bluuebunny/crossref_metadata_2025_split huggingface dataset:
H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers
Authors: Belotti Edwige , Lacoste Nicolas , Iftikhar Arslan , Simonet Thomas , Papin Christophe , Osseni Alexis , Streichenberger Nathalie , Mari Pierre-Olivier , Girard Emmanuelle , Graies Mohamed , Giglia-Mari Giuseppina , Dimitrov Stefan , Hamiche Ali , Schaeffer Laurent 
Published: January 2024

Abstract
Histone variants are key epigenetic players, but their functional and physiological roles remain poorly understood. Here, we show that depletion of the histone variant H2A.Z in mouse skeletal muscle causes oxidative stress, oxidation of proteins, accumulation of DNA damages, and both neuromuscular junction and mitochondria lesions that consequently lead to premature muscle aging and reduced life span. Investigation of the molecular mechanisms involved shows that H2A.Z is required to initiate DNA double strand break repair by recruiting Ku80 at DNA lesions. This is achieved via specific interactions of Ku80 vWA domain with H2A.Z. Taken as a whole, our data reveal that H2A.Z containing nucleosomes act as a molecular platform to bring together the proteins required to initiate and process DNA double strand break repair.
Understanding intercalative modulation of G-rich sequence folding: solution structure of a TINA-conjugated antiparallel DNA triplex
Authors: Garavís Miguel , Edwards Patrick J B , Serrano-Chacón Israel , Doluca Osman , Filichev Vyacheslav V , González Carlos 
Published: January 2024

Abstract
We present here the high-resolution structure of an antiparallel DNA triplex in which a monomer of para-twisted intercalating nucleic acid (para-TINA: (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol) is covalently inserted as a bulge in the third strand of the triplex. TINA is a potent modulator of the hybridization properties of DNA sequences with extremely useful properties when conjugated in G-rich oligonucleotides. The insertion of para-TINA between two guanines of the triplex imparts a high thermal stabilization (ΔTM = 9ºC) to the structure and enhances the quality of NMR spectra by increasing the chemical shift dispersion of proton signals near the TINA location. The structural determination reveals that TINA intercalates between two consecutive triads, causing only local distortions in the structure. The two aromatic moieties of TINA are nearly coplanar, with the phenyl ring intercalating between the flanking guanine bases in the sequence, and the pyrene moiety situated between the Watson–Crick base pair of the two first strands. The precise position of TINA within the triplex structure reveals key TINA–DNA interactions, which explains the high stabilization observed and will aid in the design of new and more efficient binders to DNA.
Structural insights into the HDAC4–MEF2A–DNA complex and its implication in long-range transcriptional regulation
Authors: Dai Shuyan , Guo Liang , Dey Raja , Guo Ming , Zhang Xiangqian , Bates Darren , Cayford Justin , Jiang Longying , Wei Hudie , Chen Zhuchu , Zhang Ye , Chen Lin , Chen Yongheng 
Published: January 2024

Abstract
Class IIa Histone deacetylases (HDACs), including HDAC4, 5, 7 and 9, play key roles in multiple important developmental and differentiation processes. Recent studies have shown that class IIa HDACs exert their transcriptional repressive function by interacting with tissue-specific transcription factors, such as members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. However, the molecular mechanism is not well understood. In this study, we determined the crystal structure of an HDAC4–MEF2A–DNA complex. This complex adopts a dumbbell-shaped overall architecture, with a 2:4:2 stoichiometry of HDAC4, MEF2A and DNA molecules. In the complex, two HDAC4 molecules form a dimer through the interaction of their glutamine-rich domain (GRD) to form the stem of the ‘dumbbell’; while two MEF2A dimers and their cognate DNA molecules are bridged by the HDAC4 dimer. Our structural observations were then validated using biochemical and mutagenesis assays. Further cell-based luciferase reporter gene assays revealed that the dimerization of HDAC4 is crucial in its ability to repress the transcriptional activities of MEF2 proteins. Taken together, our findings not only provide the structural basis for the assembly of the HDAC4–MEF2A–DNA complex but also shed light on the molecular mechanism of HDAC4-mediated long-range gene regulation.
Flexible structural arrangement and DNA-binding properties of protein p6 from Bacillus subtillis phage φ29
Authors: Alcorlo Martín , Luque-Ortega Juan Román , Gago Federico , Ortega Alvaro , Castellanos Milagros , Chacón Pablo , de Vega Miguel , Blanco Luis , Hermoso José M , Serrano Manuel , Rivas Germán , Hermoso Juan A 
Published: January 2024

