bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAK inhibitors differentially modulate B cell activation, maturation and function: A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients with rheumatoid arthritis
Authors: Frede Natalie , Lorenzetti Raquel , Hüppe Janika M , Janowska Iga , Troilo Arianna , Schleyer Marei-Theresa , Venhoff Ana C. , Voll Reinhard E. , Thiel Jens , Venhoff Nils , Rizzi Marta 
Published: January 2023

BackgroundJanus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment.MethodsTo this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways.ResultsWhile B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells.ConclusionJAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.
Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy
Authors: Zhou Jiebai , Lu Xinyuan , Zhu Haixing , Ding Ning , Zhang Yong , Xu Xiaobo , Gao Lei , Zhou Jian , Song Yuanlin , Hu Jie 
Published: January 2023

BackgroundImmune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance.Methods190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance.ResultsWe found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs.ConclusionPatients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.
Immunoinformatics design of multivalent epitope vaccine against monkeypox virus and its variants using membrane-bound, enveloped, and extracellular proteins as targets
Authors: Waqas Muhammad , Aziz Shahkaar , Liò Pietro , Khan Yumna , Ali Amjad , Iqbal Aqib , Khan Faizullah , Almajhdi Fahad Nasser 
Published: January 2023

IntroductionThe current monkeypox (MPX) outbreak, caused by the monkeypox virus (MPXV), has turned into a global concern, with over 59,000 infection cases and 23 deaths worldwide.ObjectivesHerein, we aimed to exploit robust immunoinformatics approach, targeting membrane-bound, enveloped, and extracellular proteins of MPXV to formulate a chimeric antigen. Such a strategy could similarly be applied for identifying immunodominant epitopes and designing multi-epitope vaccine ensembles in other pathogens responsible for chronic pathologies that are difficult to intervene against.MethodsA reverse vaccinology pipeline was used to select 11 potential vaccine candidates, which were screened and mapped to predict immunodominant B-cell and T-cell epitopes. The finalized epitopes were merged with the aid of suitable linkers, an adjuvant (Resuscitation-promoting factor), a PADRE sequence (13 aa), and an HIV TAT sequence (11 aa) to formulate a multivalent epitope vaccine. Bioinformatics tools were employed to carry out codon adaptation and computational cloning. The tertiary structure of the chimeric vaccine construct was modeled via I-TASSER, and its interaction with Toll-like receptor 4 (TLR4) was evaluated using molecular docking and molecular dynamics simulation. C-ImmSim server was implemented to examine the immune response against the designed multi-epitope antigen.Results and discussionThe designed chimeric vaccine construct included 21 immunodominant epitopes (six B-cell, eight cytotoxic T lymphocyte, and seven helper T-lymphocyte) and is predicted non-allergen, antigenic, soluble, with suitable physicochemical features, that can promote cross-protection among the MPXV strains. The selected epitopes indicated a wide global population coverage (93.62%). Most finalized epitopes have 70%–100% sequence similarity with the experimentally validated immune epitopes of the vaccinia virus, which can be helpful in the speedy progression of vaccine design. Lastly, molecular docking and molecular dynamics simulation computed stable and energetically favourable interaction between the putative antigen and TLR4.ConclusionOur results show that the multi-epitope vaccine might elicit cellular and humoral immune responses and could be a potential vaccine candidate against the MPXV infection. Further experimental testing of the proposed vaccine is warranted to validate its safety and efficacy profile.
Outcomes of feeding activity of the sea cucumber Holothuria tubulosa on quantity, biochemical composition, and nutritional quality of sedimentary organic matter
Authors: Pasquini Viviana , Addis Pierantonio , Giglioli Ambra Angelica , Moccia Davide , Pusceddu Antonio 
Published: January 2023

