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Mutations in POLG, the gene encoding the catalytic subunit of DNA polymerase gamma, result in clinical syndromes characterized by mitochondrial DNA (mtDNA) depletion in affected tissues with variable organ involvement. The brain is one of the most affected organs, and symptoms include intractable seizures, developmental delay, dementia, and ataxia. Patient-derived induced pluripotent stem cells (iPSCs) provide opportunities to explore mechanisms in affected cell types and potential therapeutic strategies. Fibroblasts from two patients were reprogrammed to create new iPSC models of POLG-related mitochondrial diseases. Compared with control iPSC-derived neurons, mtDNA depletion was observed upon differentiation of the POLG-mutated lines to cortical neurons. POLG-mutated neurons exhibited neurite simplification with decreased mitochondrial content, abnormal mitochondrial structure and function, and increased cell death. Expression of the mitochondrial kinase PTEN-induced kinase 1 (PINK1) mRNA was decreased in patient neurons. Overexpression of PINK1 increased mitochondrial content and ATP:ADP ratios in neurites, decreasing cell death and rescuing neuritic complexity. These data indicate an intersection of polymerase gamma and PINK1 pathways that may offer a novel therapeutic option for patients affected by this spectrum of disorders.

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective:To design a meditation protocol and test its feasibility, acceptability and efficacy in conjunction with yoga training (YT) for persons with schizophrenia (SZ).Methods:The meditation protocol consisted of Anapana (observing normal respiration) and Yoga Nidra (supine, restful awareness). In a single-blind randomised controlled trial, medicated and clinically stable outpatients diagnosed with SZ were randomised to receive treatment as usual (TAU), TAU augmented with YT or TAU augmented with meditation and yoga training (MYT) for 3 weeks (N = 145). Acceptability, clinical, social and cognitive functions were assessed after 3-week and 3-month post-randomisation using within-group and between-group analyses with repeated measures multivariate tests.Results:No group-wise differences in compliance, study discontinuation, major/serious side effects or adverse events were noted. For six assessed clinical variables, the direction of changes were in the desired direction and the effect sizes were greater in the MYT group compared with the TAU group at both time points. Changes in social function variables were greater at 3 months than at 3 weeks. Nominally significant improvement in individual cognitive domains were noted in all groups at both time points. All effect sizes were in the small to medium range.Conclusion:MYT is feasible and acceptable and shows modest benefits for persons with SZ. MYT can also improve quality of life and clinical symptoms. Larger studies of longer duration are warranted.

Supplementary Table 1 from Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors

Supplementary Figure 2 from Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors

Supplementary Figure 1 from Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors

Herpesviruses alter cognitive functions in humans following acute infections; progressive cognitive decline and dementia have also been suggested. It is important to understand the pathogenic mechanisms of such infections. The complement system - comprising functionally related proteins integral for systemic innate and adaptive immunity - is an important component of host responses. The complement system has specialized functions in the brain. Still, the dynamics of the brain complement system are still poorly understood. Many complement proteins have limited access to the brain from plasma, necessitating synthesis and specific regulation of expression in the brain; thus, complement protein synthesis, activation, regulation, and signaling should be investigated in human brain-relevant cellular models. Cells derived from human-induced pluripotent stem cells (hiPSCs) could enable tractable models.Human-induced pluripotent stem cells were differentiated into neuronal (hi-N) and microglial (hi-M) cells that were cultured with primary culture human astrocyte-like cells (ha-D). Gene expression analyses and complement protein levels were analyzed in mono- and co-cultures.Transcript levels of complement proteins differ by cell type and co-culture conditions, with evidence for cellular crosstalk in co-cultures. Hi-N and hi-M cells have distinct patterns of expression of complement receptors, soluble factors, and regulatory proteins. hi-N cells produce complement factor 4 (C4) and factor B (FB), whereas hi-M cells produce complement factor 2 (C2) and complement factor 3 (C3). Thus, neither hi-N nor hi-M cells can form either of the C3-convertases - C4bC2a and C3bBb. However, when hi-N and hi-M cells are combined in co-cultures, both types of functional C3 convertase are produced, indicated by elevated levels of the cleaved C3 protein, C3a.hiPSC-derived co-culture models can be used to study viral infection in the brain, particularly complement receptor and function in relation to cellular "crosstalk." The models could be refined to further investigate pathogenic mechanisms.

Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

Objective:The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ).Methods:We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers.Results:Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148).Conclusions:YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.

Introduction:Autism is included as a certifiable disability in the Indian Rights of Persons with Disability Act, 2016. The Indian Scale for Assessment of Autism (ISAA), developed by the Government of India and mandated for certifying disability, is a detailed instrument that needs trained mental health experts and takes time to administer. The current project was planned to develop a simple, easy to use screening tool based on the ISAA to identify possible cases in the community.Methods:The project is planned in three phases. During the first phase, data collected during the development of the ISAA ( N = 433/436 children with autism) will be used to identify questions answered as frequently, mostly, and always. During the second phase, the psychometric properties of the screening tool based on these items will be evaluated among research participants recruited from hospitals and special schools ( n = 100). In the third phase, the screening questionnaire will be administered in the community ( n = 500).Results:The most frequently answered questions will be selected for inclusion in the proposed screening tool. The number of items in the screening tool will be kept as few as possible, with yes or no responsesDiscussion:Indian Autism Screening Questionnaire (IASQ) will be tested as a screening version of ISAA, which can be used by community health workers, teachers, or school counselors. The IASQ will not provide a diagnosis of autism. A positive screening result should be followed by a thorough assessment by a trained specialist. Analyzing the psychometric properties of the test can help ensure cost-effective screening of the community to identify autism.

STUDY OBJECTIVES: High-frequency electroencephalographic activity (> 16 Hz activity) is often elevated during nonrapid eye movement sleep among individuals with insomnia, in line with the hyperarousal theory of insomnia. Evidence regarding sleep depth marked by slow-wave activity (< 4 Hz) is more mixed. Distinguishing subcomponents of slow-wave activity (slow-oscillation [< 1 Hz] or delta activity [1–4 Hz)]) may be critical in understanding these discrepancies, given that these oscillations have different neural generators and are functionally distinct. Here we tested the effects of insomnia diagnosis and insomnia treatment on nonrapid eye movement electroencephalography in older adults, distinguishing slow-oscillation and delta power. METHODS: In 93 older adults with insomnia and 71 good sleeper control participants (mean ages 68 years), effects of insomnia and cognitive behavioral therapy for insomnia (insomnia group only) on electroencephalographic spectral power were analyzed. Main effects and interactions with nonrapid eye movement period were assessed for the following frequency bands: slow-oscillation (0.5–1 Hz), delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), sigma (12–16 Hz), and beta (16–32 Hz). RESULTS: Slow-oscillation absolute and relative power were lower in the insomnia group compared with controls. There were no group differences in delta power. Insomnia was also associated with elevated 4–32 Hz absolute and relative power. After cognitive behavioral therapy for insomnia, absolute sigma and beta activity decreased. CONCLUSIONS: Deficits in slow-wave activity in insomnia are specific to the slow-oscillation. Elevated high frequency activity is reduced for sigma and beta power following cognitive behavioral therapy for insomnia . These findings inform the pathophysiology of insomnia, including the mechanisms underlying cognitive behavioral therapy for insomnia in older adults. CITATION: Hogan SE, Delgado GM, Hall MH, et al. Slow-oscillation activity is reduced and high frequency activity is elevated in older adults with insomnia. J Clin Sleep Med. 2020;16(9):1445–1454.

Background Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. Methods We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. Results Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. Conclusions We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

