Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.

BACKGROUND:ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The epi-ADNP-1 episignature included ~ 6000 mostly hypomethylated CpGs, and the epi-ADNP-2 episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome

Green and Selective Synthesis of N

N,N',N'',N'''-Tetramethyl tetra-2,3-pyridinoporphyrazinato copper(II) methyl sulfate ([Cu(2,3-tmtppa)](MeSO4)4) efficiently catalyzed the direct conversion of nitriles to N-substituted amides. The one pot selective synthesis of the N-substituted amides from nitriles and primary amines was performed in refluxing H2O. The catalyst was recovered and reused at least four times, maintaining its efficiency

Immunomodulatory and Therapeutic Effects of Mesenchymal Stem Cells on Organ Dysfunction in Sepsis

Sepsis is a life-threatening disorder that is caused by a dysregulated inflammatory response during an infection. The disease mostly affects pregnant women, newborns, and patients in intensive care units (ICU). Sepsis treatment is a significant part of a country's health budgets. Delay in the therapy causes irreversible failure of various organs due to the lack of blood supply and reduction of oxygen in the tissues and eventually increased mortality. The involvement of four or five organs by sepsis has been attributed to an increased risk of death to over 90%. Although antibiotics are at the first line of sepsis treatment, they do not possess enough potency to control the disease and prevent subsequent organ failure. The immunomodulatory, anti-inflammatory, anti-apoptotic, and anti-microbial properties of mesenchymal stem cells (MSCs) have been reported in various studies. Therefore, the application of MSCs has been considered as a potentially promising therapeutic strategy. In preclinical studies, the administration of MSCs has been associated with reduced bacterial load and decreased levels of pro-inflammatory factors as well as the improved function of the different vital organs, including heart, kidney, liver, and lungs. The current study provides a brief review of sepsis and its pathophysiology, and then highlights recent findings in the therapeutic effects of MSCs and MSC-derived secretome in improving sepsis-induced organ dysfunction. Besides, eligible sepsis candidates for MSC-therapy and the latest clinical findings in these areas have been reviewed

Effect of Transcranial Direct Current Stimulation on Dorsolateral Prefrontal Cortex to Reduce the Symptoms of the Obsessive-Compulsive Disorder

Introduction: Obsessive-Compulsive Disorder (OCD) is one of the most common debilitating mental disorders with a prevalence rate of 2% to 3% in the general population. Previous studies have indicated abnormalities in the dorsolateral prefrontal cortex (DLPFC) of OCD patients; thus, we decided to use transcranial Direct Current Stimulation (tDCS) to decline these patients’ symptoms. Methods: A total of 24 patients with OCD participated in this study with the hope of improvement after the application of tDCS. The subjects were randomly assigned to three groups of Sham, Right DLPFC, and Left DLPFC. tDCS was applied for five consecutive days and in each session, patients were subjected to 2 mA current flow for two 15 minutes followed by a 10-minute rest in between (every session lasted for 40 minutes). Results: Subsequently, the changes in obsessive-compulsive level and cognitive functions were evaluated via Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Depression, Anxiety, and Stress Scale 21 (DASS-21) by comparing the results before (pre-test) and after (post-test) tDCS treatment. Conclusion: Ultimately, the scores of the Yale-Brown scale in the Left DLPFC group showed significant changes after treatment with tDCS (mean difference compared to the sham group: -6.18 and P≤0.05). Hereupon, this study demonstrated that transcranial direct current stimulation may cause improvements in symptoms of OCD

Gender Dimensions of the U.S. Consumer Borrowing Expansion

The article calls attention to gender as a dimension of the expansion of U. S. consumer borrowing. The first section emphasizes that gender is not a dummy variable, but an evolution of habits of thought. The second section discusses how changing gender relations are connected to gendered product differentiation and market expansion. The final section connects gendered market expansion and changing gender habits of thought to the expansion of consumer borrowing. We argue that, in addition to the acknowledged role of credit, gender relations also mask the structural financial fragility of households

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

International audiencePurpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS