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Abstract High‐gain converters play a vital role in all industrial applications such as automobiles, motor drives, renewable energy systems, and railway transportation sectors. The conventional converters have low gain owing to high‐voltage stress on active MOSFET, diode and low efficiency related with high operating pulse ratio. To overcome the limitations associated with the conventional converters, this study proposes a non‐isolated configuration of multiport quasi‐resonant converter (MP‐QRC) with high gain. The proposed MP‐QRC has the merits of high‐voltage gain, reduced number of components, minimum conduction losses, realization of soft switching in the devices and improved reliability. Moreover, the proposed converter is scalable and can serve as a good candidate in microgrid environment where the integration of more than one input is essential. In this paper, first a comprehensive analysis of various operation modes and design constraints are presented. Further, the study is supported with a reliability evaluation of proposed converter based on component failure. Also, the futuristic behaviour of MP‐QRC under continuous conduction mode as a function of operational and environmental variables is investigated to ascertain the reliability. The steady‐state operation of the converter is demonstrated for off‐board electric vehilce (EV) charging using MATLAB/SIMULINK and experiments performed on a 300‐W test rig.

Background & Aims: Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid assimilation and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here, we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance., Methods: To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine-specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, and metabolic phenotyping, including body composition, indirect calorimetry, glucose tolerance analyses, quantification of the composition of the gut microbiome, and assessment of bile acid signaling pathways., Results: iKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. In addition, the alpha and beta diversity of the gut microbiome was reduced in iKO mice, with several alterations in microbe species being associated with the observed increases in plasma bile acids. These increases in plasma bile acids were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice., Conclusion: Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid homeostasis and whole-body energy balance, likely via activation of TGR5., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Different modifications of the standard bread recipe have been proposed to improve its nutritional and health benefits. Here, we utilized the in vitro Human Gut Simulator (HGS) to assess the fermentation of one such artisan bread by human gut microbiota. Dried and milled bread, composed of almond flour, psyllium husks, and flax seeds as its three main ingredients, was first subjected to an in vitro protocol designed to mimic human oro-gastro-intestinal digestion. The bread digest was then supplied to complex human gut microbial communities, replacing the typical Western diet-based medium (WM) of the GHS system. Switching the medium from WM to bread digest resulted in statistically significant alterations in the community structure, encoded functions, produced short-chain fatty acids, and available antioxidants. The abundances of dietary fiber degraders Enterocloster , Mitsuokella , and Prevotella increased; levels of Gemmiger , Faecalibacterium , and Blautia decreased. These community alterations resembled the previously revealed differences in the distal gut microbiota of healthy human subjects consuming typical Mediterranean vs. Western-pattern diets. Therefore, the consumption of bread high in dietary fiber and unsaturated fatty acids might recapitulate the beneficial effects of the Mediterranean diet on the gut microbiota.

