Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease

Microbial communities and their associated bioactive compounds1,2,3 are often disrupted in conditions such as the inflammatory bowel diseases (IBD)4. However, even in well-characterized environments (for example, the human gastrointestinal tract), more than one-third of microbial proteins are uncharacterized and often expected to be bioactive5,6,7. Here we systematically identified more than 340,000 protein families as potentially bioactive with respect to gut inflammation during IBD, about half of which have not to our knowledge been functionally characterized previously on the basis of homology or experiment. To validate prioritized microbial proteins, we used a combination of metagenomics, metatranscriptomics and metaproteomics to provide evidence of bioactivity for a subset of proteins that are involved in host and microbial cell"“cell communication in the microbiome; for example, proteins associated with adherence or invasion processes, and extracellular von Willebrand-like factors. Predictions from high-throughput data were validated using targeted experiments that revealed the differential immunogenicity of prioritized Enterobacteriaceae pilins and the contribution of homologues of von Willebrand factors to the formation of Bacteroides biofilms in a manner dependent on mucin levels. This methodology, which we term MetaWIBELE (workflow to identify novel bioactive elements in the microbiome), is generalizable to other environmental communities and human phenotypes. The prioritized results provide thousands of candidate microbial proteins that are likely to interact with the host immune system in IBD, thus expanding our understanding of potentially bioactive gene products in chronic disease states and offering a rational compendium of possible therapeutic compounds and targets.

Silver-Russel syndrome (SRS) is a representative imprinting disorder (ID) characterized by growth failure and diagnosed by clinical features. Recently, international consensus has recommended using the Netchine-Harbison clinical scoring system (NH-CSS) as clinical diagnostic criteria. Loss of methylation of H19/IGF2:intergenic differentially methylated region (H19LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) are common etiologies of SRS; however, other IDs, pathogenic variants (PVs) of genes, and pathogenic copy number variants (PCNVs) have been reported in patients meeting NH-CSS. To clarify the frequency and clinical characteristics of each etiology, we conducted (epi)genetic analysis in 173 patients satisfying NH-CSS. H19LOM and UPD(7)mat were identified in 34.1%. PCNVs, other IDs, and PVs were in 15.0%. Patients with all six NH-CSS items were most frequently observed with H19LOM and UPD(7)mat. This study confirmed the suitability of NH-CSS as clinical diagnostic criteria, the (epi)genetic heterogeneity of SRS, and showed the necessity of further discussion regarding the "SRS spectrum".

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is associated with the risk of developing some adverse cardiovascular events, including cerebral embolism and heart failure [1]. The development of AF depends on a variety of risk factors, including age, sex, race, hypertension, heart failure, coronary artery disease, valvular heart disease, obesity, diabetes, and chronic kidney disease [2]. Among these risk factors, hypertension has been established to be the most important factor [3, 4] In addition, in patients with AF, hypertension is one of the risk factors for the development of cerebral embolism [5]. In this regard, the Japanese guideline on pharmacotherapy of cardiac arrhythmias recommends the use of the CHADS2 score for the risk assessment of thromboembolism in patients with AF, in which "H" indicates hypertension [6]. An early diagnosis and the subsequent initiation of appropriate treatment for AF, including anticoagulation therapy, is strongly required in hypertensive patients. However, the diagnosis of AF is not easy in the clinical setting. Almost 40% of AF patients are asymptomatic [7]. Most of these patients are diagnosed as having AF at annual health check-up examinations [7]. The type of AF that is diagnosed at health check-up examinations is mostly the persistent type. Paroxysmal and asymptomatic AF is difficult to diagnose because there are few chances to detect AF by standard 12-lead electrocardiogram (ECG) [8]. Some of these patients unfortunately develop cerebral embolism before the diagnosis of AF. Although detailed assessment with 24-h Holter ECG is needed to detect AF, the chance of detection is limited [9]. On the other hand, ambulatory blood pressure monitoring (ABPM) is currently considered the most accurate method for diagnosing hypertension [10, 11]. Several institutions have recommended that most or all subjects with suspected hypertension undergo ABPM [12]. Notably, an ABPM device that especially implements an algorithm to automatically detect AF during each blood pressure measurement has been developed in recent years. In fact, Kollias et al. [13] demonstrated the high diagnostic accuracy of detecting AF using 24-h ABPM devices with AF detection algorithms.

