are moral and agential constraints that limit the space of permissible decision-making procedures when confronted with ‘classic’ hard, transformative, and aspirational choices. Delineating these constraints, in turn, can provide guidance to critically appraise current theories of practical rationality.
Baseline MRI predictors of successful organ preservation in the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial
Authors: Williams Hannah , Yuval Jonathan B , Verheij Floris S , Miranda Joao , Lin Sabrina T , Omer Dana M , Qin Li-Xuan , Gollub Marc J , Kim Tae-Hyung , Garcia-Aguilar Julio ,   OPRA Consortium, Patil S , Kim J K , Thompson H M , Marco M R , Lee M , Paty P B , Weiser M R , Nash G M , Pappou E , Wei I H , Widmar M , Segal N H , Cercek A , Yaeger R , Smith J J , Wu A J , Saltz L B , Dunne R F , Temple L , Marcet J , Cataldo P , Polite B , Herzig D O , Liska D , Oommen S , Friel C M , Ternent C , Coveler A L , Hunt S , Gregory A , Varma M G , Bello B L , Carmichael J C , Krauss J , Gleisner A , Guillem J G , Goodman K A 
Published: September 2024

AbstractBackgroundProspective randomized trials have not yet identified baseline features predictive of organ preservation in locally advanced rectal cancers treated with total neoadjuvant therapy and a selective watch-and-wait strategy.MethodsThis was a secondary analysis of the OPRA trial, which randomized patients with stage II–III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Patients were recommended for total mesorectal excision, or watch and wait based on clinical response at 8 ± 4 weeks after completing treatment. Standardized baseline clinical and radiological variables were collected prospectively. Survival outcomes, including total mesorectal excision-free survival, disease-free survival, and overall survival, were assessed by intention-to-treat analysis. Cox proportional hazards models were used to evaluate associations between baseline variables and survival outcomes.ResultsOf the 324 patients randomized for the OPRA trial, 38 (11.7%) had cT4 tumours, 230 (71.0%) cN-positive disease, 101 (32.5%) mesorectal fascia involvement, and 64 (19.8%) extramural venous invasion. Several baseline features were independently associated with recommendation for total mesorectal excision on multivariable analysis: nodal disease (HR 1.66, 95% c.i. 1.12 to 2.48), extramural venous invasion (HR 1.57, 1.07 to 2.29), mesorectal fascia involvement (HR 1.45, 1.01 to 2.09), and tumour length (HR 1.11, 1.00 to 1.22). Of these, nodal disease (HR 2.02, 1.15 to 3.53) and mesorectal fascia involvement (HR 2.02, 1.26 to 3.26) also predicted worse disease-free survival. Age (HR 1.03, 1.00 to 1.06) was associated with overall survival.ConclusionBaseline MRI features, including nodal disease, extramural venous invasion, mesorectal fascia involvement, and tumour length, independently predict the likelihood of organ preservation after completion of total neoadjuvant therapy. Mesorectal fascia involvement and nodal disease are associated with disease-free survival.
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Authors: Bergner Caroline Gertrud , van der Meer Franziska , Franz Jonas , Vakrakou Aigli , Würfel Thea , Nessler Stefan , Schäfer Lisa , Nau-Gietz Cora , Winkler Anne , Lagumersindez-Denis Nielsen , Wrzos Claudia , Damkou Ioanna Alkmini , Sergiou Christina , Schultz Verena , Knauer Carolin , Metz Imke , Bahn Erik , Rodriguez Enrique Garea , Merkler Doron , Simons Mikael , Stadelmann Christine 
Published: September 2024

Abstract
Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the CNS. It restores saltatory nerve conduction and ensures trophic support of axons. In patients with multiple sclerosis, remyelination has been observed in both white and grey matter and found to be more efficient in the cortex. Brain-enriched myelin-associated protein 1 (BCAS1) identifies oligodendrocyte lineage cells in the stage of active myelin formation in development and regeneration. Other than in the white matter, BCAS1+ oligodendrocytes are maintained at high densities in the cortex throughout life.
Here, we investigated cortical lesions in human biopsy and autopsy tissue from patients with multiple sclerosis in direct comparison to demyelinating mouse models and demonstrate that following a demyelinating insult BCAS1+ oligodendrocytes in remyelinating cortical lesions shift from a quiescent to an activated, internode-forming morphology co-expressing myelin-associated glycoprotein (MAG), necessary for axonal contact formation. Of note, activated BCAS1+ oligodendrocytes are found at early time points of experimental demyelination amidst ongoing inflammation. In human tissue, activated BCAS1+ oligodendrocytes correlate with the density of myeloid cells, further supporting their involvement in an immediate regenerative response.
Furthermore, studying the microscopically normal appearing non demyelinated cortex in patients with chronic multiple sclerosis, we find a shift from quiescent BCAS1+ oligodendrocytes to mature, myelin-maintaining oligodendrocytes, suggesting oligodendrocyte differentiation and limited replenishment of BCAS1+ oligodendrocytes in long-standing disease. We also demonstrate that part of perineuronal satellite oligodendrocytes are BCAS1+ and contribute to remyelination in human and experimental cortical demyelination.
In summary, our results provide evidence from human tissue and experimental models that BCAS1+ cells in the adult cortex represent a population of pre-differentiated oligodendrocytes that rapidly react after a demyelinating insult thus enabling immediate myelin regeneration. In addition, our data suggest that limited replenishment of BCAS1+ oligodendrocytes may contribute to the remyelination failure observed in the cortex in chronic multiple sclerosis.
Phenotypic characterization of people at risk of atrial fibrillation: protocol for the FIND-AF longitudinal cohort study
Authors: Wahab Ali , Nadarajah Ramesh , Reynolds Catherine , Bennett Sheena , Ambakederemo Edisemi , Harris Mohammad , Younsi Tanina , Joseph Tobin , Raveendra Keerthenan , Smith Adam , Bhatty Asad , Lip Gregory Y H , Swoboda Peter P , Wu Jianhua , Gale Chris P 
Published: September 2024

Abstract

Aims
The Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF) longitudinal cohort study is a multi-centre prospective cohort study of patients identified at risk of atrial fibrillation (AF). The aim of the FIND-AF longitudinal cohort study is to provide multi-modal phenotypic characterization of these patients.

Methods and results
A total of 1955 participants identified as at risk of AF by the FIND-AF algorithm from primary care electronic health record (EHR) data, aged 30 years and above and eligible for oral anticoagulation, will be recruited between October 2023 and November 2024 to receive home-based intermittent electrocardiogram monitoring. About 500 participants without diagnosed AF will then undergo cross-sectional phenotypic characterization including physical examination, symptoms assessment, serum blood biomarkers and echocardiography, and non-stress cardiac magnetic resonance imaging. Longitudinal information about cardio–renal–metabolic–pulmonary outcomes will be ascertained from linkages to EHR data. The study is funded by the British Heart Foundation (CC/22/250026). The study has ethical approval (North West—Greater Manchester South Research Ethics Committee reference 23/NW/0180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder’s open-access policy.

Conclusion
The FIND-AF multi-centre prospective longitudinal cohort study aims to (i) provide evidence for the impact of comorbidities on AF genesis, (ii) uncover actionable targets to prevent AF, and (iii) act as a platform for cohort randomized clinical trials that investigate enhanced detection and prevention of AF.
The role of family and environment in determining the skin bacterial communities of captive aquatic frogs, Xenopus laevis
Authors: Chapman Phoebe A , Hudson Daniel , Morgan Xochitl C , Beck Caroline W 
Published: September 2024

