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The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. CRHR2-/- mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants' dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.

Background False duplications in genome assemblies lead to false biological conclusions. We quantified false duplications in popularly used previous genome assemblies for platypus, zebra finch, and Anna's Hummingbird, and their new counterparts of the same species generated by the Vertebrate Genomes Project, of which the Vertebrate Genomes Project pipeline attempted to eliminate false duplications through haplotype phasing and purging. These assemblies are among the first generated by the Vertebrate Genomes Project where there was a prior chromosomal level reference assembly to compare with. Results Whole genome alignments revealed that 4 to 16% of the sequences are falsely duplicated in the previous assemblies, impacting hundreds to thousands of genes. These lead to overestimated gene family expansions. The main source of the false duplications is heterotype duplications, where the haplotype sequences were relatively more divergent than other parts of the genome leading the assembly algorithms to classify them as separate genes or genomic regions. A minor source is sequencing errors. Ancient ATP nucleotide binding gene families have a higher prevalence of false duplications compared to other gene families. Although present in a smaller proportion, we observe false duplications remaining in the Vertebrate Genomes Project assemblies that can be identified and purged. Conclusions This study highlights the need for more advanced assembly methods that better separate haplotypes and sequence errors, and the need for cautious analyses on gene gains.

The ETO-family transcriptional corepressors, including ETO, ETO2, and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor-the DBD binds to DNA, while the ETO moiety manifests transcriptional activity. A directly comparative study of these "homologous " fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in M2-and M7-subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs to bind DNA, they share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors, including the ETS-, bZIP- and bHLH-family proteins. AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as activator. The repressor-versus-activator functions of AML1-ETO might be determined by the abundance of cooperative transcription factors/cofactors on the target genes. Importantly, AML1-ETO and ETO2-GLIS2 differentially regulate key transcription factors in myeloid differentiation including PU.1 and C/EBP beta. Consequently, AML1-ETO inhibits, but ETO2-GLIS2 facilitates, myeloid differentiation of U937 cells. This function of ETO2-GLIS2 is reminiscent of a similar effect of MLL-AF9 as previously reported. Taken together, this directly comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context provides insights into context-dependent transcription regulatory mechanisms that may underlie how these seemingly "homologous " fusion transcription factors exert distinct functions to drive different subtypes of leukemia.

Objective To describe neurologic, radiologic and laboratory features in children with central nervous system (CNS) inflammatory disease complicating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Study design We focused on CNS inflammatory diseases in children referred from 12 hospitals in the Paris area to Necker-Sick Children Reference Centre. Results We identified 19 children who had a history of SARS-CoV-2 infection and manifest a variety of CNS inflammatory diseases: encephalopathy, cerebellar ataxia, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, or optic neuritis. All patients had a history of SARS-CoV-2 exposure, and all tested positive for circulating antibodies against SARS-CoV-2. At the onset of the neurologic disease, SARS-CoV-2 PCR results (nasopharyngeal swabs) were positive in 8 children. Cerebrospinal fluid was abnormal in 58% (11/19) and magnetic resonance imaging was abnormal in 74% (14/19). We identified an autoantibody co-trigger in 4 children (myelinoligodendrocyte and aquaporin 4 antibodies), representing 21 % of the cases. No autoantibody was found in the 6 children whose CNS inflammation was accompanied by a multisystem inflammatory syndrome in children. Overall, 89% of patients (17/19) received anti-inflammatory treatment, primarily high-pulse methylprednisolone. All patients had a complete long-term recovery and, to date, no patient with autoantibodies presented with a relapse. Conclusions SARS2-CoV-2 represents a new trigger of postinfectious CNS inflammatory diseases in children.