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1"‰+"‰GDA, CRMP1"‰+"‰CRMP2, NSE"‰+"‰STIP1, CRMP2"‰+"‰STIP1, LDHA"‰+"‰YBOX, LDHB"‰+"‰YBOX, GDA"‰+"‰YBOX, STIP1"‰+"‰YBOX, and CRMP1"‰+"‰STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD"‰="‰540), intellectual disability without autism (ID"‰="‰184) and general population controls (GP"‰="‰420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR)"‰="‰7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR"‰="‰2.77, 95% CI (1.19"“7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1"‰+"‰CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to >999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD"‰+"‰ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child's needs.

Environmental temperature is now well known to have a U-shaped relationship with cardiovascular (CV) and all-cause mortality. Both heat and cold above and below an optimum temperature, respectively, are associated with adverse outcomes. However, cold in general and moderate cold specifically is predominantly responsible for much of temperature-attributable adversity. Importantly, hypertension-the most important CV risk factor-has seasonal variation such that BP is significantly higher in winter. Besides worsening BP control in established hypertensives, cold-induced BP increase also contributes to long-term BP variability among normotensive and pre-hypertensive patients, also a known CV risk factor. Disappointingly, despite the now well-stablished impact of temperature on BP and on CV mortality separately, direct linkage between seasonal BP change and CV outcomes remains preliminary. Proving or disproving this link is of immense clinical and public health importance because if seasonal BP variation contributes to seasonal adversity, this should be a modifiable risk. Mechanistically, existing evidence strongly suggests a central role of the sympathetic nervous system (SNS), and secondarily, the renin"“angiotensin"“aldosterone axis (RAAS) in mediating cold-induced BP increase. Though numerous other inflammatory, metabolic, and vascular perturbations likely also contribute, these may also well be secondary to cold-induced SNS/RAAS activation. This review aims to summarize the current evidence linking temperature, BP and CV outcomes. We also examine underlying mechanisms especially in regard to the SNS/RAAS axis, and highlight possible mitigation measures for clinicians.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) &. Assess if maternal betamethasone administration at 34"“35 weeks accelerated neonatal amplitude integrated EEG (aEEG) maturation. Study design. Nested, observational cohort in 7 centers participating in the Antenatal Late Preterm Steroid randomized trial. Up...

Nature Reviews Disease Primers volume 8, Article number: 35 (2022) Cite this article. You have full access to this article via your institution. We thank Ian Roberts and Francois-Xavier Ageron for their interest in our Primer (Moore, E. E. et al. Trauma-induced coagulopathy. Nat. Rev. Dis. Primers 7, 30 (2021))1, which raised some important points (Roberts, I. & Ageron, F.-X. The role of tranexamic acid in trauma - a life-saving drug with proven benefit. Nat. Rev. Dis. Primers https://doi.org/10.1038/s41572-022-00367-5 (2022))2. We were surprised by the statement that we proposed guidelines for the use of tranexamic acid (TXA) post-injury. In actuality, the Primer (a narrative review, not a guideline) described the current TXA-related practices in Europe versus those in the USA and provided a critical appraisal of the evidence (as in Box 1 of the Primer) behind both approaches.

Automated driving systems (ADS) have undergone a significant improvement in the last years. ADS and more precisely self-driving cars technologies will change the way we perceive and know the world of transportation systems in terms of user experience, mode choices and business models. The emerging field of Deep Learning (DL) has been successfully applied for the development of innovative ADS solutions. However, the attempt to single out the best deep neural network architecture and tuning its hyperparameters are all expensive processes, both in terms of time and computational resources. In this work, Bayesian optimization (BO) is used to optimize the hyperparameters of a Spatiotemporal-Long Short Term Memory (ST-LSTM) network with the aim to obtain an accurate model for the prediction of the steering angle in a ADS. BO was able to identify, within a limited number of trials, a model-namely BO_ST-LSTM-which resulted, on a public dataset, the most accurate when compared to classical end-to-end driving models.

A meta-analysis was performed by the authors in this issue regarding perinatal inflammation in preterm infants who were assessed by electroencephalography (EEG).1 Their selected methodology resulted in only 2 studies from 41 eligible articles that met their chosen criteria. These authors' critique based on these two studies concluded that a meta-analysis could not be performed given the small number of subjects with heterogeneity in study design. Both studies statistically compared selected prenatal and neonatal variables with amplitude-integrated EEG (aEEG) findings. Only one study assessed correlations with specific reference to placental findings concerning clinical and histologically confirmed chorioamnionitis and lesions of malperfusion. Preclinical and clinical research articles were discussed that support an association of perinatal inflammation with altered EEG maturation. These authors advocated for the use of conventional EEG to assess preterm children associated with inflammatory etiologies, stressing peripartum timing of diseases that promote brain injury.