We evaluated two models to link stressful life events (SLEs) with the psychopathology of schizophrenia spectrum disorders (SSD). We separated SLEs into independent (iSLEs, unlikely influenced by one's behavior) and dependent (dSLEs, likely influenced by one's behavior). Stress-diathesis and stress generation models were evaluated for the relationship between total, i- and d- SLEs and the severity of positive, negative, and depressive symptoms in participants with SSD. Participants with SSD (n = 286; 196 males; age = 37.5 ± 13.5 years) and community controls (n = 121; 83 males; 35.4 ± 13.9 years) completed self-report of lifetime negative total, i- and d- SLEs. Participants with SSD reported a significantly higher number of total SLEs compared to controls (B = 1.11, p = 6.4 × 10 -6 ). Positive symptom severity was positively associated with the total number of SLEs (β = 0.20, p = 0.001). iSLEs (β = 0.11, p = 0.09) and dSLEs (β = 0.21, p = 0.0006) showed similar association with positive symptoms (p = 0.16) suggesting stress-diathesis effects. Negative symptom severity was negatively associated with the number of SLEs (β = -0.19, p = 0.003) and dSLEs (β = -0.20, p = 0.001) but not iSLEs (β = -0.04, p = 0.52), suggesting stress generation effects. Depressive symptom severity was positively associated with SLEs (β = 0.34, p = 1.0 × 10 -8 ), and the association was not statistically stronger for dSLEs (β = 0.33, p = 2.7 × 10 -8 ) than iSLEs (β = 0.21, p = 0.0006), p = 0.085, suggesting stress-diathesis effects. The SLE - symptom relationships in SSD may be attributed to stress generation or stress-diathesis, depending on symptom domain. Findings call for a domain-specific approach to clinical intervention for SLEs in SSD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target-specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1g bw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1g bw/bw mice had no substantial retinal degeneration compared with Ush1g bw /+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Introduction: Bullying is an aggressive act with a hostile intent to dominate, abuse, or intimidate an individual(s) with a lesser social or physical power, repeatedly over a period of time. Though bullying can manifest in any social situation, its pernicious presence in the educational institutions has become a source of concern to all stakeholders. With their self-esteem and world view entwined in cyberspace, the present generation of young adults derive their social status and self-worth through affirmations through the internet via social networking sites. Cyberspace is an ideal environment for bullies as it is relatively anonymous, allows the participation of a large audience, and is almost impossible to supervise., Aim: To estimate the extent, coping resources, and psychological impact of cyberbullying among Indian college students., Methodology: This cross-sectional study was carried out among undergraduate medical students of Sikkim. Cyberbullying, cybervictimization, coping strategies used by students, self-esteem, and levels of depression, anxiety, and stress were estimated using standardized self-report scales., Results: Out of 213 medical students, more than half of the college students (60.6%) were victims of cyberbullying. Coping strategies commonly used by cybervictims were technical coping, support from friends, and assertively confronting the bully online. Victims of cyberbullying had significantly more depression, anxiety, stress, and lower self-esteem (p values <0.05) compared to students who did not experience cyberbullying., Conclusion: This study illuminates the extent and nature of cyberbullying among Indian medical students. The negative mental health consequences of cyberbullying are worrying. Mental health professionals and stakeholders need to create an awareness and formulate strategies to combat cyberbullying in colleges., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Industrial Psychiatry Journal.)

Integrating warm-season grasses into cool-season equine grazing systems can increase pasture availability during summer months. The objective of this study was to evaluate effects of this management strategy on the fecal microbiome and relationships between fecal microbiota, forage nutrients, and metabolic responses of grazing horses. Fecal samples were collected from 8 mares after grazing cool-season pasture in spring, warm-season pasture in summer, and cool-season pasture in fall as well as after adaptation to standardized hay diets prior to spring grazing and at the end of the grazing season. Random forest classification was able to predict forage type based on microbial composition (accuracy: 0.90 ± 0.09); regression predicted forage crude protein (CP) and non-structural carbohydrate (NSC) concentrations ( p < 0.0001). Akkermansia and Clostridium butyricum were enriched in horses grazing warm-season pasture and were positively correlated with CP and negatively with NSC; Clostridum butyricum was negatively correlated with peak plasma glucose concentrations following oral sugar tests ( p ≤ 0.05). These results indicate that distinct shifts in the equine fecal microbiota occur in response different forages. Based on relationships identified between the microbiota, forage nutrients, and metabolic responses, further research should focus on the roles of Akkermansia spp. and Clostridium butyricum within the equine hindgut.

Aberrant gamma frequency neural oscillations in schizophrenia have been well demonstrated using auditory steady-state responses (ASSR). However, the neural circuits underlying 40 Hz ASSR deficits in schizophrenia remain poorly understood. Sixty-six patients with schizophrenia spectrum disorders and 85 age- and gender-matched healthy controls completed one electroencephalography session measuring 40 Hz ASSR and one imaging session for resting-state functional connectivity (rsFC) assessments. The associations between the normalized power of 40 Hz ASSR and rsFC were assessed via linear regression and mediation models. We found that rsFC among auditory, precentral, postcentral, and prefrontal cortices were positively associated with 40 Hz ASSR in patients and controls separately and in the combined sample. The mediation analysis further confirmed that the deficit of gamma band ASSR in schizophrenia was nearly fully mediated by three of the rsFC circuits between right superior temporal gyrus-left medial prefrontal cortex (MPFC), left MPFC-left postcentral gyrus (PoG), and left precentral gyrus-right PoG. Gamma-band ASSR deficits in schizophrenia may be associated with deficient circuitry level connectivity to support gamma frequency synchronization. Correcting gamma band deficits in schizophrenia may require corrective interventions to normalize these aberrant networks., (© 2023. The Author(s).)