This descriptive case series retrospectively reviewed medical records from thirty-one previously healthy, war-fighting veterans who self-reported exposure to airborne hazards while serving in Iraq and Afghanistan between 2003 and the present. They all noted new-onset dyspnea, which began during deployment or as a military contractor. Twenty-one subjects underwent non-invasive pulmonary diagnostic testing, including maximum expiratory pressure (MEP) and impulse oscillometry (IOS). In addition, five soldiers received a lung biopsy; tissue results were compared to a previously published sample from a soldier in our Iraq Afghanistan War Lung Injury database and others in our database with similar exposures, including burn pits. We also reviewed civilian control samples (5) from the Stony Brook University database. Military personnel were referred to our International Center of Excellence in Deployment Health and Medical Geosciences, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell under the auspices of Northwell IRB: 17-0140-FIMR Feinstein Institution for Medical Research "Clinicopathologic characteristics of Iraq Afghanistan War Lung Injury." We retrospectively examined medical records, including exposure data, radiologic imaging, and non-invasive pulmonary function testing (MGC Diagnostic Platinum Elite Plethysmograph) using the American Thoracic Society (ATS) standard interpretation based on Morgan et al., and for a limited cohort, biopsy data. Lung tissue, when available, was examined for carbonaceous particles, polycyclic aromatic hydrocarbons (Raman spectroscopy), metals, titanium connected to iron (Brookhaven National Laboratory, National Synchrotron Light Source II, Beamline 5-ID), oxidized metals, combustion temperature, inflammatory cell accumulation and fibrosis, neutrophil extracellular traps, Sirius red, Prussian Blue, as well as polarizable crystals/particulate matter/dust. Among twenty-one previously healthy, deployable soldiers with non-invasive pulmonary diagnostic tests, post-deployment, all had severely decreased MEP values, averaging 42% predicted. These same patients concurrently demonstrated abnormal airways reactance (X5Hz) and peripheral/distal airways resistance (D5-D20%) via IOS, averaging - 1369% and 23% predicted, respectively. These tests support the concept of airways hyperresponsiveness and distal airways narrowing, respectively. Among the five soldiers biopsied, all had constrictive bronchiolitis. We detected the presence of polycyclic aromatic hydrocarbons (PAH)-which are products of incomplete combustion-in the lung tissue of all five warfighters. All also had detectable titanium and iron in the lungs. Metals were all oxidized, supporting the concept of inhaling burned metals. Combustion temperature was consistent with that of burned petrol rather than higher temperatures noted with cigarettes. All were nonsmokers. Neutrophil extracellular traps were reported in two biopsies. Compared to our prior biopsies in our Middle East deployment database, these histopathologic results are similar, since all database biopsies have constrictive bronchiolitis, one has lung fibrosis with titanium bound to iron in fixed mathematical ratios of 1:7 and demonstrated polarizable crystals. These results, particularly constrictive bronchiolitis and polarizable crystals, support the prior data of King et al. (N. Engl. J. Med. 365:222-230, 2011) Soldiers in this cohort deployed to Iraq and Afghanistan since 2003, with exposure to airborne hazards, including sandstorms, burn pits, and improvised explosive devices, are at high risk for developing chronic clinical respiratory problems, including: (1) reduction in respiratory muscle strength; (2) airways hyperresponsiveness; and (3) distal airway narrowing, which may be associated with histopathologic evidence of lung damage, reflecting inhalation of burned particles from burn pits along with particulate matter/dust. Non-invasive pulmonary diagnostic tests are a predictor of burn pit-induced lung injury

The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-g and IFN-a/f3 immunity underlying rare infections with weakly virulent mycobacteria and seasonal influenza virus have inspired studies of two common infections: tuberculosis and COVID-19. A TYK2 genotype impairing IFN-g production accounts for about 1% of tuberculosis cases, and autoantibodies neutralizing IFN-a/f3 account for about 15% of critical COVID-19 cases. The discovery of inborn errors and mechanisms underlying rare infec-tions drove the identification of common monogenic or autoimmune determinants of related common infections. This "rare-to-common"genetic and mechanistic approach to infectious diseases may be of heuristic value.

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of Sao Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.

Background and aims: Cardiovascular Disease (CVD) poses significant health risks for seniors, especially among low-income and minority communities. Senior centers offer multiple services. We tested whether implementing two evidence-based interventions- DASH-aligned meals provided through an existing congregate meal program, and support for home Self-Measured Blood Pressure (SMBP) monitoring-lowers blood pressure among participants at two senior centers serving low-income, racially diverse communities. Methods and results: Open-label study, enrolling clients aged >= 60, eating >= 4 meals/week at two NYC senior centers. Participants received DASH-aligned congregate meals, and training in nutrition, BP management education, and personal SMBP device. Co-Primary outcomes: a) change in systolic BP measured by independent health professionals, and b) change in percent with "controlled BP" (Eighth Joint National Committee (JNC-8) Guidelines), at Month 1 compared to Baseline. Secondary outcomes: Changes in BP at Months 3 and 5/6 (last measure). We enrolled 94 participants; COVID closures interrupted implementation mid-study. Mean systolic BP at Month-1 changed by -4.41 mmHg (n = 61 p = 0.07) compared to Baseline. Participants with controlled BP increased (15.7%) at Month 1. Change in mean BP at Month 1 was significantly correlated with BMI (p = 0.02), age (p = 0.04), and baseline BP (p < 0.001). Mean systolic SMBP changed by -6.9 mmHg (p = 0.004) at Months 5/6. Conclusions: Implementing an evidence-based multi-component BP-lowering intervention within existing congregate meal programs at senior centers serving minority and low-income communities is feasible, and early findings show promising evidence of effectiveness. This approach to cardiovascular risk reduction should be further tested for widespread adoption and impact. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University.