Signal Transduction and Targeted Therapy volume 7, Article number: 169 (2022) Cite this article. The recent research published in The New England Journal of Medicine by Y. Doki et al. has reported the interim findings from the CheckMate 648, which is an international, multi-center, open-label, and randomized phase 3 clinical trial to explore the role of dual immune checkpoints inhibitors combination for patients with advanced esophageal squamous cell carcinoma (ESCC)1.

Due to the prolonged inflammatory process induced by infection of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indices of autonomic nervous system dysfunction may persist long after viral shedding. Previous studies showed significant changes in HRV parameters in severe (including fatal) infection of SARS-CoV-2. However, few studies have comprehensively examined HRV in individuals who previously presented as asymptomatic or mildly symptomatic cases of COVID-19. In this study, we examined HRV in asymptomatic or mildly symptomatic individuals 5"“7 weeks following positive confirmation of SARS-CoV-2 infection. Sixty-five ECG Holter recordings from young (mean age 22.6"‰Â±"‰3.4 years), physically fit male subjects 4"“6 weeks after the second negative test (considered to be the start of recovery) and twenty-six control male subjects (mean age 23.2"‰Â±"‰2.9 years) were considered in the study. Night-time RR time series were extracted from ECG signals. Selected linear as well as nonlinear HRV parameters were calculated. We found significant differences in Porta's symbolic analysis parameters V0 and V2 (p"‰<"‰0.001), α2 (p"‰<"‰0.001), very low-frequency component (VLF; p"‰="‰0.022) and respiratory peak (from the PRSA method; p"‰="‰0.012). These differences may be caused by the changes of activity of the parasympathetic autonomic nervous system as well as by the coupling of respiratory rhythm with heart rate due to an increase in pulmonary arterial vascular resistance. The results suggest that the differences with the control group in the HRV parameters, that reflect the functional state of the autonomic nervous system, are measurable after a few weeks from the beginning of the recovery even in the post-COVID group-a young and physically active population. We indicate HRV sensitive markers which may be used in long-term monitoring of patients after recovery.

Evidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium. Methods. A total of 9438 cases and 20,451 controls from 22 studies...

In the version of this article initially published, the second paragraph of the Discussion had several incorrect reference citations (62"“65 in the original). They have been removed and the remaining references renumbered throughout. The changes have been made to the HTML and PDF versions of the article. Public Health...

Neonates admitted to a level IV neonatal intensive care unit (NICU) frequently have complex medical conditions and require prolonged stays beyond 28 days of age. Given the acuity of medical problems and surgeries required, these neonates are at risk for cardiopulmonary events necessitating resuscitation. Two universally accepted programs address these issues-neonatal resuscitation program (NRP) which concentrates on delivery room resuscitation and pediatric advanced life support program (PALS) which focuses on a broader range of cardiopulmonary events [1, 2]. Over the past ten years, there have been several questions, discussions, and surveys evaluating the best form of resuscitation for neonates outside of the delivery room. In most NICUs, neonates receive NRP until they are discharged from the NICU [3]. In contrast, if a neonate is transferred to the PICU, they are likely to receive PALS, regardless of their age. Given the increasing population of older, chronic infants present in our level IV NICU, we sought to design and implement a new resuscitation guideline incorporating PALS and NRP for cardiopulmonary events at the University of Wisconsin and UWÂ Health Kids American Family Children's Hospital. Our study design did not address improvement in patient care or value of the intervention.

Polypropylene fibres are difficult to dye using commonly used techniques due to the high crystallinity and non-polar aliphatic structure, that lack reactive places for dyes in the molecule. Dyeing PP fabric in scCO2 with antibacterial dyes merged the dyeing and finishing methods, resulting in a more productive technique in terms of water and energy consumption. Unmodified polypropylene fabric was dyed with 4-[2-[4-(ethenylsulphonyl)phenyl]diazenyl]-N,N-diethylbenzenamine antibacterial dye under scCO2 medium. The influences of scCO2 working parameters, such as dye concentration, pressure, dyeing time, and temperature, on fabric dye absorption expressed as color strength were studied. The color strength (K/S) was measured as well as CIELAB color parameters. The results were compared with its water dyeing analogue and it was observed that color strength as well as color depth (L) of the samples dyed in scCO2 were noticeably better than its water counterpart. In both scCO2 and water, the fastness properties (washing, rubbing, and light) of the dyed samples were excellent. Antibacterial activity of the dyed polypropylene sample in scCO2 was estimated and the results indicated good antibacterial efficiency.