Schizophrenia is a clinically and genetically heterogeneous neuropsychiatric disorder, with a polygenic basis but identification of the specific determinants is a continuing challenge. In this study, we analyzed a multigenerational family, with all healthy individuals in the first two generations, and four progeny affected with schizophrenia in the subsequent two generations, using whole exome sequencing. We identified five rare protein sequence altering heterozygous variants, in five different genes namely SMARCA5, PDE1B, TNIK, SMARCA2 and FLRT shared among all affected members and predicted to be damaging. Variants in SMARCA5 and PDE1B were inherited from the unaffected father whereas variants in TNIK, SMARCA2 and FLRT1 were inherited from the unaffected mother in all the three affected individuals in the third generation; and notably all these five variants were transmitted by an affected mother to her affected son. Microsatellite based analysis lent a modest linkage support (LOD score of 1.2; θ=0.0 at each variant). Of note, analysis of exome data of an ancestry matched unrelated schizophrenia cohort (n = 350), revealed a total of 16 rare variants (MAF 0.01) in these five genes. Interestingly, these five genes involved in neurodevelopmental and/or neurotransmitter signaling processes are implicated in the etiology of schizophrenia previously. This study provides good evidence for a likely cumulative contribution of multiple rare variants from disease relevant genes with a threshold effect in disease development and seems to explain the unusual disease transmission pattern generally witnessed in such conditions, but warrants extensive replication efforts in families with similar complex disease inheritance profiles.

Cognition shares substantial genetic overlap with schizophrenia, yet it remains unclear whether such genetic effects become significant during developmental periods of elevated risk for schizophrenia, such as the peak age of onset. We introduce an investigative framework integrating epidemiological, developmental, and genetic approaches to determine whether genetic effects shared between schizophrenia and cognition are significant across periods of differing risk for schizophrenia onset, and whether these effects are shared with depression. 771 European-American participants, including 636 (ages 15-84 years) from families with at least two first-degree relatives with schizophrenia and 135 unrelated controls, were divided into three age-risk groups based on ages relative to epidemiological age of onset patterns for schizophrenia: Pre-Peak (before peak age-of-onset: 15 to 22 years), Post-Peak (after peak age-of-onset: 23-42 years), and Plateau (during plateau of age-of-onset: over 42 years). For general cognition and 11 specific cognitive traits, we estimated genetic correlations with schizophrenia and with depression within each age-risk group. Genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant before peak age of onset, yet were high and significant after peak age of onset and during the plateau of onset. These age-dependent genetic effects were largely consistent across specific cognitive traits and not transdiagnostically shared with depression. Schizophrenia genetic effects appear to influence cognitive traits in an age-dependent manner, supporting late developmental and perhaps neurodegenerative models that hypothesize increased expression of schizophrenia risk genes during and after the peak age of risk. Our findings underscore the utility of cognitive traits for tracking schizophrenia genetic effects across the lifespan.

IntroductionStructural and functional brain connectomes built using macroscale data collected through magnetic resonance imaging (MRI) may contain noise that contributes to false-positive edges, which can obscure structure-function relationships with implications for data interpretation. Thresholding procedures are routinely applied in practice to optimize network density by removing low-signal edges, but there is limited consensus regarding the appropriate selection of thresholds. We compare existing methods and propose a novel alternative objective function thresholding (OFT) method.MethodsThe performance of thresholding approaches, including a percolation-based approach and an objective function-based approach, is assessed by (a) computing the normalized mutual information (NMI) of community structure between a known network and a simulated, perturbed networks to which various forms of thresholding have been applied, and (b) comparing the density and the clustering coefficient (CC) between the baseline and thresholded networks.ResultsIn our analysis, the proposed objective function-based threshold exhibits the best performance in terms of high similarity between the underlying networks and their perturbed, thresholded counterparts, as quantified by NMI and CC analysis on the simulated functional networks.DiscussionExisting network thresholding methods yield widely different results when graph metrics are computed. Thresholding based on the objective function appears to maintain a set of edges such that the resulting network shares the community structure and clustering features present in the original network. This outcome provides proof-of-principle evidence that thresholding based on the objective function could offer a useful approach to reducing the network density of functional connectivity data.Impact StatementNetwork thresholding refers to removing edges between node pairs in a functional network that have weak edge-weights that may arise from unwanted variability or noise. Since edge-weight cutoffs used to generate a binary network can be sensitive to thresholding, we introduce a novel thresholding algorithm. We find that when applied to networks derived via perturbations, namely through simulated functional connectivity of a known network, this approach yields a binary network that is more similar to the known network compared to using existing thresholding approaches. Thus, our algorithm is a competitive candidate for use in thresholding of brain connectome.

