Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Phenotypic and genomic characteristics of members of the “Burkholderia cepacia complex”

The aim of my project was to compare representatives of each of seven genomovars/species comprising the “Burkholderia cepacia complex” with respect to overall genome size and chromosome number and also to examine their capacity to form N-acyl homoserine lactones (AHLs). A major goal was to determine whether there were significant differences between clinical and non-clinical isolates of these bacteria. My working hypothesis was that clinical isolates (primarily members of genomovar III) might have reduced catabolic and biosynthetic potential and correspondingly smaller genomes than non-clinical isolates. It also seemed reasonable that AHL-dependent quorum sensing, a mechanism that commonly governs expression of genes important for host colonization, would be more prominent in clinical isolates. A survey of 34 B. cepacia complex isolates including representatives of all seven genomovars indicated that all had large multichromosomal genomes. Randomly linearized replicons from preparations of intact chromosomal DNA were resolved by pulsed-field gel electrophoresis and their sizes estimated by comparison of their electrophoretic mobilities with yeast DNA size markers. Overall genome size was confirmed by determining the sums of the molecular weights of macro restrict ion fragments obtained by digestion of chromosomal DNA with enzymes such as CeuI and SwaI. Analysis of a larger group of 62 isolates indicated that all of the strains were prototrophs which exhibited a high degree of nutritional versatility. Thus the notion that clinical isolates had lost DNA and functions important for survival as free-living bacteria proved incorrect. A survey for ability to produce AHLs indicated that members of genomovars I–IV formed low levels of these compounds compared to members of genomovars V–VII. I subsequently isolated mutant derivatives of representatives of genomovars II and III which produced extremely high levels of AHL. I characterized a genetic locus, bmuIR from strain 17616 which contained genes encoding AHL synthase and AHL-binding transcriptional activator. The mutations leading to increased AHL formation were located outside of the bmuIR locus, indicating that other regulatory genes influence AHL formation. An important result of my studies of AHL formation was the development of a rapid procedure for concentration of AHLs from culture supernatants, which involved their adsorption to a copolymer of divinylbenzene and N-vinylpyrrolidone

Independent and Interchangeable Multimerization Domains of the AbrB, Abh, and SpoVT Global Regulatory Proteins

The global regulators AbrB, Abh, and SpoVT are paralogous proteins showing their most extensive sequence homologies in the DNA-binding amino-terminal regions (about 50 residues). The carboxyl-terminal portion of AbrB has been hypothesized to be a multimerization domain with little if any role in DNA-binding recognition or specificity. To investigate the multimerization potentials of the carboxyl-terminal portions of AbrB, Abh, and SpoVT we utilized an in vivo multimerization assay system based upon fusion of the domains to the DNA binding domain of the λ cI repressor protein. The results indicate that the N and C domains of all three paralogues are independent dimerization modules and that the intact Abh and SpoVT proteins are most probably tetramers. Chimeric proteins consisting of the AbrB N-terminal DNA-binding domain fused to the C domain of either Abh or SpoVT are indistinguishable from wild-type AbrB in their ability to regulate an AbrB target promoter in vivo

Abh and AbrB Control of Bacillus subtilis Antimicrobial Gene Expression▿

The Bacillus subtilis abh gene encodes a protein whose N-terminal domain has 74% identity to the DNA-binding domain of the global regulatory protein AbrB. Strains with a mutation in abh showed alterations in the production of antimicrobial compounds directed against some other Bacillus species and gram-positive microbes. Relative to its wild-type parental strain, the abh mutant was found deficient, enhanced, or unaffected for the production of antimicrobial activity. Using lacZ fusions, we examined the effects of abh upon the expression of 10 promoters known to be regulated by AbrB, including five that transcribe well-characterized antimicrobial functions (SdpC, SkfA, TasA, sublancin, and subtilosin). For an otherwise wild-type background, the results show that Abh plays a negative regulatory role in the expression of four of the promoters, a positive role for the expression of three, and no apparent regulatory role in the expression of the other three promoters. Binding of AbrB and Abh to the promoter regions was examined using DNase I footprinting, and the results revealed significant differences. The transcription of abh is not autoregulated, but it is subject to a degree of AbrB-afforded negative regulation. The results indicate that Abh is part of the complex interconnected regulatory system that controls gene expression during the transition from active growth to stationary phase

Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat

Promoting development and function of brown and beige fat may reduce obesity. Here, we show that fat SIRT6 expression is markedly induced by cold exposure and a β-adrenergic agonist. Deletion of SIRT6 in adipose tissue impairs the thermogenic function of brown adipocytes, causing a morphological “whitening” of brown fat, reduced oxygen (O2) consumption, obesity, decreased core body temperature, and cold sensitivity. Fat SIRT6-deleted mice exhibit increased blood glucose levels, severe insulin resistance, and hepatic steatosis. Moreover, SIRT6 deficiency inhibits the browning of white adipose tissue (WAT) following cold exposure or β3-agonist treatment. Depletion of SIRT6 expression in brown adipocytes reduces expression of thermogenic genes, causing a reduction in cellular respiration. Conversely, SIRT6 overexpression in primary fat cells stimulates the thermogenic program. Mechanistically, SIRT6 interacts with and promotes phospho-ATF2 binding to the PGC-1α gene promoter to activate its expression. The present study reveals a critical role for SIRT6 in regulating thermogenesis of fat

Spherical Neutralizing Aptamer Inhibits SARS-CoV-2 Infection

New neutralizing agents against SARS-CoV-2 and the associated mutant strains are urgently needed for the treatment and prophylaxis of COVID-19. Herein, we develop a spherical cocktail neutralizing aptamer-gold nanoparticle (SNAP) to synergistically block the interaction of SARS-CoV-2 receptor-binding domain (RBD) and angiotensin-converting enzyme-2 (ACE2). Taking advantage of the simultaneous recognition of multi-homologous and multi-heterogenous neutralizing aptamers and dimensionally matched nano-scaffolds, the SNAP exhibits increased affinity to the RBD with a dissociation constant value of 5.46 pM and potent neutralization against authentic SARS-CoV-2 with a half-maximal inhibitory concentration of 142.80 aM. Additional benefits include the multi-epitope blocking capability of the aptamer cocktail and the steric hindrance of the nano-scaffold, which further covers the ACE2 binding interfaces and affects the conformational transition of the spike protein. As a result, the SNAP strategy exhibits broad neutralizing activity, almost completely blocking the infection of N501Y and D614G mutant strains. Overall, the SNAP strategy provides a new direction for development of anti-virus infection mechanisms, both to fight the COVID-19 pandemic and serve as a powerful technical reserve for future unknown pandemics.</p

Decreased Gray Matter Volume of Cuneus and Lingual Gyrus in Schizophrenia Patients with Tardive Dyskinesia is Associated with Abnormal Involuntary Movement

Abstract Tardive dyskinesia (TD) is a devastating motor disorder associated with the etiological process of schizophrenia or antipsychotic medication treatments. To examine whether cerebral morphological changes may manifest in TD, we used voxel-based morphometry to analyze high-resolution T1-weighted brain structural magnetic resonance images from 32 schizophrenics with TD (TD group), 31 schizophrenics without TD (non-TD group), and 32 healthy controls (HC group). We also assessed psychopathological symptoms with the Positive and Negative Syndrome Scale (PANSS), and TD severity with the Abnormal Involuntary Movement Scale (AIMS). We compared gray matter volumes (GMVs) among groups, and tested for correlations between GMV changes and psychopathological symptoms or TD severity. The results showed significant differences in GMV in the frontal and temporal cortices, insula and cerebellum among the three groups. Brainstem and inferior frontal and precentral gyri GMVs were significantly larger, whereas cuneus and lingual gyrus GMVs were significantly smaller in the TD group as compared to non-TD group. Further, the cuneus and lingual gyrus GMVs were positively correlated with AIMS scores in the TD group. The current results suggest that TD may be associated with the alterations in GMV that are different from that of schizophrenics without TD. Further studies are needed to confirm and to examine the functional significance of these structural findings