Aim of the study was to assess: (a) the prevalence and type of strabismus, ptosis and eyelid dynamic disorders features, (b) the prevalence of refractive errors, amblyopia and, (c) their association with ocular/systemic syndromes in a cohort of patients. This is a retrospective observational multicenter cohort study. Patients with coexisting ocular motility disorders, comitant and incomitant strabismus, ptosis and dynamic eyelid disorders who have never undergone surgery were enrolled throughout a 3-years a study period. 137 out of 19,089 patients were enrolled, of which 97 with uniocular and 40 with binocular disease. Isolated congenital ptosis was observed in 84 patients. A polymalformative syndrome was present in almost one third of cases, whilst among strabismus type, esotropia was slightly more prevalent. Most patients were hypermetropic. In monocular disease, myopia mainly affected older patients, who were characterized by a worse ptosis margin reflex distance and levator function, and significantly higher astigmatism. Amblyopia occurred in 67.4% of the study sub-population. Of note, in monocular disease this was mild in 25.8%, moderate in 24.2% and severe in 11.3% of cases, whilst in binocular disease it was mild in 25%, moderate in 41.7% and severe in 16.7%. All patients with coexisting eyelid and ocular motility dysfunctions in pediatric age need ophthalmologic and systemic evaluation to accurately assess amblyopia, refractive errors and systemic/ocular disorders.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Liu HL, Sun ZM, Geng LQ, Wang XB, Ding KY, Tong J, et al. Similar survival, but better quality of life after myeloablative transplantation using unrelated cord blood vs matched sibling donors in adults with hematologic malignancies. Bone Marrow Transplant. 2014;49:1063"“9.

Signal Transduction and Targeted Therapy volume 7, Article number: 163 (2022) Cite this article. Hepcidin is a 25-amino acid peptide acting as a pivotal negative regulator in iron homeostasis, which can bind to an iron exporter, ferroportin 1, and induce its internalization and degradation.1 Hepcidin is produced in hepatocytes mainly under the control of BMP signaling. BMP2/6, secreted by liver endothelial cells in response to iron level, binds to BMP type I and type II receptors and triggers the phosphorylation of Smad1/5/8 which directly promotes hepcidin expression.1 The immunophilin family protein FKBP12 is associated with BMP type I receptors to prevent uncontrolled receptor activation.2 A previous study revealed FKBP12 ligands FK506 and Rapamycin can release FKBP12 from BMP type I receptors to activate BMP signaling and hepcidin expression.2 Other groups also demonstrated that FK506-activated BMP signaling accelerated the wound healing process or inhibited cancer metastasis. However, by binding to FKBP12, FK506, and Rapamycin potently inhibit the activities of Calcineurin or mTOR, respectively, and function as immunosuppression reagents in the clinic.3 This makes FK506 and Rapamycin unlikely useful for hepcidin regulation in the clinic. Proteolysis-targeting chimera (PROTAC) is an emerging chemical approach capable of degrading target proteins through a ubiquitin-proteasome system.4 Several PROTAC molecules targeting FKBP12 were developed using various FKBP12 ligands,4 RC32 was developed by linking Rapamycin with Pomalidomide and proved highly potent and applicable in vivo.5 We, therefore, testified RC32 for hepcidin regulation in vitro and in vivo. Our results revealed that PROTAC-mediated FKBP12 degradation is an ideal strategy to upregulate hepcidin expression without immunosuppression activity.

Nature Reviews Gastroenterology & Hepatology (2022)Cite this article. Certain dietary patterns have been associated with an increased risk of colorectal cancer (CRC). However, less is known about dietary factors that can inhibit colonic tumorigenesis. In a new study published in Nature, researchers identify a ketone body, β-hydroxybutyrate (BHB), as being a suppressor of colonic tumour growth.

The first biosimilar of ranibizumab (Byooviz, Biogen, USA) has received approval from the United States- Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) recently [1, 2]. And the International Retina Biosimilar Study Group (Inter BIOS Group) has conducted a survey (Bio-USER- unpublished data) which has revealed that many retinal physicians from Europe and the US have concerns regarding the safety of biosimilars. Safety is predominantly related to drug-induced intraocular inflammation (IOI) apart from nonocular safety parameters. Anti-vascular endothelial growth factors (Anti-VEGF) are biologics under the category of monoclonal antibodies. Biologics are exogenous proteins and thus, inherently have the potential to cause immunogenicity [3].