The Indian Autism Screening Questionnaire (IASQ), derived from the Indian Scale for Assessment of Autism ISAA (the mandated tool for autism in India), is an autism screening instrument for use in the general population by minimally trained workers. While ISAA has 40 items with four anchor points, the IASQ is a 10-item questionnaire with yes/no answers. It was initially validated using the ISAA. During its development the ISAA was itself compared to the Childhood Autism Rating Scale version 1 (ISAA Manual). In the present study, we evaluated both the ISAA and the IASQ in relation to the Childhood Autism Rating Scale version 2 (CARS-2). Methods: Participants were recruited from three settings: a referral clinic for neurodevelopmental conditions run by the Department of Paediatrics of a tertiary care teaching hospital (NDC OPD), the outpatient department of an institute for disability and rehabilitation (NIEPID), and from the community (CGOC). Persons between ages 3–18 were recruited following consent or assent (parent and child/adolescent). The IASQ was administered by a minimally trained administrator. It was followed by ISAA and the CARS-2 (in alternating order, by different evaluators blind to each other) (CARS2 SV (Standard Version) and CARS2 HF (High Functioning) as applicable). Sensitivity, specificity and area under the Receiver Operator Characteristics (ROC) curve were calculated for IASQ and CARS2, as well as for ISAA and CARS2. Concordance between CARS2 and ISAA was calculated using kappa coefficient. Results: A total of 285 participants (NIEPD n = 124; NDC OPD, n = 4; CGOC n = 157) (a total of 70 with autism and 215 controls) participated. IASQ and CARS2 were administered on 285 participants, while IASQ and ISAA were administered on 264 participants. When IASQ was compared to CARS2, sensitivity was 97%, specificity 81%, PPV 63%, NPV 99% at cut off 1 while these values were 97%, 92%, 79% and 99% respectively at cut off 2. There was high concordance between CARS2 and ISAA (Kappa 0.907, pConclusions: IASQ has satisfactory sensitivity, specificity and concordance when compared with CARS2; it can be used for screening children with autism in community. The ISAA also showed a high concordance with CARS2, as it had with the older version of CARS.

Background Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. Results We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. Conclusions These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

Background Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. Methods Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. Results Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. Conclusions There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

The pathogen hypothesis of Alzheimer’s disease (AD) proposes that brain HSV-1 infection is an initial source of amyloid beta (Aβ) peptide-containing amyloid plaque development. Aβ accumulation was reported in HSV-1-infected 2D neuronal cultures and neural stem cell cultures as well as in HSV-1-infected 3D neuronal culture models., Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by the presence of extracellular amyloid plaques composed of fibrillar amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles. Postmortem and in vivo studies implicate herpes simplex virus 1 (HSV-1) infection in the brain as a precipitating factor in disease/pathology initiation. HSV-1 infection of two-dimensional (2D) neuronal cultures causes intracellular accumulation of Aβ42 peptide, but these 2D models do not recapitulate the three-dimensional (3D) architecture of brain tissue. We employed human induced pluripotent stem cells (hiPSCs) to compare patterns of Aβ42 accumulation in HSV-1-infected 2D (neuronal monolayers) and 3D neuronal cultures (brain organoids). Akin to prior studies, HSV-1-infected 2D cultures showed Aβ42 immunoreactivity in cells expressing the HSV-1 antigen ICP4 (ICP4+). Conversely, accumulation of Aβ42 in ICP4+ cells in infected organoids was rarely observed. These results highlight the importance of considering 3D cultures to model host-pathogen interaction. IMPORTANCE The pathogen hypothesis of Alzheimer’s disease (AD) proposes that brain HSV-1 infection is an initial source of amyloid beta (Aβ) peptide-containing amyloid plaque development. Aβ accumulation was reported in HSV-1-infected 2D neuronal cultures and neural stem cell cultures as well as in HSV-1-infected 3D neuronal culture models. The current study extends these findings by showing different patterns of Aβ42 accumulation following HSV-1 infection of 2D compared to 3D neuronal cultures (brain organoids). Specifically, 2D neuronal cultures showed Aβ42 immunoreactivity mainly in HSV-1-infected cells and only rarely in uninfected cells or infected cells exposed to antivirals. Conversely, 3D brain organoids showed accumulation of Aβ42 mainly in noninfected cells surrounding HSV-1-infected cells. We suggest that because brain organoids better recapitulate architectural features of a developing brain than 2D cultures, they are a more suitable model to investigate the involvement of HSV-1 in the onset of AD pathology.