IntroductionHolothuria tubulosa is one of the most common sea cucumbers in the Mediterranean Sea, generally associated with organically enriched coastal sediments and seagrass beds. As a deposit-feeder, it is responsible for strong bioturbation processes and plays a putative key role in sedimentary carbon cycling and benthic trophodynamics. With the aim of exploring the potential use of holothuroids as a tool for remediating eutrophicated sediments, we investigated the effects of H. tubulosa on sedimentary organic matter quantity, biochemical composition, and nutritional quality.MethodsHolothuroids and associated samples of ambient sediments were collected in two sites located in the Central-Western Mediterranean Sea (Sardinia, Italy) and characterized by different trophic status backgrounds: the site of Oristano characterized by sandy-muddy sediments and the presence of mariculture plants (ranked as meso-eutrophic) and the site of Teulada characterized by sandy sediments and Posidonia oceanica meadows (ranked as oligo-mesotrophic). We compared the biochemical composition (proteins, carbohydrates, lipids) of ambient sediment vs sea cucumbers feces and the sedimentary protein content vs protein content in the sediments retrieved in different gut sections (esophagus, mid gut, end gut) of the holothuroid.ResultsOur results reveal that holothuroids feeding on meso-eutrophic sediments can increase protein (1.5 times) and lipid (1.3 times) content through their defecation, thus making these substrates a more labile food source for other benthic organisms. We report here that H. tubulosa feeding on meso-eutrophic sediment is most likely able to actively select particles rich in labile organic matter with buccal tentacles, as revealed by the protein content in the esophagus that is up to 2-folds higher than that in the source sediment. According to the inverse relationship between assimilation rates and availability of organic substrates and the optimal foraging theory, H. tubulosa feeding on oligo-mesotrophic sediments showed potential assimilation of proteins ca. 25% higher than that of specimens feeding on meso-eutrophic sediments.DiscussionOur results reveal that H. tubulosa feeding on meso-eutrophic sediments can profoundly influence the benthic trophic status, specifically modifying the biochemical composition and nutritional quality of organic matter, thus paving the way to its possible use in bioremediation actions of eutrophicated sediments and in Integrated Multi-Trophic Aquaculture systems.
Case report:Multiple abscesses caused by Porphyromonas gingivalis diagnosed by metagenomic next-generation sequencing
Authors: Zhang Yichen , Zhu Youfeng , Wan Huijuan 
Published: January 2023

BackgroundExtraoral infection by Porphyromonas gingivalis (P. gingivalis) is extremely rare and challenging to diagnose because the fastidious pathogen is difficult to culture by traditional methods. We report the first case of a patient with multiple abscesses in muscles and the brain with dura empyema due to P. gingivalis, which was diagnosed by metagenomic next-generation sequencing (mNGS).Case presentationA 65-year-old male patient was admitted to our hospital for multiple lumps in his body. Brain magnetic resonance imaging (MRI) and lower-limb computed tomography (CT) revealed multiple abscesses in the brain and muscles. A diagnosis of P. gingivalis infection was made based on mNGS tests of blood, cerebrospinal fluid (CSF), and pus samples, as the traditional bacterial culture of these samples showed negative results. Target antibiotic therapy with meropenem and metronidazole was administered, and CT-guided percutaneous catheter drainage of abscesses in both thighs was performed. The size of muscle abscesses reduced significantly and neurological function improved. The patient was followed up for 4 months. No abscesses re-appeared, and the remaining abscesses in his backside and both legs were completely absorbed. He can speak fluently and walk around freely without any neurological deficits.ConclusionMetagenomic next-generation sequencing is helpful for early diagnosis and subsequent treatment of P. gingivalis-associated multiple abscesses.
A Maverick-like cluster in the genome of a pathogenic, moderately virulent strain of Gallibacterium anatis, ESV200, a transient biofilm producer
Authors: Sanchez-Alonso Patricia , Cobos-Justo Elena , Avalos-Rangel Miguel Angel , López-Reyes Lucía , Paniagua-Contreras Gloria Luz , Vaca-Paniagua Felipe , Anastacio-Marcelino Estela , López-Ochoa Ana Jaqueline , Pérez Marquez Victor M. , Negrete-Abascal Erasmo , Vázquez-Cruz Candelario 
Published: January 2023