Abstract
The genome-organizing protein p6 of Bacillus subtilis bacteriophage φ29 plays an essential role in viral development by activating the initiation of DNA replication and participating in the early-to-late transcriptional switch. These activities require the formation of a nucleoprotein complex in which the DNA adopts a right-handed superhelix wrapping around a multimeric p6 scaffold, restraining positive supercoiling and compacting the viral genome. Due to the absence of homologous structures, prior attempts to unveil p6’s structural architecture failed. Here, we employed AlphaFold2 to engineer rational p6 constructs yielding crystals for three-dimensional structure determination. Our findings reveal a novel fold adopted by p6 that sheds light on its self-association mechanism and its interaction with DNA. By means of protein–DNA docking and molecular dynamic simulations, we have generated a comprehensive structural model for the nucleoprotein complex that consistently aligns with its established biochemical and thermodynamic parameters. Besides, through analytical ultracentrifugation, we have confirmed the hydrodynamic properties of the nucleocomplex, further validating in solution our proposed model. Importantly, the disclosed structure not only provides a highly accurate explanation for previously experimental data accumulated over decades, but also enhances our holistic understanding of the structural and functional attributes of protein p6 during φ29 infection.
Porcine endogenous retroviruses in xenotransplantation
Authors: Denner Joachim 
Published: January 2024

ABSTRACT
Xenotransplantation using pig cells, tissues or organs is under development to alleviate the shortage of human donor organs. Meanwhile, remarkably long survival times of pig organs in non-human primates have been reported, as well as the functionality of pig kidneys and hearts in brain-dead humans. Most importantly, two transplantations of pig hearts in patients were performed with survival times of the patients of 8 and 6 weeks. Xenotransplantation may be associated with the transmission of porcine microorganisms including viruses to the recipient. Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs and cannot be eliminated like other viruses can. PERVs are able to infect certain human cells and therefore pose a risk for xenotransplantation. It is well known that retroviruses are able to induce tumors and immunodeficiencies. However, until now, PERVs were not transmitted in all infection experiments using small animals and non-human primates, in all preclinical xenotransplantation trials in non-human primates and in all clinical trials in humans. In addition, several strategies including antiretrovirals, PERV-specific small interfering RNA, vaccines and genome editing using CRISPR/Cas have been developed to prevent PERV transmission.
Abundance models of endemic birds of the Sierra Nevada de Santa Marta, northern South America, suggest small population sizes and dependence on montane elevations
Authors: Botero-Delgadillo Esteban , Meza-Angulo Enrick , Bayly Nicholas J 
Published: January 2024

