bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2
Authors: Ehlers Lisa , Hombrouck Anneleen , Wouters Marjon , Pillay Bethany , Delafontaine Selket , Bucciol Giorgia , Baggio Marco , Dzhus Mariia , Ebstein Frédéric , Jacquemyn Maarten , De Somer Lien , Schrijvers Rik , Vanderschueren Steven , Cassiman David , Kirchner Marieluise , Mertins Philipp , Mashreghi Mir-Farzin , Kallinich Tilmann , Daelemans Dirk , Agostinis Patrizia , Moens Leen , Meyts Isabelle 
Published: October 2023

AbstractHuman deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease with a complex clinical phenotype of recurrent fever, vasculitis and stroke as well as immunodeficiency and bone marrow failure. It is caused by pathogenic variants inADA2that lead to impaired ADA2 protein secretion and reduced deaminase activity. However, the mechanisms driving the disease on a cellular level remain elusive. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify a low-molecular-weight (LMW) form of ADA2 expressed exclusively intracellularly in healthy control macrophages. This LMW-ADA2 is subject to glycan trimming by α-mannosidases after transfer to the Golgi and is distinct from secreted high- molecular-weight (HMW) ADA2. DADA2 patients’ monocyte-derived macrophages lack LMW- ADA2 and mutant ADA2 does not undergo glycan processing in the Golgi. We confirm the absence of LMW-ADA2 upon overexpression of 11 pathogenicADA2variants in HEK293T cells and monocytic U-937 cells. By subcellular fractionation, we show that LMW-ADA2 localizes to the cytosolic and lysosomal compartments. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2.
Continental species distribution and biodiversity predictions depend on modeling grain
Authors: Cohen Jeremy M. , Jetz Walter 
Published: October 2023

AbstractAs global change accelerates, accurate predictions of species distributions and biodiversity patterns are critical to prevent population declines and biodiversity loss. However, at continental and global scales, these predictions are often derived from species distribution models (SDMs) fit at coarse spatial grains uninformed by ecological processes. Coarse-grain models may systematically bias predictions of distributions and biodiversity if they are consistently over- or under-estimating area with suitable habitat, and this bias may intensify in regions with heterogenous landscapes or with poor data coverage. To test this, we fit presence-absence SDMs characterizing both the summer and winter distributions of 572 North American bird species – nearly the entire avian diversity of the US and Canada – across five spatial grains from 1 to 50 km, using observations from the eBird citizen science initiative. We find that across both seasons, models fit at 1 km performed better under cross-validation than those at coarser scales and more accurately predicted species’ presences and absences at local sites. Coarser-grain models, including models fit at 3 km, consistently under-predicted range area relative to 1 km models, suggesting that coarse-grain estimates of distributions could be missing important habitat. This bias intensified during summer (83% of species) when many birds have smaller ‘operational scales’ via localized home ranges and greater habitat specificity while breeding. Biases were greatest in heterogenous desert and scrubland regions and lowest in more homogenous boreal forest and taiga-dominated regions. When aggregating distributions to produce continental biodiversity predictions, coarse-grain models overpredicted diversity in the west and underpredicted it in the great plains, prairie pothole region and boreal/taiga zones. The modern availability of high-performance computing and high-resolution observational and environmental data provides opportunities to improve continental predictions of species distributions and biodiversity.
Evaluating ChatGPT as an Agent for Providing Genetic Education
Authors: Walton Nephi , Gracefo Sara , Sutherland Nykole , Kozel Beth A. , Danford Christopher J. , McGrath Scott P. 
Published: October 2023

SummaryGenetic disorders are complex and can greatly impact an individual’s health and well-being. In this study, we assess the ability of ChatGPT, a language model developed by OpenAI, to answer questions related to three specific genetic disorders: BRCA1, MLH1, and HFE. ChatGPT has shown it can supply articulate answers to a wide spectrum of questions. However, its ability to answer questions related to genetic disorders has yet to be evaluated. The aim of this study is to perform both quantitative and qualitative assessments of ChatGPT’s performance in this area. The ability of ChatGPT to provide accurate and useful information to patients was assessed by genetic experts. Here we show that ChatGPT answered 64.7% of the 68 genetic questions asked and was able to respond coherently to complex questions related to the three genes/conditions. Our results reveal that ChatGPT can provide valuable information to individuals seeking information about genetic disorders, however, it still has some limitations and inaccuracies, particularly in understanding human inheritance patterns. The results of this study have implications for both genomics and medicine and can inform future developments in this area. AI platforms, like ChatGPT, have significant potential in the field of genomics. As these technologies become integrated into consumer-facing products, appropriate oversight is required to ensure accurate and safe delivery of medical information. With such oversight and training specifically for genetic information, these platforms could have the potential to augment some clinical interactions.
Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care
Authors: Ye Xinjian , Bai Yijing , Li Mengjun , Ye Yuhang , Chen Yitong , Liu Bin , Dai Yuwei , Wang Shan , Pan Weiyi , Wang Zhiyong , Mao Yingying , Chen Qianming 
Published: October 2023

AbstractPeriodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of "predictive, preventive, and personalized" periodontics. In the present study, genetic proxies identified through genome-wide association studies (GWAS) for circulating immune cells and periodontitis were incorporated into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study (TWAS) and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genesS100A9andS100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to thoroughly comprehend the biological underpinnings and ascertain the clinical relevance.
Synaptic Zn2+contributes to deleterious consequences of spreading depolarizations
Authors: Bennett Michael C. , Morton Russell A. , Carlson Andrew P. , Shuttleworth C. William 
Published: October 2023

ABSTRACTSpreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+chelator with rapid kinetics (ZX-1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX-1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+during SD. These results demonstrate a role for synaptic Zn2+release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.
Antagonistic Regulation of Arabidopsis Leaf Senescence by SCOOP10 and SCOOP12 Peptides via MIK2 Receptor-Like Kinase
Authors: Zhang Zhenbiao , Gigli-Bisceglia Nora , Li Wei , Testerink Christa , Guo Yongfeng 
Published: October 2023

AbstractLeaf senescence plays a critical role in a plant’s overall reproductive success due to its involvement in nutrient remobilization and allocation. However, our current understanding of the molecular mechanisms controlling leaf senescence remains limited. In this study, we demonstrate that the receptor-like kinase MALE DISCOVERER 1-INTERACTING RECEPTOR-LIKE KINASE 2 (MIK2) functions as a negative regulator of leaf senescence. We report that the SERINE-RICH ENDOGENOUS PEPTIDES 10 and 12 (SCOOP10 and SCOOP12), previously known to physically interact with MIK2, compete with each other to control MIK2-dependent senescence mechanisms. We observed that increased expression of SCOOP10 or the application of exogenous SCOOP10 peptides accelerated leaf senescence in a MIK2-dependent manner. Conversely, SCOOP12 acted as a suppressor of MIK2-dependent senescence. Thus, the SCOOP10-MIK2 and the SCOOP12-MIK2 modules function antagonistically, allowing for fine-tuning the modulation of the leaf senescence process. Our research sheds light on the complex mechanisms underlying leaf senescence and provides valuable insights into the interplay between receptors, peptides, and the regulation of plant senescence.
Multi-scale photocatalytic proximity labeling reveals cell surface neighbors on and between cells
Authors: Lin Zhi , Schaefer Kaitlin , Lui Irene , Yao Zi , Fossati Andrea , Swaney Danielle L. , Palar Ajikarunia , Sali Andrej , Wells James A. 
Published: October 2023

AbstractThe cell membrane proteome is the primary biohub for cell communication, yet we are only beginning to understand the dynamic protein neighborhoods that form on the cell surface and between cells. Proximity labeling proteomics (PLP) strategies using chemically reactive probes are powerful approaches to yield snapshots of protein neighborhoods but are currently limited to one single resolution based on the probe labeling radius. Here, we describe a multi-scale PLP method with tunable resolution using a commercially available histological dye, Eosin Y, which upon visible light illumination, activates three different photo-probes with labeling radii ranging from ∼100 to 3000 Å. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor (EGFR) and orthogonally validated >20 neighbors using immuno-assays and AlphaFold-Multimer prediction that generated plausible binary interaction models. We further profiled the protein neighborhoods of cell-cell synapses induced by bi-specific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)T cells at longer length scales. This integrated multi-scale PLP platform maps local and distal protein networks on cell surfaces and between cells. We believe this information will aid in the systematic construction of the cell surface interactome and reveal new opportunities for immunotherapeutics.
Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast
Authors: Sottnik Joseph L. , Shackleford Madeleine T. , Nesiba Camryn S. , Richer Amanda L. , Swartz Jordan M. , Rowland Carmen E. , Musick Maggie , Fu Rui , Opresko Patricia L. , Mehrotra Sanjana , Hesselberth Jay R. , Diamond Jennifer R. , Sikora Matthew J. 
Published: October 2023

