bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion
Authors: Karakus Ibrahim Serhat , Catak Mehmet Cihangir , Frohne Alexandra , Bayram Catak Feyza , Yorgun Altunbas Melek , Babayeva Royala , Bal Sevgi Kostel , Eltan Sevgi Bilgic , Yalcin Gungoren Ezgi , Esen Fehim , Zemheri Itir Ebru , Karakoc-Aydiner Elif , Ozen Ahmet , Caki-Kilic Suar , Kraakman Michael J. , Boztug Kaan , Baris Safa 
Published: April 2024

Abstract
Purpose
Deficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder.

Methods
Clinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities.

Results
A novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cTFH and increased circulating follicular regulatory (cTFR) cells. Abnormal skewing towards TH2-like responses in certain T-cell subpopulations like cTFH, non-cTFH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia.

Conclusions
This study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.
Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib
Authors: Dotta Laura , Todaro Francesca , Baronio Manuela , Giacomelli Mauro , Pinelli Marinella , Giambarda Martina , Brognoli Beatrice , Greco Silvia , Rota Francesca , Cortesi Manuela , Soresina Annarosa , Moratto Daniele , Tomasi Cesare , Ferraro Rosalba Monica , Giliani Silvia , Badolato Raffaele 
Published: April 2024

Abstract
Introduction
The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity.

Methods
In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation.

Results
STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment.

Conclusion
In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.
Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF
Authors: Koh June-Young , Kim Doo Ri , Son Sohee , Park Hwanhee , Kim Kyung-Ran , Min Sunwoo , Lee Ha Seok , Jhun Byung Woo , Kang Eun-Suk , Jung Inkyung , Kang Ji-Man , Kim Yae-Jean , Shin Eui-Cheol 
Published: April 2024

Abstract
Purpose
Patients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF.

Methods
A patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq).

Results
CITE-seq analysis revealed that before treatment, the patient’s PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs—e.g., STAT1, IRF1, MX1, and OAS1—were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient’s autoimmune features were aggravated, which is in line with sustained epigenetic abnormality.

Conclusions
In a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs.
Effectiveness of Interventions on Work Outcomes After Road Traffic Crash-Related Musculoskeletal Injuries: A Systematic Review and Meta-analysis
Authors: Brakenridge Charlotte L. , Smits Esther J. , Gane Elise M. , Andrews Nicole E. , Williams Gina , Johnston Venerina 
Published: April 2024

Abstract

Background
Musculoskeletal injuries are common after road traffic crash (RTC) and can lead to poor work-related outcomes. This review evaluated the impact of interventions on work-related (e.g. sick leave), health, and functional outcomes in individuals with a RTC-related musculoskeletal injury, and explored what factors were associated with work-related outcomes.

Methods
Searches of seven databases were conducted up until 9/03/2023. Eligible interventions included adults with RTC-related musculoskeletal injuries, a comparison group, and a work-related outcome, and were in English. Meta-analyses were conducted using RevMan and meta-regressions in Stata.

Results
Studies (n = 27) were predominantly conducted in countries with third-party liability schemes (n = 26), by physiotherapists (n = 17), and in participants with whiplash injuries (94%). Pooled effects in favour of the intervention group were seen overall (SMD = − 0.14, 95% CI: − 0.29, 0.00), for time to return to work (− 17.84 days, 95% CI: − 24.94, − 10.74), likelihood of returning to full duties vs. partial duties (RR = 1.17, 95% CI: 1.01, 1.36), decreased pain intensity (− 6.17 units, 95% CI: − 11.96, − 0.39, 100-point scale), and neck disability (− 1.77 units, 95% CI: − 3.24, − 0.30, 50-point scale).