IntroductionGallibacterium anatis causes gallibacteriosis in birds. These bacteria produce biofilms and secrete several fimbrial appendages as tools to cause disease in animals. G. anatis strains contain up to three types of fimbriae. Complete genome sequencing is the strategy currently used to determine variations in the gene content of G. anatis, although today only the completely circularized genome of G. anatis UMN179 is available.MethodsThe appearance of growth of various strains of G. anatis in liquid culture medium was studied. Biofilm production and how the amount of biofilm was affected by DNase, Proteinase K, and Pronase E enzymes were analyzed. Fimbrial gene expression was performed by protein analysis and qRT-PCR. In an avian model, the pathogenesis generated by the strains G. anatis ESV200 and 12656-12 was investigated. Using bioinformatic tools, the complete genome of G. anatis ESV200 was comparatively studied to search for virulence factors that would help explain the pathogenic behavior of this strain.Results and DiscussionG. anatis ESV200 strain differs from the 12656-12 strain because it produces a biofilm at 20%. G. anatis ESV200 strain express fimbrial genes and produces biofilm but with a different structure than that observed for strain 12656-12. ESV200 and 12656-12 strains are pathogenic for chickens, although the latter is the most virulent. Here, we show that the complete genome of the ESV200 strain is similar to that of the UNM179 strain. However, these strains have evolved with many structural rearrangements; the most striking chromosomal arrangement is a Maverick-like element present in the ESV200 strain.
Dynamic changes in the glycocalyx and clinical outcomes in patients undergoing endovascular treatments for large vessel occlusion
Authors: Liang Dan , Zeng Xiuli , Yao Mingzheng , Li Fei , Lin Jiaxing , Zhang Liang , Liu Jialin , Huang Li'an 
Published: January 2023

PurposeWe aimed to verify the prognostic value of the glycocalyx as a marker of blood–brain barrier damage in patients with acute ischemic stroke undergoing endovascular therapy.MethodsWe recruited patients with large vessel occlusion who were undergoing recanalization and tested their glycocalyx at multiple time points. On the basis of the 90-day follow-up data, the patients were divided into a survivor group and a nonsurvivor group. In addition, neurological function was tracked, and patients were divided into a neurological deterioration group and a group without neurological deterioration. Associations between outcomes and dynamic changes in the glycocalyx were determined using a linear mixed model, and significant factors were used as covariates.ResultsNonsurvivors and patients with neurological deterioration had significantly higher syndecan-1 concentrations than survivors and patients without neurological deterioration, and syndecan-1 tended to decline after endovascular therapy (p &lt; 0.05). The increased level of syndecan-1 at 36 h after endovascular treatment was positively correlated with the National Institute of Health Stroke Scale score for neurological deterioration (r = 0.702, p = 0.005). However, there was no significant difference in the level of hyaluronic acid or heparan sulfate in the plasma of patients with different clinical outcomes.ConclusionPre-reperfusion syndecan-1 levels in patients with large vessel occlusion stroke are associated with 90-day mortality and the re-degradation of syndecan-1 is positively associated with neurological deterioration.
Attitudes of people with multiple sclerosis toward brain donation
Authors: Marrie Ruth Ann , Kosowan Leanne , Cutter Gary R. , Fox Robert J. , Salter Amber 
Published: January 2023

ObjectiveResearch directly examining brain tissue has played an important role in understanding the pathology and pathogenesis of multiple sclerosis (MS) and other diseases of the central nervous system. Such research relies heavily on donations of post-mortem brain tissue yet little is known about the attitudes of people with multiple sclerosis (MS) about brain donation. We aimed to assess the attitudes of people with MS toward brain donation, their preferences related to discussions of brain donation, and factors associated with attitudes toward brain donation including sociodemographic and clinical characteristics, health literacy and religiosity.MethodsIn a cross-sectional study, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their attitudes toward brain donation, reasons for participating or not participating in brain donation, and related communication preferences. We used multivariable logistic regression analyses to test factors associated with attitudes regarding brain donation.ResultsMost of the 4,520 participants were women (80.8%), self-identified as white (88.1%), with a post-secondary education, functional health literacy and moderate-severe disability. Sixty-two percent of participants would consider brain donation. Factors associated with considering brain donation included female gender, having a post-secondary education, being physically active, having moderate-severe disability and more comorbidities, and alcohol intake. Seventy-five percent of participants indicated that they preferred to receive information regarding brain donations from physicians.ConclusionTwo-thirds of people with MS would consider brain donation. People with MS desire to hear about brain donation from their health care providers rather than other sources.
Brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of circadian desynchronization on activity and sleep in male mice
Authors: Phillips Derrick J. , Blaine Scott , Wallace Naomi K. , Karatsoreos Ilia N. 
Published: January 2023