Introduction: India’s National Mental Health Programme (NMHP) was initiated in 1982. In 2016, the Indian Council of Medical Research (ICMR) organized a Brainstorming Meeting on Prioritization of Mental Health Research. Recognizing the need for improving mental healthcare by building a cadre of mental health researchers based on focus areas of the NMHP, the ICMR organized a research training cum capacity building workshop in collaboration with the Cross-Fertilized Research Training Programme (funded by Fogarty International Centre, NIH, USA) in 2016. The workshop successfully prepared and reviewed 12 single and multicenter research proposals in priority areas of mental health research, which were awarded by the ICMR to middle- and junior-level research faculty and NGO. Methods: A National Coordination Unit (NCU) was set up to mentor investigators and to coordinate, train, and monitor the progress of their projects. Investigators were paired with senior mentors and also participated in four capacity building workshops focusing on proposal-writing, evaluation, and process tracking. Results: Following discussions with ICMR program officers, the NCU formulated standard operating procedures for ethical conduct, data collection, data sharing, progress reporting procedures, and manuscript preparation for all research projects. Regularly scheduled long-distance communications with investigators using social media and group communications were planned. NCU partnered with the ICMR Database Management Unit to build a shared online platform for real-time data entry and storage, and organized two project review meetings where it also coordinated with US faculty to organize public workshops on manuscript writing and qualitative research. Conclusions: The NCU will ensure timely completion of research projects, data entry and analysis, and reports and project publications. It is feasible to evaluate progress with the NMHP through coordinated multisite research that also enables research capacity building. Results from these projects will help in formulating policies by the Ministry of Health Government of India for achieving objectives of the NMHP.

Herpes simplex virus 1 (HSV-1) can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important because they are associated with memory formation and are highly enriched with neural progenitor cells (NPCs). The susceptibility and fate of HSV-1-infected NPCs are largely unexplored. We differentiated human induced pluripotent stem cells (hiPSCs) into NPCs to generate two-dimensional (2D) and three-dimensional (3D) culture models to examine the interaction of HSV-1 with NPCs. Here, we show that (i) NPCs can be efficiently infected by HSV-1, but infection does not result in cell death of most NPCs, even at high multiplicities of infection (MOIs); (ii) limited HSV-1 replication and gene expression can be detected in the infected NPCs; (iii) a viral silencing mechanism is established in NPCs exposed to the antivirals (E)-5-(2-bromovinyl)-2'-deoxyuridine (5BVdU) and alpha interferon (IFN-α) and when the antivirals are removed, spontaneous reactivation can occur at low frequency; (iv) HSV-1 impairs the ability of NPCs to migrate in a dose-dependent fashion in the presence of 5BVdU plus IFN-α; and (v) 3D cultures of NPCs are less susceptible to HSV-1 infection than 2D cultures. These results suggest that NPC pools could be sites of HSV-1 reactivation in the central nervous system (CNS). Finally, our results highlight the potential value of hiPSC-derived 3D cultures to model HSV-1-NPC interaction.

Herpes simplex virus, type 1 (HSV-1) infection is highly prevalent and globally affects approximately 67% of people under age 50. It causes substantial morbidity, including recurrent ocular disease, cold sores, and rare cases of devastating encephalitis. Its pathogenicity stems primarily from the ability of the virus to cause recurrent lytic lesions, a consequence of its ability to persist for life as a latent infection in neurons. Latency is an elusive, poorly understood, and to date, untreatable process that involves a dynamic interplay between the virus and host cells. While considerable knowledge of the HSV-1 latent state has been gleaned from small animal modeling, we are now at the cusp of needing to examine HSV-1 in more human relevant models, as HSV-1 is a human-specific virus, and the underlying mechanisms of latency have presumably evolved over millennia through human host–virus interactions. Neuron-virus studies have been substantially hampered by the absence of satisfactory human models. Human induced pluripotent stem cell (hiPSC) and embryonic stem cell (hESC) technologies are profoundly changing this picture, as they can provide human neuron models to examine the interaction of pathogens with their hosts. They are also aiding in the development of novel therapeutic approaches. Herein, we describe the use of hiPSCs to derive human models of HSV-1 acute and latent infections and to generate human neuronal platforms for antiviral drug screening.