ABSTRACTInvasive lobular carcinoma of the breast (ILC) are typically estrogen receptor α (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, yet patients with ILC face uniquely poor long-term outcomes with increased recurrence risk, suggesting endocrine response and ER function are unique in ILC. We previously found specifically in ILC cells that ER is co-regulated by the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1). This novel MDC1 activity, however, was associated with dysfunction in the canonical DNA repair activity of MDC1, but absent typical features of DNA repair deficiency. To understand reciprocal activities of MDC1, we profiled the MDC1 interactome and found MDC1-associated proteins in ILC cells mirror a “BRCA-like” state lacking key homologous recombination (HR) proteins, consistent with HR dysfunction but distinct from classic “BRCAness”. HR dysfunction in ILC cells was mirrored in single-cell transcriptome and DNA repair activity analyses, along with DNA repair signaling and functional data, showing dysfunctional HR induction and resolution. In parallel, ILC tumor data are consistent with a distinct form of HR dysfunction via impaired HR resolution, lacking BRCA-like genomic scarring but with elevated signatures of PARP inhibitor sensitivity. We tested whether this HR dysfunction could indeed be exploited using PARP inhibition and found that talazoparib treatment produced a durable growth suppressionin vitroand in multiple ILC xenograftsin vivo. ILC-specific ER:MDC1 activity creates a new context for ER and MDC1 function in ILC, at the cost of a DNA repair dysfunction that is therapeutically targetable.SignificanceILC are rarely associated with biomarkers of HR deficiency, and as such patients are rarely eligible for treatment with PARP inhibitors. Our work suggests ILC present with a previously unappreciated form of HR dysfunction, linked to ILC-specific genomic activity of ER and MDC1, which imparts sensitivity to PARP inhibition.
BenzoHTag, a fluorogenic self-labeling protein developed using molecular evolution
Authors: Lampkin Bryan J. , Goldberg Benjamin J. , Kritzer Joshua A. 
Published: October 2023

AbstractSelf-labeling proteins are powerful tools in chemical biology as they enable the precise cellular localization of a synthetic molecule, often a fluorescent dye, with the genetic specificity of a protein fusion. HaloTag7 is the most popular self-labeling protein due to its fast labeling kinetics and the simplicity of its chloroalkane ligand. Reaction rates of HaloTag7 with different chloroalkane-containing substrates is highly variable and rates are only very fast for rhodamine-based dyes. This is a major limitation for the HaloTag system because fast labeling rates are critical for live-cell assays. Here, we report a molecular evolution system for HaloTag using yeast surface display that enables the screening of libraries up to 108variants to improve reaction rates with any substrate of interest. We applied this method to produce a HaloTag variant, BenzoHTag, which has improved performance with a fluorogenic benzothiadiazole dye. The resulting system has improved brightness and conjugation kinetics, allowing for robust, no-wash fluorescent labeling in live cells. The new BenzoHTag-benzothiadiazole system has improved performance in live-cell assays compared to the existing HaloTag7-silicon rhodamine system, including saturation of intracellular enzyme in under 100 seconds and robust labeling at dye concentrations as low as 7 nM. It was also found to be orthogonal to the silicon HaloTag7-rhodamine system, enabling multiplexed no-wash labeling in live cells. The BenzoHTag system, and the ability to optimize HaloTag for a broader collection of substrates using molecular evolution, will be very useful for the development of cell-based assays for chemical biology and drug development.
First assessment of a cost questionnaire for its agreement with administrative databases in females with stress urinary incontinence in Switzerland: a validation study
Authors: Moetteli Céline , Taeymans Jan , Koenig Irene 
Published: October 2023