Background: 7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Godmania , Tridax , and Primula species that confers protection against high-fat diet (HFD) induced metabolic pathologies selectively in female mice. We have previously reported that this metabolic protection is associated with early and stable remodeling of the intestinal microbiome, evident in female but not male DHF-supplemented mice. Early changes in the gut microbiome in female DHF-fed mice were highly predictive of subsequent metabolic protection, suggesting a causative association between the gut microbiome and the metabolic effects of DHF., Objective: To investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation., Materials and Methods: Age-matched male and female C57Bl6/J mice were given ad libitum access to HFD and drinking water containing vehicle or DHF for 12 weeks. For antibiotic (Abx) treatment, female mice were given drinking water containing a cocktail of antibiotics for 2 weeks prior to HFD feeding and throughout the feeding period. Metabolic phenotyping consisted of longitudinal assessments of body weights, body composition, food, and water intake, as well as measurement of energy expenditure, glucose tolerance, and plasma and hepatic lipids. Protein markers mediating the cellular effects of DHF were assessed in brown adipose tissue (BAT) and skeletal muscle., Results: Metabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial "activation" of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity., Conclusion: These results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sharma, Silva, Pfreundschuh, Ye and Sampath.)

Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice., Competing Interests: Declaration of interests M.K. is a founder of Elgia Pharmaceuticals, a member of its scientific advisory board, and received research support from Gossamer Bio, Jansen Pharmaceuticals, and Merck. UCSD is in the process of applying for a patent covering the generation and use of novel anti-inflammatory therapy for ARDS listing H.X., E.S.-L., and M.K. as inventors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Adherence to medication for tuberculosis (TB) has been found to be deleteriously affected by psychosocial issues, including internalized and perceived stigma (IPS) and depression, usually resulting in the emergence of multidrug-resistant TB (MDR-TB). The objective of the study was to find the prevalence of depression among patients receiving treatment for pulmonary TB, and how stigma and depression affect the relationship between drug sensitivity status (DSS) and treatment adherence., Method: It was a cross-sectional observational study conducted between January 2019 and July 2020 in two centers in Sikkim, India. The Patient Health Questionnaire-9 (PHQ-9), Internalized Social Stigma Scale (ISSS), and Tuberculosis Medication Adherence Scale were used to assess depression, IPS, and medication adherence, respectively. A path analysis was performed with DSS, treatment adherence, IPS, and depression. Education in years was included in the model as it was significantly correlated with IPS., Results: A total of 71 patients who were on drug-sensitive TB (DS-TB) regimen ( n = 26) and MDR-TB regimen ( n = 45) participated in the study. Notably, 56.3% ( n = 40) of the participants were found to have depression. Among the depressed participants, 32.5% were on the DS-TB regimen and 67.5% were on the MDR-TB regimen. The path analysis indicated that IPS and depression were serially mediating the relationship between DSS and treatment adherence (β = -0.06, p < 0.05, 95% CI = -3.20, -0.02). Finally, years of education had an exogenous predictor role, not only directly affecting IPS (β = -0.38, p < 0.001, 95% CI = -0.99, -0.31) but also affecting treatment adherence through IPS and depression (β = 0.08, p = 0.02, 95% CI = 0.03, 0.47). This indicated that with more years of education, the IPS decreases, which decreases depression and ultimately leads to better adherence., Conclusion: We found an important relationship between different psychosocial factors which may affect treatment adherence. Patients who have higher IPS are more likely to develop depression which negatively affect adherence. Patients on the MDR-TB regimen have higher stigma. There is an urgent need to integrate mental health services with TB Control Programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pradhan, Koirala, Bhandari, Dutta, García-Grau, Sampath and Sharma.)