Abstract
Skin microbes play an important role in amphibian tissue regeneration. Xenopus spp. (African clawed frogs) are well-established model organisms, and standard husbandry protocols, including use of antibiotics, may affect experimental outcomes by altering bacterial assemblages. It is therefore essential to improve knowledge of Xenopus bacterial community characteristics and inheritance. We undertook bacterial 16S rRNA gene sequencing and source tracking of a captive Xenopus laevis colony, including various life stages and environmental samples across multiple aquarium systems. Tank environments supported the most complex bacterial communities, while egg jelly bacteria were the most diverse of frog life stages; tadpole bacterial communities were relatively simple. Rhizobium (Proteobacteria) and Chryseobacterium (Bacteroidota) were dominant in tadpoles, whereas Chryseobacterium, Vogesella (Proteobacteria), and Acinetobacter (Proteobacteria) were common in females. Tadpoles received approximately two-thirds of their bacteria via vertical transmission, though 23 genera were differentially abundant between females and tadpoles. Female frog skin appears to select for specific taxa, and while tadpoles inherit a proportion of their skin bacteria from females via the egg, they support a distinct and less diverse community. The outcomes of this study suggest the impacts of breaking the bacterial transmission chain with antibiotic treatment should be considered when raising tadpoles for experimental purposes.
Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff
Authors: Boyle Gabriel E , Sitko Katherine A , Galloway Jared G , Haddox Hugh K , Bianchi Aisha Haley , Dixon Ajeya , Wheelock Melinda K , Vandi Allyssa J , Wang Ziyu R , Thomson Raine E S , Garge Riddhiman K , Rettie Allan E , Rubin Alan F , Geck Renee C , Gillam Elizabeth M J , DeWitt William S , Matsen Frederick A , Fowler Douglas M 
Published: September 2024

Abstract
The cytochrome P450s enzyme family metabolizes ∼80% of small molecule drugs. Variants in cytochrome P450s can substantially alter drug metabolism, leading to improper dosing and severe adverse drug reactions. Due to low sequence conservation, predicting variant effects across cytochrome P450s is challenging. Even closely related cytochrome P450s like CYP2C9 and CYP2C19, which share 92% amino acid sequence identity, display distinct phenotypic properties. Using variant abundance by massively parallel sequencing, we measured the steady-state protein abundance of 7,660 single amino acid variants in CYP2C19 expressed in cultured human cells. Our findings confirmed critical positions and structural features essential for cytochrome P450 function, and revealed how variants at conserved positions influence abundance. We jointly analyzed 4,670 variants whose abundance was measured in both CYP2C19 and CYP2C9, finding that the homologs have different variant abundances in substrate recognition sites within the hydrophobic core. We also measured the abundance of all single and some multiple wild type amino acid exchanges between CYP2C19 and CYP2C9. While most exchanges had no effect, substitutions in substrate recognition site 4 reduced abundance in CYP2C19. Double and triple mutants showed distinct interactions, highlighting a region that points to differing thermodynamic properties between the 2 homologs. These positions are known contributors to substrate specificity, suggesting an evolutionary tradeoff between stability and enzymatic function. Finally, we analyzed 368 previously unannotated human variants, finding that 43% had decreased abundance. By comparing variant effects between these homologs, we uncovered regions underlying their functional differences, advancing our understanding of this versatile family of enzymes.
PhageGE: an interactive web platform for exploratory analysis and visualization of bacteriophage genomes
Authors: Zhao Jinxin , Han Jiru , Lin Yu-Wei , Zhu Yan , Aichem Michael , Garkov Dimitar , Bergen Phillip J , Nang Sue C , Ye Jian-Zhong , Zhou Tieli , Velkov Tony , Song Jiangning , Schreiber Falk , Li Jian 
Published: September 2024

Abstract

Background
Antimicrobial resistance is a serious threat to global health. Due to the stagnant antibiotic discovery pipeline, bacteriophages (phages) have been proposed as an alternative therapy for the treatment of infections caused by multidrug-resistant pathogens. Genomic features play an important role in phage pharmacology. However, our knowledge of phage genomics is sparse, and the use of existing bioinformatic pipelines and tools requires considerable bioinformatic expertise. These challenges have substantially limited the clinical translation of phage therapy.

Findings
We have developed PhageGE (Phage Genome Explorer), a user-friendly graphical interface application for the interactive analysis of phage genomes. PhageGE enables users to perform key analyses, including phylogenetic analysis, visualization of phylogenetic trees, prediction of phage life cycle, and comparative analysis of phage genome annotations. The new R Shiny web server, PhageGE, integrates existing R packages and combines them with several newly developed functions to facilitate these analyses. Additionally, the web server provides interactive visualization capabilities and allows users to directly export publication-quality images.