Abstract
Abundance measures are almost non-existent for several bird species threatened with extinction, particularly range-restricted Neotropical taxa, for which estimating population sizes can be challenging. Here we use data collected over 9 years to explore the abundance of 11 endemic birds from the Sierra Nevada de Santa Marta (SNSM), one of Earth’s most irreplaceable ecosystems. We established 99 transects in the “Cuchilla de San Lorenzo” Important Bird Area within native forest, early successional vegetation, and areas of transformed vegetation by human activities. A total of 763 bird counts were carried out covering the entire elevation range in the study area (~175–2,650 m). We applied hierarchical distance-sampling models to assess elevation- and habitat-related variation in local abundance and obtain values of population density and total and effective population size. Most species were more abundant in the montane elevational range (1,800–2,650 m). Habitat-related differences in abundance were only detected for 5 species, which were more numerous in either early succession, secondary forest, or transformed areas. Inferences of effective population size indicated that at least 4 endemics likely maintain populations no larger than 15,000–20,000 mature individuals. Inferences of species’ area of occupancy and effective population size were lower than most values previously described, a possible consequence of increasing anthropogenic threats. At least 4 of the endemics exceeded criteria for threatened species listing and a thorough evaluation of their extinction risk should be conducted. Population strongholds for most of the study species were located on the northern and western slopes of the SNSM between 1,500 and 2,700 m. We highlight the urgent need for facilitating effective protection of native vegetation in premontane and montane ecosystems to safeguard critical habitats for the SNSM’s endemic avifauna. Follow-up studies collecting abundance data across the SNSM are needed to obtain precise range-wide density estimations for all species.
Heavy Ion Injection of Fixed-Field Alternating Gradient Accelerator
Authors: Yonemura Yujiro , Arima Hidehiko , Nishibata Hiroki , Teranishi Takashi , Wakasa Tomotsugu , Ikeda Nobuo , Watanabe Kenichi , Shigyo Nobuhiro , Iwamura Tatsunori , Adachi Kyosuke , Takamatsu Koki , Kotani Motoki , Tanaka Hisato , Matsunaga Rintaro , Matsumoto Taichi , Takenaka Kyohei , Kajihara Takafumi , Matsunaga Sotaro , Shinohara Yusuke , Mori Yoshiharu 
Published: January 2024

Abstract
Much research in recent years has focused on circular accelerators that accelerate and store secondary particles with a large momentum spread, such as muons, unstable nuclei, and heavy ions with different charge states. A fixed-field alternating gradient (FFAG) accelerator with large transverse and momentum acceptance has obvious advantages for such requirements. A versatile beam injection method is required to accelerate secondary particles with a large momentum spread and different charge states with an FFAG accelerator. In the present study, a method for charge exchange injection of positive heavy ions using the large momentum acceptance of an FFAG accelerator is proposed. A charge injection system, which converts a He1+ beam to a He2+ beam, is developed for a 150 MeV FFAG accelerator at the Center for Accelerator and Beam Applied Science (CABAS) of Kyushu University. As the first step to verify the injection method, an orbit shift from one charge state to the other is demonstrated. This is the first demonstration of heavy ion injection using an FFAG accelerator.
Therapeutic high-dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double-blind, placebo-controlled study (SHADE-S)
Authors: Singh Ajay , Rastogi Ashu , Puri Goverdhan Dutt , Ganesh Venkata , Naik Naveen Bal , Kajal Kamal , Kahlon Shubhkarman , Soni Shiv Lal , Kaloria Narender , Saini Kulbhushan , Hazarika Amarjyoti , Mahajan Varun , Singla Karan , Bhadada Sanjay , Soni Vaishali 
Published: January 2024

Abstract

Background
efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied.

Objective
effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19.

Methods
participants with moderate to severe COVID-19 with PaO2/FiO2 ratio &lt; 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo.

Outcomes
primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality.

Results
in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10–16) and 13 (12–18) ng/ml (P = 0.06) at baseline; and 60 (55–65) ng/ml and 4 (1–7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2–5) versus 5 (95% CI, 3–7), P = 0.01, intergroup difference − 2 (95% CI, −4 to −0.01); r = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P = 0.046)] was observed with vitamin D.

Conclusions
single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19.
ClinicalTrials.gov id: NCT04952857 registered dated 7 July 2021.
What is already known on this topic—vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs.
What this study adds—high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D &gt; 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19.
How this study might affect research, practice or policy—vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.
Identifying high cholesterol in the ambulance setting: a mixed-methods cohort study to tackle health inequality
Authors: Charlton Karl , Rees Jon , Burrow Emma 
Published: January 2024

Abstract

Background
Individuals with low socio-economic status (SES) have disproportionate rates of cardio- vascular disease (CVD) but poorer engagement with preventative health. This study aimed to compare characteristics of individuals with and without hyperlipidaemia and describe their health behaviours.