AbstractIntroductionEconomic research in the field of pelvic floor rehabilitation is lacking in transparency of methodology and consideration of indirect costs. Service use questionnaires collect cost data with the broad approach needed for the societal perspective of health economic studies. Nevertheless, these questionnaires are seldom validated. Therefore, this study aimed to evaluate the accuracy of a questionnaire to assess healthcare costs of females with stress urinary incontinence (SUI) in Switzerland.MethodsA questionnaire was developed to measure direct medical, direct non-medical and indirect costs in females with stress urinary incontinence living in the larger Bern area in Switzerland. Participants were recruited out of a prior study sample, where they had already completed the cost questionnaire. Administrative databases’ cost data were obtained for the investigation period. The agreement between the reported direct medical costs of the questionnaire with those from the providers’ billings was assessed using Pearson correlation coefficient (r), intraclass correlation coefficient (ICC) for agreement, Lin’s concordance correlation coefficient (LINCCC) and limits of agreement (LOA).ResultsFourteen participants were eligible for this study. Agreement between the two methods presented a Pearson’srof 0.64 [95%CI 0.16 to 1.00], ICC of 0.79 [95% CI 0.33 to 0.93] and LINCCC 0.75 [95% CI 0.19 to 0.86]. LOA results showed no evidence for systematically under- or overreporting.ConclusionsThe developed questionnaire seemed to be an acceptable representative for direct medical costs in females with stress urinary incontinence in Switzerland. However, direct non-medical and indirect costs were not compared to an external criterion.
An efficient approach to nowcasting the time-varying reproduction number
Authors: Sumalinab Bryan , Gressani Oswaldo , Hens Niel , Faes Christel 
Published: October 2023

AbstractEstimating the instantaneous reproduction number (ℛt) in near real-time is crucial for monitoring and responding to epidemic outbreaks on a daily basis. However, such estimates often suffer from bias due to reporting delays inherent in surveillance systems. A fast and flexible Bayesian methodology is proposed to overcome this challenge by estimatingℛtwhile taking into account reporting delays. Furthermore, the uncertainty associated with the nowcasting of cases is naturally taken into account to get a valid uncertainty estimation of the nowcasted reproduction number. The proposed methodology is evaluated through a simulation study and applied to COVID-19 incidence data in Belgium.
Assessing adherence to National Institute for Health and Care Excellence dementia assessment and diagnosis guidelines in adults with intellectual disability: a retrospective cohort study
Authors: Duncan Caroline , Wilkinson Ewan , Jaydeokar Sujeet , Acton Daniel James 
Published: October 2023

Purpose
This study aims to evaluate the dementia assessment and diagnosis care provided to adults with intellectual disability. The authors selected recommendations from the National Institute for Health and Care Excellence (NICE) standards which could be evidenced in clinical notes and aimed to identify characteristics which may be associated with improved adherence to these recommendations.

Design/methodology/approach
The study population was adults with an intellectual disability who were diagnosed with dementia between January 2019 and December 2022 by a UK-based intellectual disability service. Data to demonstrate adherence to selected recommendations and demographic and clinical characteristics were extracted from electronic patient records.

Findings
The authors identified 41 individuals. A mean of six of the eight recommendations were adhered to. There was low adherence with structural imaging to support dementia subtype diagnosis (9 individuals, 22%). This may be linked with the low percentage of people diagnosed with vascular dementia (1 individual, 2%) despite a national figure of 20%. No demographic or clinical characteristics were associated with level of adherence recorded. The authors found incomplete recording of diagnostic clinical coding in electronic patient records. This may disadvantage this population, as they cannot be readily identified for post diagnostic support or resource allocation.

Originality/value
To the best of the authors’ knowledge, this is the first study to examine adherence to these NICE guidelines in this population.
Tone complexity and analyst forecast behaviors: evidence from earnings conference calls
Authors: Kwon Kyungeun , Zhou Mi , Wang Tawei , Cheng Xu , Qiao Zhilei 
Published: October 2023

PurposeBoth the SEC (Securities and Exchange Commission) and the popular press have routinely criticized firms for the complexity of their financial disclosures. This study aims to investigate how financial analysts respond to the tone complexity of firm disclosures.Design/methodology/approachUsing approximately 20,000 earnings conference call transcripts of S&P 1,500 firms between 2005 and 2015, the authors first calculate the abnormal negative tone, the measure of tone complexity; then use such tone measure in econometric models to examine analyst forecast behavior. The authors also test the robustness of the results under different model specifications, tone word lists and alternative tone measure calculations.FindingsConsistent with the notion that analysts respond to the information demand from investors and incur more costs and effort to analyze firm disclosure when the tone is more complex, the authors find that higher tone complexity is positively and significantly associated with more analyst following, longer report duration, more forecast revisions, larger forecast error and larger forecast dispersion. In addition, the authors find that tone complexity has a long-term impact on analyst following but has a limited long-term impact on analyst report duration, analyst revision, forecast error and dispersion.Originality/valueThis study complements existing literature by highlighting the information role of financial analysts and by providing evidence that analysts incorporate the management tone disclosed during conference calls to adjust their forecasting behaviors. The results can be used by policymakers as evidence and support for further improving firm communication from a new dimension of disclosure tone.