Conclusions
PhageGE is a valuable tool that simplifies the analysis of phage genome data and may expedite the development and clinical translation of phage therapy. PhageGE is publicly available at https://jason-zhao.shinyapps.io/PhageGE_Update/.
Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways
Authors: Arumugam Priya , Saha Kushal , Nighot Prashant 
Published: September 2024

Abstract
Intestinal epithelial tight junctions (TJs), a dynamically regulated barrier structure composed of occludin and claudin family of proteins, mediate the interaction between the host and the external environment by allowing selective paracellular permeability between the luminal and serosal compartments of the intestine. TJs are highly dynamic structures and can undergo constant architectural remodeling in response to various external stimuli. This is mediated by an array of intracellular signaling pathways that alters TJ protein expression and localization. Dysfunctional regulation of TJ components compromising the barrier homeostasis is an important pathogenic factor for pathological conditions including inflammatory bowel disease (IBD). Previous studies have elucidated the significance of TJ barrier integrity and key regulatory mechanisms through various in vitro and in vivo models. In recent years, considerable efforts have been made to understand the crosstalk between various signaling pathways that regulate formation and disassembly of TJs. This review provides a comprehensive view on the novel mechanisms that regulate the TJ barrier and permeability. We discuss the latest evidence on how ion transport, cytoskeleton and extracellular matrix proteins, signaling pathways, and cell survival mechanism of autophagy regulate intestinal TJ barrier function. We also provide a perspective on the context-specific outcomes of the TJ barrier modulation. The knowledge on the diverse TJ barrier regulatory mechanisms will provide further insights on the relevance of the TJ barrier defects and potential target molecules/pathways for IBD.
An unconditionally energy dissipative, adaptive IMEX BDF2 scheme and its error estimates for Cahn–Hilliard equation on generalized SAV approach
Authors: Wei Yifan , Zhang Jiwei , Zhao Chengchao , Zhao Yanmin 
Published: September 2024

Abstract
An adaptive implicit-explicit (IMEX) BDF2 scheme is investigated on generalized SAV approach for the Cahn–Hilliard equation by combining with Fourier spectral method in space. It is proved that the modified energy dissipation law is unconditionally preserved at discrete levels. Under a mild ratio restriction, i.e., A1: $0&lt;r_{k}:=\tau _{k}/\tau _{k-1}&lt; r_{\max }\approx 4.8645$, we establish a rigorous error estimate in $H^{1}$-norm and achieve optimal second-order accuracy in time. The proof involves the tools of discrete orthogonal convolution (DOC) kernels and inequality zoom. It is worth noting that the presented adaptive time-step scheme only requires solving one linear system with constant coefficients at each time step. In our analysis, the first-consistent BDF1 for the first step does not bring the order reduction in $H^{1}$-norm. The $H^{1}$ bound of numerical solution under periodic boundary conditions can be derived without any restriction (such as zero mean of the initial data). Finally, numerical examples are provided to verify our theoretical analysis and the algorithm efficiency.
Senescence-associated T cells in immunosenescence and diseases
Authors: Fukushima Yuji , Ueno Ryuji , Minato Nagahiro , Hattori Masakazu 
Published: September 2024

Abstract
Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ programmed cell death protein 1 (PD-1)+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant pro-inflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions, including autoimmunity, and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, as well as autoimmune and chronic inflammatory diseases, and it provides a novel therapeutic clue.
The Beast Computer of Brussels: An American Invention That Conquered the World
Authors: Clay J Eugene 
Published: September 2024

Abstract
In 1972, the American Pentecostal preacher David Wilkerson produced a fifty-minute film, The Rapture, depicting “the return of Jesus Christ.” Subtly alluding to the apocalyptic “mark of the beast” (Revelation 13:16–18), the film featured a gigantic computer called “the Beast.” Located in Brussels, the Beast controlled global commerce by tracking every human on earth with numbers “invisibly ‘laser’ tatooed on the forehead or the back of the hand.” Within months of the film’s release, American Evangelical Protestant networks were reporting the existence of the beast computer as an actual fact and spread the story worldwide. By the 1980s, Greek and Russian Orthodox Christians, skeptical of the European Community, eagerly integrated the beast computer into their own eschatologies. The legend demonstrates the dynamism of the American evangelical imagination, which created this flexible symbol of globalization and technology, as well as the power of the global networks that disseminated it.