Methods
A mixed-methods study between January and December 2022. Patients aged ≥40 years using the ambulance service with blood pressure of ≥140/90 had their total cholesterol measured using a point of care device. Data including blood pressure, smoking status, National Early Warning Score 2 and clinical frailty scale (CFS) were analysed.

Results
Of 203 patients (59% female, mean age 65.7 years), 115 (56.7%) had total cholesterol ≥5.1 mmol/L. Thirty patients (14.8%) sought treatment and received either statins (n = 9; 4.4%), dietary modification (n = 7; 3.4%) or no further intervention (n = 14; 6.9%), whilst 85 patients (41.9%) took no further action. Lower CFS (OR 0.53 [0.31–0.93]) and higher total cholesterol (OR 2.07 [1.03–2.76]) predicted seeking further management. SES was not associated with hyperlipidaemia or likelihood of seeking further management, rather this was dictated by competing co-morbidity, poor health literacy and digital divide.

Conclusions
Undiagnosed hyperlipidaemia exists in patients using the ambulance service, irrespective of SES. Individual and healthcare system factors prevent engagement in cholesterol lowering behaviours.
A rare form of calcinosis in patients with systemic sclerosis–myositis overlap: report of four cases
Authors: Achieng Sheilla , Harris Jonathan , Samaranayaka Muditha , Herrick Ariane L 
Published: January 2024

Abstract

Objectives
Calcinosis is a well-described entity that occurs in patients with systemic sclerosis (SSc) and dermatomyositis (DM). Calcinosis in SSc typically occurs over pressure points and is usually nodular. We present a case series of four patients with SSc with a much rarer, diffuse form of calcinosis to illustrate this poorly recognized pattern of extensive and debilitating disease.

Methods
Four patients with SSc and extensive calcinosis were identified from patients attending a tertiary rheumatology centre in the preceding 3 years. Their electronic case notes, radiographic images and medical photographs were reviewed.

Results
All four patients had the diffuse cutaneous subtype of SSc (dcSSc) and additionally a myositis overlap. This was in the context of 102 of 461 (22%) patients with SSc whose clinical details had been recorded in the preceding 3 years having dcSSc. Their ages at diagnosis ranged from 27 to 65 years. Three were female, two were anti-Scl70 antibody positive, and two were anti-PMScl antibody positive. Development of calcinosis occurred between 1 and 6 years after onset of SSc. Plain radiography showed very extensive calcinosis in various sites, distributed in a pattern akin to sheets of calcium-containing deposits in the skin and subcutaneous tissue.

Conclusions
Although calcinosis is common in SSc, extensive sheet-like calcinosis is very rare. Our experience suggests that when this form of calcinosis does occur, this is in the context of the diffuse cutaneous subtype of disease and with myositis overlap. The four cases described should raise awareness of this unusual and extensive pattern of disease.
Vasculitic neuropathy-related disability, pain, quality of life, and autonomic symptoms: a survey of 312 patients
Authors: Collins Michael P , Hadden Robert D M , Luqmani Raashid A 
Published: January 2024

Abstract

Objectives
To assess self-reported symptoms of neuropathy, disability, pain, health-related quality of life (HR-QOL) and autonomic dysfunction in patients with vasculitis.

Methods
Patients with vasculitis (with or without neuropathy) were invited by Vasculitis UK to complete an anonymous online survey.

Results
Three hundred and twelve patients (71% female) responded. Median age was 61–70 years. Median duration of vasculitis was 4 years (&lt;2 months to &gt;15 years). Vasculitic types included granulomatosis with polyangiitis (34%), unspecified ANCA-associated vasculitis (13%), microscopic polyangiitis (11%), eosinophilic granulomatosis with polyangiitis (11%), giant cell arteritis (10%), non-systemic vasculitic neuropathy (2%) and other (19%). Many patients reported foot/hand symptoms suggestive of neuropathy, including numbness (64%), pain (54%) or weakness (40%). Two hundred and forty-two patients (78%) met our definition of probable vasculitic neuropathy: diagnosis of neuropathy by vasculitis team OR numbness OR weakness in feet/hands. Only 52% had been formally diagnosed with neuropathy. Compared with 70 patients without neuropathy, neuropathy patients had greater disability measured by the inflammatory Rasch-built Overall Disability Scale (centile mean 63.1 [s.d. 17.3] vs 75.2 [16.7]; P &lt; 0.0001), Inflammatory Neuropathy Cause and Treatment scale (median 2 [interquartile range 1–4] vs 0.5 [0–2]; P &lt; 0.0001) and modified Rankin scale (median 2 [interquartile range 1–3] vs 2 [1–2)]; P = 0.0002); greater pain on an 11-point rating scale (mean 4.6 [s.d. 2.6] vs 3.5 [2.8]; P = 0.0009); and poorer HR-QOL on the EQ5D-3L (summary index mean 0.58 [s.d. 0.29] vs 0.69 [0.28]; P &lt; 0.0001). Two-thirds reported autonomic symptoms (not associated with neuropathy).