Discussion
Interventions after RTC can reduce time to return to work and increase the likelihood of returning to normal duties, but the results for these outcomes were based on a small number of studies with low-quality evidence. Further research is needed to evaluate a broader range of interventions, musculoskeletal injury types, and to include better quality work-related outcomes.
Anxiety, Sleep Problems, and Vigorous Physical Activity: Bidirectional Associations from Early Adolescence to Early Adulthood in Swedish Adolescents
Authors: Giannotta F. , Nilsson K. W. , Åslund C. , Olofdotter S. , Vadlin S. , Larm P. 
Published: April 2024

AbstractAnxiety symptoms and sleep problems typically emerge during adolescence and are frequently intertwined. However, there is a dearth of knowledge concerning their reciprocal influence and whether physical activity might play a protective role in this relationship. The present study aims at filling this gap exploring also the moderating role of sex. 915 13-year-old Swedish adolescents (56% girls) answered a survey conducted four times: at ages 13 (T1), 16 (T2), 19 (T3), and 22 (T4). A random intercept cross-lagged panel model was used. At within-levels, sleep problems and anxiety symptoms had a bidirectional positive association in middle adolescence. Vigorous physical activity and anxiety symptoms showed a reciprocal negative association from middle adolescence. Vigorous physical activity and sleep problems were reciprocally associated only in late adolescence. Associations were the same for girls and boys. This study demonstrated that the relations between anxiety symptoms, sleep problems, and vigorous physical activity cannot be understood without adopting a developmental perspective and that middle adolescence is a crucial period to plan interventions to reduce anxiety symptoms and sleep problems.
The relationships between biotic uniqueness and abiotic uniqueness are context dependent across drainage basins worldwide
Authors: Snåre Henna , García-Girón Jorge , Alahuhta Janne , Bini Luis Mauricio , Boda Pál , Bonada Núria , Brasil Leandro S. , Callisto Marcos , Castro Diego M. P. , Chen Kai , Csabai Zoltán , Datry Thibault , Domisch Sami , García-Marquez Jaime R. , Floury Mathieu , Friberg Nikolai , Gill Brian A. , González-Trujillo Juan David , Göthe Emma , Haase Peter , Hamada Neusa , Hill Matthew J. , Hjort Jan , Juen Leandro , Jupke Jonathan F. , de Faria Ana Paula Justino , Li Zhengfei , Ligeiro Raphael , Linares Marden S. , Luiza-Andrade Ana , Macedo Diego R. , Mathers Kate L. , Mellado-Diaz Andres , Milosevic Djuradj , Moya Nabor , Poff N. LeRoy , Rolls Robert J. , Roque Fabio O. , Saito Victor S. , Sandin Leonard , Schäfer Ralf B. , Scotti Alberto , Siqueira Tadeu , Martins Renato Tavares , Valente-Neto Francisco , Wang Beixin , Wang Jun , Xie Zhicai , Heino Jani 
Published: April 2024

Abstract
Context
Global change, including land-use change and habitat degradation, has led to a decline in biodiversity, more so in freshwater than in terrestrial ecosystems. However, the research on freshwaters lags behind terrestrial and marine studies, highlighting the need for innovative approaches to comprehend freshwater biodiversity.

Objectives
We investigated patterns in the relationships between biotic uniqueness and abiotic environmental uniqueness in drainage basins worldwide.

Methods
We compiled high-quality data on aquatic insects (mayflies, stoneflies, and caddisflies at genus-level) from 42 drainage basins spanning four continents. Within each basin we calculated biotic uniqueness (local contribution to beta diversity, LCBD) of aquatic insect assemblages, and four types of abiotic uniqueness (local contribution to environmental heterogeneity, LCEH), categorized into upstream land cover, chemical soil properties, stream site landscape position, and climate. A mixed-effects meta-regression was performed across basins to examine variations in the strength of the LCBD-LCEH relationship in terms of latitude, human footprint, and major continental regions (the Americas versus Eurasia).

Results
On average, relationships between LCBD and LCEH were weak. However, the strength and direction of the relationship varied among the drainage basins. Latitude, human footprint index, or continental location did not explain significant variation in the strength of the LCBD-LCEH relationship.