Intestinal fatty acid-binding protein (IFABP; FABP2) and liver fatty acid-binding protein (LFABP; FABP1) are small intracellular lipid-binding proteins. Deficiency of either of these proteins in mice leads to differential changes in intestinal lipid transport and metabolism, and to markedly divergent changes in whole-body energy homeostasis. The gut microbiota has been reported to play a pivotal role in metabolic process in the host and can be affected by host genetic factors. Here, we examined the phenotypes of wild-type (WT), LFABP -/- , and IFABP -/- mice before and after high-fat diet (HFD) feeding and applied 16S rRNA gene V4 sequencing to explore guild-level changes in the gut microbiota and their associations with the phenotypes. The results show that, compared with WT and IFABP -/- mice, LFABP -/- mice gained more weight, had longer intestinal transit time, less fecal output, and more guilds containing bacteria associated with obesity, such as members in family Desulfovibrionaceae . By contrast, IFABP -/- mice gained the least weight, had the shortest intestinal transit time, the most fecal output, and the highest abundance of potentially beneficial guilds such as those including members from Akkermansia , Lactobacillus , and Bifidobacterium . Twelve out of the eighteen genotype-related bacterial guilds were associated with body weight. Interestingly, compared with WT mice, the levels of short-chain fatty acids in feces were significantly higher in LFABP -/- and IFABP -/- mice under both diets. Collectively, these studies show that the ablation of LFABP or IFABP induced marked changes in the gut microbiota, and these were associated with HFD-induced phenotypic changes in these mice.

Background: Social networking sites (SNSs) have become an indispensable part of young adults in India. The content on one's profile and that of others on social media makes social comparison easier among young adults leading to poor mental health and life dissatisfaction., Aims: To assess the relationship between the pattern of SNS use among young adults and depression, anxiety, and social comparison., Materials and Methods: This was a cross-sectional study among medical students done using a questionnaire consisting of pattern of SNS use and scales for social comparison, depression, and anxiety., Results: We collected data from 220 students (mean age 20.44 years). Impression management was associated with higher social comparison, depression, and anxiety scores. Social comparison had a significant correlation between depression and anxiety scores., Conclusion: A complex association exists between duration or time spent on SNS use and psychopathology., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Psychiatry.)

Obesity and related metabolic disorders are pressing public health concerns, raising the risk for a multitude of chronic diseases. Obesity is multi-factorial disease, with both diet and lifestyle, as well as genetic and developmental factors leading to alterations in energy balance. In this regard, a novel role for DNA repair glycosylases in modulating risk for obesity has been previously established. Global deletion of either of two different glycosylases with varying substrate specificities, Nei-like endonuclease 1 (NEIL1) or 8-oxoguanine DNA glycosylase-1 (OGG1), both predispose mice to diet-induced obesity (DIO). Conversely, enhanced expression of the human OGG1 gene renders mice resistant to obesity and adiposity. This resistance to DIO is mediated through increases in whole body energy expenditure and increased respiration in adipose tissue. Here, we report that hOGG1 expression also confers resistance to genetically-induced obesity. While Agouti obese ( A y /a ) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in A y /a mice ( A y /a Tg ) prevents increased body weight, without reducing food intake. Instead, obesity resistance in A y /a Tg mice is accompanied by increased whole body energy expenditure and tissue mitochondrial content. We also report for the first time that OGG1-mediated obesity resistance in both the A y /a model and DIO model requires maternal transmission of the hOGG1 transgene. Maternal, but not paternal, transmission of the hOGG1 transgene is associated with obesity resistance and increased mitochondrial content in adipose tissue. These data demonstrate a critical role for OGG1 in modulating energy balance through changes in adipose tissue function. They also demonstrate the importance of OGG1 in modulating developmental programming of mitochondrial content and quality, thereby determining metabolic outcomes in offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burchat, Sharma, Ye, Komakula, Dobrzyn, Vartanian, Lloyd and Sampath.)

Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R 2  = 0.06, p = 2 × 10 -5 ) and current stress measured by Perceived Stress Scale (R 2  = 0.13, p < 1 × 10 -6 ) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R 2  = 0.41, p < 1 × 10 -6 ). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h 2 ) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h 2 for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae , which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.

Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 ( Ogg1 -/- ) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 ( Ogg1 Tg ) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1 -/- mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1 Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Lecithin:retinol acyltransferase and retinol-binding protein enable vitamin A (VA) storage and transport, respectively, maintaining tissue homeostasis of retinoids (VA derivatives). The precarious VA status of the lecithin:retinol acyltransferase-deficient (Lrat -/- ) retinol-binding protein-deficient (Rbp -/- ) mice rapidly deteriorates upon dietary VA restriction, leading to signs of severe vitamin A deficiency (VAD). As retinoids impact gut morphology and functions, VAD is often linked to intestinal pathological conditions and microbial dysbiosis. Thus, we investigated the contribution of VA storage and transport to intestinal retinoid homeostasis and functionalities. We showed the occurrence of intestinal VAD in Lrat -/- Rbp -/- mice, demonstrating the critical role of both pathways in preserving gut retinoid homeostasis. Moreover, in the mutant colon, VAD resulted in a compromised intestinal barrier as manifested by reduced mucins and antimicrobial defense, leaky gut, increased inflammation and oxidative stress, and altered mucosal immunocytokine profiles. These perturbations were accompanied by fecal dysbiosis, revealing that the VA status (sufficient vs. deficient), rather than the amount of dietary VA per se, is likely a major initial discriminant of the intestinal microbiome. Our data also pointed to a specific fecal taxonomic profile and distinct microbial functionalities associated with VAD. Overall, our findings revealed the suitability of the Lrat -/- Rbp -/- mice as a model to study intestinal dysfunctions and dysbiosis promoted by changes in tissue retinoid homeostasis induced by the host VA status and/or intake., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

OGG1-deficient (Ogg1-/-) animals display increased propensity to age-induced and diet-induced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1-/- mice subjected to different nutritional challenges. Interestingly, Ogg1-/- mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. Consistent with this observation, Ogg1-/- mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1-/- mice., Competing Interests: The authors have declared that no competing interests exist.

Cognitive deficits contribute to functional disability in patients with schizophrenia and may be related to altered functional networks that serve cognition. We evaluated the integrity of major functional networks and assessed their role in supporting two cognitive functions affected in schizophrenia: processing speed (PS) and working memory (WM). Resting-state functional magnetic resonance imaging (rsfMRI) data, N = 261 patients and 327 controls, were aggregated from three independent cohorts and evaluated using Enhancing NeuroImaging Genetics through Meta Analysis rsfMRI analysis pipeline. Meta- and mega-analyses were used to evaluate patient-control differences in functional connectivity (FC) measures. Canonical correlation analysis was used to study the association between cognitive deficits and FC measures. Patients showed consistent patterns of cognitive and resting-state FC (rsFC) deficits across three cohorts. Patient-control differences in rsFC calculated using seed-based and dual-regression approaches were consistent (Cohen's d: 0.31 ± 0.09 and 0.29 ± 0.08, p < 10 -4 ). RsFC measures explained 12-17% of the individual variations in PS and WM in the full sample and in patients and controls separately, with the strongest correlations found in salience, auditory, somatosensory, and default-mode networks. The pattern of association between rsFC (within-network) and PS (r = .45, p = .07) and WM (r = .36, p = .16), and rsFC (between-network) and PS (r = .52, p = 8.4 × 10 -3 ) and WM (r = .47, p = .02), derived from multiple networks was related to effect size of patient-control differences in the functional networks. No association was detected between rsFC and current medication dose or psychosis ratings. Patients demonstrated significant reduction in several FC networks that may partially underlie some of the core neurocognitive deficits in schizophrenia. The strength of connectivity-cognition relationships in different networks was strongly associated with network's vulnerability to schizophrenia., (© 2019 Wiley Periodicals, Inc.)