Conclusion
Neuropathy is common and associated with significant disability, pain and impaired HR-QOL in patients with systemic vasculitis.
Multimorbidity in psoriasis as a risk factor for psoriatic arthritis: a population-based study
Authors: Karmacharya Paras , Chakradhar Rikesh , Hulshizer Cassondra A , Gunderson Tina M , Ogdie Alexis , Davis III John M , Wright Kerry , Tollefson Megha M , Duarte-García Alí , Bekele Delamo , Maradit-Kremers Hilal , Crowson Cynthia S 
Published: January 2024

Abstract

Objectives
To examine multimorbidity in psoriasis and its association with the development of psoriatic arthritis (PsA).

Methods
A retrospective cohort study was performed using the Rochester Epidemiology Project. Population-based incidence (2000–09) and prevalence (1 January 2010) cohorts of psoriasis were identified by manual chart review. A cohort of individuals without psoriasis (comparators) were identified (1:1 matched on age, sex and county). Morbidities were defined using two or more Clinical Classification Software codes ≥30 days apart within prior 5 years. PsA was defined using ClASsification of Psoriatic ARthritis (CASPAR) criteria. χ2 and rank-sum tests were used to compare morbidities, and age-, sex- and race-adjusted Cox models to examine the association of baseline morbidities in psoriasis with development of PsA.

Results
Among 817 incident psoriasis patients, the mean age was 45.2 years with 52.0% females, and 82.0% moderate/severe psoriasis. No multimorbidity differences were found between incident psoriasis patients and comparators. However, in the 1088 prevalent psoriasis patients, multimorbidity was significantly more common compared with 1086 comparators (odds ratio 1.35 and 1.48 for two or more and five or more morbidities, respectively). Over a median 13.3-year follow-up, 23 patients (cumulative incidence: 2.9% by 15 years) developed PsA. Multimorbidity (two or more morbidities) was associated with a 3-fold higher risk of developing PsA.

Conclusion
Multimorbidity was more common in the prevalent but not incident cohort of psoriasis compared with the general population, suggesting that patients with psoriasis may experience accelerated development of multimorbidity. Moreover, multimorbidity at psoriasis onset significantly increased the risk of developing PsA, highlighting the importance of monitoring multimorbid psoriasis patients for the development of PsA.
A path to Glucocorticoid Stewardship: a critical review of clinical recommendations for the treatment of systemic lupus erythematosus
Authors: Bertsias George , Askanase Anca , Doria Andrea , Saxena Amit , Vital Edward M 
Published: January 2024

Abstract
Glucocorticoids (GCs) have revolutionized the management of SLE, providing patients with rapid symptomatic relief and preventing flares when maintained at low dosages. However, there are increasing concerns over GC-associated adverse effects and organ damage, which decrease patients’ quality of life (QOL) and increase healthcare costs. This highlights the need to balance effective GC use and minimize toxicity in patients with SLE. Herein, we provide an overview of the theoretical considerations and clinical evidence, in addition to the variations and similarities across nine national and eight international recommendations regarding the use of GCs across SLE manifestations and how these compare with real-world usage. In line with this, we propose possible actions toward the goal of GC Stewardship to improve the QOL for patients with lupus while managing the disease burden.