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Chimeric antigen receptor T-cell (CAR-T) therapy is emerging as a novel treatment for systemic autoimmune rheumatic diseases. To date, CAR-T therapy in rheumatology has been reported only in case studies and conference abstracts, but clinical trial results are forthcoming. Current evidence indicates a rapid and highly effective therapeutic response with a favourable side effect profile, suggesting that CD19 CAR-T therapy could be beneficially established for these conditions.

KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain.

Heterozygous mutations in the histone lysine acetyltransferase gene () underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular , which is a key driver of neural progenitor proliferation, multipotency and brain development.

Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS.

Functional mapping of epigenetic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes.

Epigenetic dysregulation is widespread in cancer. However, the specific epigenetic regulators and the processes they control to drive cancer phenotypes are poorly understood. Here, we employed a novel, scalable and high-throughput method to perform iterative functional screens of over 250 epigenetic regulatory genes within autochthonous oncogenic KRAS-driven lung tumors.

Enzymatic Modulation of the Pulmonary Glycocalyx Enhances Susceptibility to .

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction.

Single-cell-resolved interspecies comparison shows a shared inflammatory axis and a dominant neutrophil-endothelial program in severe COVID-19.

A key issue for research on COVID-19 pathogenesis is the lack of biopsies from patients and of samples at the onset of infection. To overcome these hurdles, hamsters were shown to be useful models for studying this disease. Here, we further leverage the model to molecularly survey the disease progression from time-resolved single-cell RNA sequencing data collected from healthy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected Syrian and Roborovski hamster lungs.

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Individuals with antiphospholipid syndrome (APS) have antibodies directed against phospholipid-binding proteins (aPL). The condition is most associated with an increased risk of thromboembolism and obstetric complications. The 2023 classification criteria for APS include six clinical domains (venous thromboembolism, arterial thrombosis, microvascular events, obstetric events, cardiac valve, thrombocytopaenia) and two laboratory domains (lupus anticoagulant, and anti-cardiolipin or anti-β2-glycoprotein-I antibodies).

Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease.

The histone acetyltransferase KAT6B is required for hematopoietic stem cell development and function.

The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing hematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined the role of KAT6B in the hematopoietic system. We found that KAT6B sustained the fetal hematopoietic stem cell pool but did not affect viability or differentiation.

PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.

The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis.

The Mendelian disorders of chromatin machinery: Harnessing metabolic pathways and therapies for treatment.

The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions.

An intranasal live-attenuated SARS-CoV-2 vaccine limits virus transmission.

The development of effective SARS-CoV-2 vaccines has been essential to control COVID-19, but significant challenges remain. One problem is intramuscular administration, which does not induce robust mucosal immune responses in the upper airways-the primary site of infection and virus shedding. Here we compare the efficacy of a mucosal, replication-competent yet fully attenuated virus vaccine, sCPD9-ΔFCS, and the monovalent mRNA vaccine BNT162b2 in preventing transmission of SARS-CoV-2 variants B.

Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth.

(human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterized these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated.

Genome-wide CRISPR screening identifies a role for ARRDC3 in TRP53-mediated responses.

Whole-genome screens using CRISPR technologies are powerful tools to identify novel tumour suppressors as well as factors that impact responses of malignant cells to anti-cancer agents. Applying this methodology to lymphoma cells, we conducted a genome-wide screen to identify novel inhibitors of tumour expansion that are induced by the tumour suppressor TRP53. We discovered that the absence of Arrestin domain containing 3 (ARRDC3) increases the survival and long-term competitiveness of MYC-driven lymphoma cells when treated with anti-cancer agents that activate TRP53.

Correction: State-of-the-art analytical methods of viral infections in human lung organoids.

[This corrects the article DOI: 10.1371/journal.pone.

Therapy with direct oral anticoagulants for secondary prevention of thromboembolic events in the antiphospholipid syndrome: a systematic review and meta-analysis of randomised trials.

Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by venous thrombosis (VT) or arterial thrombosis (AT) and/or pregnancy morbidity and the presence of antiphospholipid antibodies. Direct oral anticoagulants (DOACs) hold several advantages to vitamin K antagonists (VKAs) for prevention of thrombosis and we wish to evaluate DOACs compared with VKAs in secondary prevention of thromboembolic events in patients with APS.

Methods: We conducted searches of the published literature using relevant data sources (MEDLINE, Embase and Cochrane CENTRAL), and of trial registers for unpublished data and ongoing trials.

Extracellular Matrix Remodeling in Atopic Dermatitis Harnesses the Onset of an Asthmatic Phenotype and Is a Potential Contributor to the Atopic March.

The development of atopic dermatitis in infancy, and subsequent allergies, such as asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, however the course of disease indicates an inter-epithelial crosstalk, through the onset of inflammation in the skin and progression to other mucosal epithelia. In this study, we investigated if and how skin-lung epithelial crosstalk contributes to the development of the atopic march.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer.

The impact of an ultrasound atlas for scoring salivary glands in primary Sjögren's syndrome: a pilot study.

The objective of this pilot study was to assess the impact of a salivary gland ultrasound (SGUS) atlas for scoring parenchymal changes in Sjögren's syndrome by assessing the reliability of the scoring system (0-3), without and with the use of the SGUS atlas. Ten participants with varying experience in SGUS contributed to the reliability exercise. Thirty SGUS images of the submandibular and parotid gland with abnormalities ranging from 0 to 3 were scored using the written definitions of the OMERACT SGUS scoring system and using the SGUS atlas based on the OMERACT scoring system.

Early protective effect of a ("pan") coronavirus vaccine (PanCoVac) in Roborovski dwarf hamsters after single-low dose intranasal administration.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the danger posed by human coronaviruses. Rapid emergence of immunoevasive variants and waning antiviral immunity decrease the effect of the currently available vaccines, which aim at induction of neutralizing antibodies. In contrast, T cells are marginally affected by antigen evolution although they represent the major mediators of virus control and vaccine protection against virus-induced disease.

Absolute risk estimation of new-onset proteinuria in patients with systemic lupus erythematosus: a Danish nationwide cohort study.

Objectives: Kidney involvement and medical compliance are frequent challenges in systemic lupus erythematosus (SLE). Additional data reporting such as absolute risk estimates may strengthen risk stratification and compliance. This study provides absolute risk estimations of risk of new-onset proteinuria among SLE patients.

The chromatin reader protein ING5 is required for normal hematopoietic cell numbers in the fetal liver.

ING5 is a component of KAT6A and KAT7 histone lysine acetylation protein complexes. ING5 contains a PHD domain that binds to histone H3 lysine 4 when it is trimethylated, and so functions as a 'reader' and adaptor protein. KAT6A and KAT7 function are critical for normal hematopoiesis.

A non-transmissible live attenuated SARS-CoV-2 vaccine.

Live attenuated vaccines (LAVs) administered via the mucosal route may offer better control of the COVID-19 pandemic than non-replicating vaccines injected intramuscularly. Conceptionally, LAVs have several advantages, including presentation of the entire antigenic repertoire of the virus, and the induction of strong mucosal immunity. Thus, immunity induced by LAV could offer superior protection against future surges of COVID-19 cases caused by emerging SARS-CoV-2 variants.