Schizophrenia (SZ) is a common, potentially debilitating disorder. Over 70% of risk for SZ at the population level is attributable to genetic factors. Large-scale genome-wide association studies (GWAS) have revealed risk attributable to over 170 genomic loci, with varied effect sizes. Statistically, the most significant risk locus maps to the major histocompatibility complex (MHC) region on chromosome 6 (odds ratio ~1.28). One of the associated MHC loci involved the complement C4 gene. There is population-wide variation in C4 gene copy number, and SZ risk rises with the number of C4 genes that an individual’s genome encodes. C4 is a component of an immunologic defense mechanism that predates antibody-based adaptive immunity. In mammals, complement proteins also participate in neurodevelopment. Based on rodent model studies, it has been proposed that the C4-related risk for SZ could be explained by aberrant synaptic pruning—a developmental process also implicated in SZ risk. We review the synaptic pruning hypothesis and propose additional mechanisms to explain the C4-SZ link, including disruption in classical immunologic processes and changes in human endogenous retroviral sequences associated with C4. The evidence supporting these hypotheses is discussed, and empirical investigations are proposed.

Background: Alcohol use disorder is elevated among members of indigenous tribes in India, like native populations in several other countries. Despite constituting 8.6% of the Indian population, tribals are among the most geographically isolated, socioeconomically underdeveloped, and underserved communities in the country. Based on the experience from our centers (in Tamil Nadu, Meghalaya, and Gujarat), we are aware of escalating alcohol use among tribal communities. The aims of this study are (a) to estimate alcohol use and psychiatric morbidity among teenagers from indigenous tribes, and (b) pilot test a psychoeducational efficacy study. Methods: The biphasic study is being conducted in three states of India: Tamil Nadu in South, Meghalaya in Northeast, and Gujarat in West. Phase 1 is a cross-sectional study of tribal adolescents at each site. The MINI 6.0/MINI Kid 6.0 questionnaire was used to estimate extent of psychiatric morbidity and substance addiction. Phase 2 is an intervention trial of 40 participants at each site to assess the effectiveness of NIMHANS LSE module in protecting the tribal adolescents from alcohol use. Conclusions: The desired primary outcome will be forestalling the onset of alcohol use among this group. This paper focuses on the methodology and strategies to be used to achieve the objectives.

BackgroundTo test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438).MethodsWe examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections.ResultsSignificant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts.Conclusions:Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Schizophrenia has substantial variation in symptom severity, course of illness, and overall functioning. Earlier age of onset (AOO) is consistently associated with negative outcomes and yet the causes of this association are still unknown. We used a multiplex, extended pedigree design (total N = 771; 636 relatives from 43 multigenerational families with at least 2 relatives diagnosed with schizophrenia and 135 matched controls) to examine among the schizophrenia relatives (N = 103) the relationship between AOO and negative and positive symptom severity, cognition, and community functioning. Most importantly, we assessed whether there are shared genetic effects between AOO and negative symptoms, positive symptoms, cognition, and community functioning. As expected, earlier AOO was significantly correlated with increased severity of negative and positive symptoms and poorer cognition and community functioning among schizophrenia patients. Notably, the genetic correlation between AOO of schizophrenia and negative symptoms was significant (R(g) = −1.00, p = .007). Although the genetic correlations between AOO and positive symptoms, cognition, and community functioning were estimated at maximum and in the predicted direction, they were not statistically significant. AOO of schizophrenia itself was modestly heritable, although not significant and negative symptoms, positive symptoms, and cognition were all strongly and significantly heritable. In sum, we replicated prior findings indicating that earlier AOO is associated with increased symptom severity and extended the literature by detecting shared genetic effects between AOO and negative symptoms, suggestive of pleiotropy.