IntroductionUnderstanding how environmental interact challenges with genetic predispositions modulate health and wellbeing is an important area of biomedical research. Circadian rhythms play an important role in coordinating the multitude of cellular and tissue processes that organisms use to predict and adapt to regular changes in the environment, and robust circadian rhythms contribute to optimal physiological and behavioral responses to challenge. However, artificial lighting and modern round-the-clock lifestyles can disrupt the circadian system, leading to desynchronization of clocks throughout the brain and body. When coupled with genetic predispositions, circadian desynchronization may compound negative outcomes. Polymorphisms in the brain-derived neurotrophic (BDNF) gene contribute to variations in neurobehavioral responses in humans, including impacts on sleep, with the common Val66Met polymorphism linked to several negative outcomes.MethodsWe explored how the Val66Met polymorphism modulates the response to environmental circadian desynchronization (ECD) in a mouse model. ECD was induced by housing adult male mice in a 20 h light-dark cycle (LD10:10; 10 h light, 10 h dark). Sleep and circadian activity were recorded in homozygous (Met) mice and their wild-type (Val) littermates in a standard 24 h LD cycle (LD12:12), then again after 20, 40, and 60 days of ECD.ResultsWe found ECD significantly affected the sleep/wake timing in Val mice, however, Met mice maintained appropriate sleep timing after 20 days ECD, but not after 40 and 60 days of ECD. In addition, the rise in delta power at lights on was absent in Val mice but was maintained in Met mice. To elucidate the circadian and homeostatic contribution to disrupted sleep, mice were sleep deprived by gentle handling in LD12:12 and after 20 days in ECD. Following 6 h of sleep deprivation delta power was increased for both Val and Met mice in LD12:12 and ECD conditions. However, the time constant was significantly longer in the Val mice during ECD compared to LD12:12, suggesting a functioning but altered sleep homeostat.DiscussionThese data suggest the Val66Met mutation is associated with an ability to resist the effects of LD10:10, which may result in carriers suffering fewer negative impacts of ECD.
Assessing MR-compatibility of somatosensory stimulation devices: A systematic review on testing methodologies
Authors: Travassos Carolina , Sayal Alexandre , Direito Bruno , Pereira João , Sousa Teresa , Castelo-Branco Miguel 
Published: January 2023

Functional magnetic resonance imaging (fMRI) has been extensively used as a tool to map the brain processes related to somatosensory stimulation. This mapping includes the localization of task-related brain activation and the characterization of brain activity dynamics and neural circuitries related to the processing of somatosensory information. However, the magnetic resonance (MR) environment presents unique challenges regarding participant and equipment safety and compatibility. This study aims to systematically review and analyze the state-of-the-art methodologies to assess the safety and compatibility of somatosensory stimulation devices in the MR environment. A literature search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, was performed in PubMed, Scopus, and Web of Science to find original research on the development and testing of devices for somatosensory stimulation in the MR environment. Nineteen records that complied with the inclusion and eligibility criteria were considered. The findings are discussed in the context of the existing international standards available for the safety and compatibility assessment of devices intended to be used in the MR environment. In sum, the results provided evidence for a lack of uniformity in the applied testing methodologies, as well as an in-depth presentation of the testing methodologies and results. Lastly, we suggest an assessment methodology (safety, compatibility, performance, and user acceptability) that can be applied to devices intended to be used in the MR environment.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42021257838.