Conclusions
We detected strong context dependence in the LCBD-LCEH relationship across the drainage basins. Varying environmental conditions and gradient lengths across drainage basins, land-use change, historical contingencies, and stochastic factors may explain these findings. This context dependence underscores the need for basin-specific management practices to protect the biodiversity of riverine systems.
Friction modeling from a practical point of view
Authors: Schuderer Matthias , Rill Georg , Schaeffer Thomas , Schulz Carsten 
Published: April 2024

Abstract
Regularized static friction models have been used successfully for many years. However, they are unable to maintain static friction in detail. For this reason, dynamic friction models have been developed and published in the literature. However, commercial multibody simulation packages such as Adams, RecurDyn, and Simpack have developed their own specific stick-slip models instead of adopting one of the public domain approaches. This article introduces the fundamentals of these commercial models and their behavior from a practical point of view. The stick-slip models were applied to a simple test model and a more sophisticated model of a festoon cable system using their standard parameters.
The quality of life impact of the COVID-19 pandemic and lockdowns for people living with multiple sclerosis (MS): evidence from the Australian MS Longitudinal Study
Authors: Henson Glen J. , van der Mei Ingrid , Taylor Bruce V. , Blacklow Paul , Claflin Suzi B. , Palmer Andrew J. , Hurst Carol , Campbell Julie A. 
Published: April 2024

Abstract
Purpose
People living with multiple sclerosis (PwMS) in metropolitan Victoria, Australia, experienced a 112-day, COVID-19-related lockdown in mid-2020. Contemporaneously, Australian PwMS elsewhere experienced minimal restrictions, resulting in a natural experiment. This study investigated the relationships between lockdowns, COVID-19-related adversity, and health-related quality of life (HRQoL). It also generated health state utilities (HSU) representative of changes in HRQoL.

Methods
Data were extracted from Australian MS Longitudinal Study surveys, which included the Assessment of Quality of Life-Eight Dimensions (AQoL-8D) instrument and a COVID-19 questionnaire. This COVID-19 questionnaire required participants to rank their COVID-19-related adversity across seven health dimensions. Ordered probits were used to identify variables contributing to adversity. Linear and logit regressions were applied to determine the impact of adversity on HRQoL, defined using AQoL-8D HSUs. Qualitative data were examined thematically.

Results
N = 1666 PwMS (average age 58.5; 79.8% female; consistent with the clinical presentation of MS) entered the study, with n = 367 (22.0%) exposed to the 112-day lockdown. Lockdown exposure and disability severity were strongly associated with higher adversity rankings (p < 0.01). Higher adversity rankings were associated with lower HSUs. Participants reporting major adversity, across measured health dimensions, had a mean HSU 0.161 (p < 0.01) lower than participants reporting no adversity and were more likely (OR: 2.716, p < 0.01) to report a clinically significant HSU reduction. Themes in qualitative data supported quantitative findings.

Conclusions
We found that COVID-19-related adversity reduced the HRQoL of PwMS. Our HSU estimates can be used in health economic models to evaluate lockdown cost-effectiveness for people with complex and chronic (mainly neurological) diseases.
Life scientists’ experience with posting preprints during the COVID-19 pandemic
Authors: Biesenbender Kristin , Toepfer Ralf , Peters Isabella 
Published: April 2024

AbstractIn the COVID-19 pandemic, it was much more critical for many life science researchers to rapidly disseminate research results—so they used preprints as upstream publication opportunities. This was rather new to the life sciences where preprint servers had only appeared as early as 2013. With a mixed-methods-study we examined this development and investigated whether preprint posting is a temporary phenomenon or the beginning of a cultural shift in publishing behavior in the life sciences. First, we conducted a survey of researchers who have posted COVID-19 related preprints. We investigated experiences with posting preprints during the COVID-19 pandemic, motivations for and concerns about posting preprints, the role of research institutions or funders, and the future of preprint publishing. Answers were grouped to compare differences between respondents’ gender, career stage, region of origin (global south or global north) and experience with posting preprints before and during the COVID-19 pandemic. We further analyzed eight popular preprint repositories regarding the number of posted preprints and preprint characteristics, such as the number of authors and citations. Interestingly, survey and preprint server analysis have presented different, if not contradicting results: While the majority of surveyed researchers was willing to continue posting preprints, the numbers of preprints published, especially on servers for the life sciences, have stagnated or declined. Also, while certain preprints garnered substantial citations during the COVID-19 pandemic, this has not resulted in a significant shift in researchers’ publishing behavior, and the posting of preprints has not become a routine. We concluded that the sustainability of preprint publishing practices is more strongly influenced by disciplinary norms and practices than by external shocks as the COVID-19 pandemic.
Discourses about grades and competency-based evaluation: Exploring communicative and situated meanings at an Italian high school
Authors: Costa Sara , Norton Laura Soledad , Pirchio Sabine 
Published: April 2024