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h 2  = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h 2  = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC-striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

Background: Delirium is a frequent yet underdiagnosed neuropsychiatric condition encountered in intensive care units (ICUs). Being both a preventable and potentially reversible process associated with significant morbidity and mortality, understanding risk factors that predispose and precipitate delirium in any given patient are critical in ICUs., Aims and Objectives: The aim of this study is to evaluate the incidence, motor subtypes, risk factors, and clinical outcome of delirium in the medical ICU., Materials and Methods: We used a prospective study design on a cohort of consecutive medical ICU admissions of a tertiary care teaching hospital. The Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale were used to diagnose and motor subtype delirium, respectively, along with a checklist to assess risk factors., Results: Of the 280 ICU admissions, 88 (31.4%) developed delirium. Hypoactive delirium was the most common motor subtype (55.7%). The detection rate of delirium was 12.5% (lowest for hypoactive delirium at 2.04%). Age, gender, and years of education did not significantly predict delirium (all P > 0.05). Tobacco use, chronic liver disease, and past episodes of delirium significantly predisposed, while mechanical ventilation, hypoxia, fever, raised levels of bilirubin and creatinine, and benzodiazepine administration significantly precipitated ICU delirium. Delirium was significantly associated with longer ICU stay ( t = 4.23, P = 0.000) and 1-month postdischarge mortality ( χ 2 = 6.867, P = 0.009)., Conclusion: Detection of delirium is challenging, especially in ICU patients on mechanical ventilation and hypoactive delirium. Screening and monitoring for predisposing and precipitating risk factors can greatly improve the odds of detection and intervention as ICU delirium is associated with significant morbidity and mortality., Competing Interests: There are no conflicts of interest.

Introduction: Eating disorders are increasingly becoming common among men and women across the world. Body dissatisfaction is found to be one of the prominent risk factors for the development and maintenance of eating disorders. Research suggests that the internalization of culturally unattainable ideals is in fact mediated by self-esteem and personality factors such as high neuroticism, perfectionism, and impulsiveness. Studies on body image concerns in the cultural context of the Indian population are limited. We aimed to study the prevalence of body image dissatisfaction and its association with self-esteem and personality traits among young Indian women., Materials and Methods: Using a cross-sectional design we studied on 555 female college students of North India. Data was collected using self-reported questionnaires: Sociodemographic pro forma, Body Shape Questionnaire (-8C), Rosenberg's Self-Esteem Scale, and Mini-International Personality Item Pool., Results: The mean age of the participants in the study was 22.24 years (±2.75). Twenty-seven percent of the participants had moderate-to-severe body concern. Body shape dissatisfaction significantly correlated with higher body mass index (BMI) (rs = 0.12, P = 0.003) and lower self-esteem (rs = -0.22, P < 0.001). Among the personality traits, only neuroticism (beta = 0.35, P = 0.01) and conscientiousness (beta = 0.29, P = 0.031) significantly predicted body shape dissatisfaction., Conclusion: A significant percentage of young women in this study had a negative body image associated with higher BMI, lower self-esteem, high neuroticism, and high conscientiousness. Thus, consideration of individual variations in personality traits and self-esteem is important understanding body image concerns. This can help in selection of better interventions in the treatment of body image dissatisfaction., Competing Interests: There are no conflicts of interest.

Obesity and related metabolic pathologies represent a significant public health concern. Obesity is associated with increased oxidative stress that damages genomic and mitochondrial DNA. Oxidatively-induced lesions in both DNA pools are repaired via the base-excision repair pathway, initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). Global deletion of OGG1 and common OGG1 polymorphisms render mice and humans susceptible to metabolic disease. However, the relative contribution of mitochondrial OGG1 to this metabolic phenotype is unknown. Here, we demonstrate that transgenic targeting of OGG1 to mitochondria confers significant protection from diet-induced obesity, insulin resistance, and adipose tissue inflammation. These favorable metabolic phenotypes are mediated by an increase in whole body energy expenditure driven by specific metabolic adaptations, including increased mitochondrial respiration in white adipose tissue of OGG1 transgenic (Ogg1 Tg ) animals. These data demonstrate a critical role for a DNA repair protein in modulating mitochondrial energetics and whole-body energy balance.