AbstractGrades are the universal tool for measuring students’ performance at school. However, other competency-based evaluation methods have shown to have a stronger impact on the learning quality. We investigated how different methods are collectively represented and discursively constructed among students at an Italian high school class. Thematic analysis was applied to 4 focus groups of about one hour conducted with 18 students (F = 12, M = 6) attending the second year of a scientific high school, at the end of the second year of “At School Beyond the Grade” project. The main themes emerged were linked to the cultural and communicational meanings constructed around each method, showing how they are used for different purposes and yet stay strictly related. Comments were used in a self-reflective manner to improve learning competencies individually. Grades were used to communicate with others their position as a socially shared code. The emerged narratives show the students’ expectations about the way teachers manage evaluation tools and their struggles on translating one into the other. Considerations on the shared ideal of both methods as complementary were discussed in terms of intercultural, identity and learning process.
Prey-mediated effects of Mpp51Aa2-producing cotton on longevity and reproduction of Orius majusculus
Authors: Meissle Michael 
Published: April 2024

AbstractGenetically engineered (GE) cotton event MON 88702, producing Mpp51Aa2 (previously mCry51Aa2) from Bacillus thuringiensis (Bt), controls sucking pests, such as Lygus spp. (Hemiptera: Miridae) and thrips (Thysanoptera). Ingesting high doses of the insecticidal protein resulted in adverse effects on life table parameters of beneficial, predatory Orius spp. (Hemiptera: Anthocoridae). This triggered laboratory studies with more realistic food treatments, including different combinations of prey types with and without Bt protein to further characterize risks to this important group of non-target organisms. In this work, exclusive feeding of frozen spider mites (Tetranychus urticae, Acari: Tetranychidae) from Bt cotton confirmed adverse effects on longevity and fecundity of O. majusculus adults. Alternate feeding of Bt protein-containing spider mites and Bt-free Ephestia kuehniella (Lepidoptera: Pyralidae) eggs mitigated effects on longevity, but not on fecundity. When living larvae of Spodoptera littoralis (Lepidoptera: Noctuidae) from Bt cotton were fed to the predators, however, no effects on longevity and reproduction of female O. majusculus were observed, despite the fact that Bt protein concentrations in larvae were almost as high as concentrations in spider mites. When a diverse mix of prey species with various Bt protein concentrations is consumed in the field, it is unlikely that exposure of Orius spp. to Mpp51Aa2 is high enough to exert adverse effects on predator populations. MON 88702 cotton may thus be a valuable tool for integrated management of sucking pests.
Predicting ischemic stroke patients’ prognosis changes using machine learning in a nationwide stroke registry
Authors: Lin Ching-Heng , Chen Yi-An , Jeng Jiann-Shing , Sun Yu , Wei Cheng-Yu , Yeh Po-Yen , Chang Wei-Lun , Fann Yang C. , Hsu Kai-Cheng , Lee Jiunn-Tay ,   Taiwan Stroke Registry Investigators
Published: April 2024

AbstractAccurately predicting the prognosis of ischemic stroke patients after discharge is crucial for physicians to plan for long-term health care. Although previous studies have demonstrated that machine learning (ML) shows reasonably accurate stroke outcome predictions with limited datasets, to identify specific clinical features associated with prognosis changes after stroke that could aid physicians and patients in devising improved recovery care plans have been challenging. This study aimed to overcome these gaps by utilizing a large national stroke registry database to assess various prediction models that estimate how patients’ prognosis changes over time with associated clinical factors. To properly evaluate the best predictive approaches currently available and avoid prejudice, this study employed three different prognosis prediction models including a statistical logistic regression model, commonly used clinical-based scores, and a latest high-performance ML-based XGBoost model. The study revealed that the XGBoost model outperformed other two traditional models, achieving an AUROC of 0.929 in predicting the prognosis changes of stroke patients followed for 3 months. In addition, the XGBoost model maintained remarkably high precision even when using only selected 20 most relevant clinical features compared to full clinical datasets used in the study. These selected features closely correlated with significant changes in clinical outcomes for stroke patients and showed to be effective for predicting prognosis changes after discharge, allowing physicians to make optimal decisions regarding their patients’ recovery.
Graphical Abstract