This study employed human induced pluripotent stem cells (hiPSCs) to model the interaction of HSV-1 with NPCs, which reside in the neurogenic niches of the CNS and play a fundamental role in adult neurogenesis. Herein, we provide evidence that in NPCs infected at an MOI as low as 0.001, HSV-1 can establish a latent state, suggesting that (i) a variant of classical HSV-1 latency can be established during earlier stages of neuronal differentiation and (ii) neurogenic niches in the brain may constitute additional sites of viral reactivation. Lytic HSV-1 infections impaired NPC migration, which represents a critical step in neurogenesis. A difference in susceptibility to HSV-1 infection between two-dimensional (2D) and three-dimensional (3D) NPC cultures was observed, highlighting the potential value of 3D cultures for modeling host-pathogen interactions. Together, our results are relevant in light of observations relating HSV-1 infection to postencephalitic cognitive dysfunction., Herpes simplex virus 1 (HSV-1) can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important because they are associated with memory formation and are highly enriched with neural progenitor cells (NPCs). The susceptibility and fate of HSV-1-infected NPCs are largely unexplored. We differentiated human induced pluripotent stem cells (hiPSCs) into NPCs to generate two-dimensional (2D) and three-dimensional (3D) culture models to examine the interaction of HSV-1 with NPCs. Here, we show that (i) NPCs can be efficiently infected by HSV-1, but infection does not result in cell death of most NPCs, even at high multiplicities of infection (MOIs); (ii) limited HSV-1 replication and gene expression can be detected in the infected NPCs; (iii) a viral silencing mechanism is established in NPCs exposed to the antivirals (E)-5-(2-bromovinyl)-2′-deoxyuridine (5BVdU) and alpha interferon (IFN-α) and when the antivirals are removed, spontaneous reactivation can occur at low frequency; (iv) HSV-1 impairs the ability of NPCs to migrate in a dose-dependent fashion in the presence of 5BVdU plus IFN-α; and (v) 3D cultures of NPCs are less susceptible to HSV-1 infection than 2D cultures. These results suggest that NPC pools could be sites of HSV-1 reactivation in the central nervous system (CNS). Finally, our results highlight the potential value of hiPSC-derived 3D cultures to model HSV-1–NPC interaction. IMPORTANCE This study employed human induced pluripotent stem cells (hiPSCs) to model the interaction of HSV-1 with NPCs, which reside in the neurogenic niches of the CNS and play a fundamental role in adult neurogenesis. Herein, we provide evidence that in NPCs infected at an MOI as low as 0.001, HSV-1 can establish a latent state, suggesting that (i) a variant of classical HSV-1 latency can be established during earlier stages of neuronal differentiation and (ii) neurogenic niches in the brain may constitute additional sites of viral reactivation. Lytic HSV-1 infections impaired NPC migration, which represents a critical step in neurogenesis. A difference in susceptibility to HSV-1 infection between two-dimensional (2D) and three-dimensional (3D) NPC cultures was observed, highlighting the potential value of 3D cultures for modeling host-pathogen interactions. Together, our results are relevant in light of observations relating HSV-1 infection to postencephalitic cognitive dysfunction.

The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported.

Schizophrenia is a complex disorder with many comorbid conditions. In this study, we used polygenic risk scores (PRSs) from schizophrenia and comorbid traits to explore consistent cluster structure in schizophrenia patients. With 10 comorbid traits, we found a stable 4-cluster structure in two datasets (MGS and SSCCS). When the same traits and parameters were applied for the patients in a clinical trial of antipsychotics, the CATIE study, a 5-cluster structure was observed. One of the 4 clusters found in the MGS and SSCCS was further split into two clusters in CATIE, while the other 3 clusters remained unchanged. For the 5 CATIE clusters, we evaluated their association with the changes of clinical symptoms, neurocognitive functions, and laboratory tests between the enrollment baseline and the end of Phase I trial. Class I was found responsive to treatment, with significant reduction for the total, positive, and negative symptoms (p=0.0001, 0.0099, and 0.0028, respectively), and improvement for cognitive functions (VIGILANCE,p=0.0099; PROCESSING SPEED,p=0.0006; WORKING MEMORY,p=0.0023; and REASONING,p=0.0015). Class II had modest reduction of positive symptoms (p=0.0492) and better PROCESSING SPEED (p=0.0071). Class IV had a specific reduction of negative symptoms (p=0.0111) and modest cognitive improvement for all tested domains. Interestingly, Class IV was also associated with decreased lymphocyte counts and increased neutrophil counts, an indication of ongoing inflammation or immune dysfunction. In contrast, Classes III and V showed no symptom reduction but a higher level of phosphorus. Overall, our results suggest that PRSs from schizophrenia and comorbid traits can be utilized to classify patients into subtypes with distinctive clinical features. This genetic susceptibility based subtyping may be useful to facilitate more effective treatment and outcome prediction.

Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores.

Right to privacy of health-related information is a foundational bioethical principle. In India, the importance of protecting privacy is included in law and ethical guidelines. Institutional Ethics Committees (IECs) are entrusted with the responsibility of protecting fundamental ethical principles, including privacy and confidentiality. The present qualitative study was designed to understand IECs' privacy-related obligations and the members' experience in implementing ethical guidelines and privacy protections in their institutions. An interview guide was prepared regarding knowledge of ethical guidelines. Interviews of nineteen IEC members were recorded, transcribed, and translated. Interviews were analysed using thematic analysis. Themes related to these issues were extracted after analysis: awareness, understanding, and implementation of ethical guidelines; understanding of privacy-related obligations and their implementation; and juridical risks to privacy of patients and research participants. The results suggest that training programmes and awareness workshops should be organised for IEC members to protect the rights of research participants, especially in confidentiality issues.

Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals. This research was supported by National Institute of Mental Health grants U01 MH105630 (DCG), U01 MH105634 (REG), U01 MH105632 (JB), R01 MH078143 (DCG), R01 MH083824 (DCG & JB), R01 MH078111 (JB), R01 MH061622 (LA), R01 MH042191 (REG), and R01 MH063480 (VLN). UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM) UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biología

Several studies have indicated infectious and immune-related abnormalities in schizophrenia (Scz), including elevated serum C-reactive protein (CRP) - a well-known proxy for infections/immune abnormalities. A portion of the genetic risk for Scz can be estimated using the polygenic risk score (PGRS). It is not known whether there is an interaction in the risks traceable to CRP and PGRS. Patients with Scz and individuals without psychosis were evaluated systematically using DSM IV criteria (N=794, N=446, respectively). To estimate risk for Scz attributable to CRP and PGRS, serum from these participants was assayed for CRP levels using enzyme linked immunosorbent assays. PGRS was estimated from common DNA polymorphisms associated with Scz from genome wide association studies. CRP level and PGRS were not significantly correlated. Using a generalized linear logistic model, case/control status was evaluated in relation to the following predictors: CRP, PGRS, and demographic variables. CRP and PGRS were individually associated with case status; CRP: odds ratio (OR) 1.27, 95% confidence intervals (95% CI) 1.12, 1.43; p = 0.0001; PGRS: OR 1.66, 95% CI 1.47, 1.89; p = 1.28 ×10-15. There were no significant interactions between PGRS and CRP for predicting Scz versus control status.

Although cognition is one of the most important predictors of community functioning in schizophrenia, little is known about the causes of this correlation. To our knowledge, this study is the first to examine the extent to which this correlation is genetically mediated and whether the genetic correlation is specific to schizophrenia. Six hundred thirty-six participants from 43 multigenerational families with at least two relatives with schizophrenia and 135 unrelated controls underwent diagnostic interview and cognition and functioning assessment. Quantitative genetic analyses were conducted using maximum-likelihood variance decomposition methods implemented in SOLAR (Almasy & Blangero, 1998). Among patients with schizophrenia, cognition and community functioning were positively correlated and genetic effects shared between them were significant contributors to this relationship whereas environmental effects shared between them were not. In contrast, genetic effects were not shared significantly between cognition in depressed or nondiagnosed relatives and community functioning in schizophrenia. In all analyses, the contributions of social cognition to community functioning were accounted for by general cognition. These findings support heritable factors that contribute to the correlation between cognition and community functioning that are relatively specific to schizophrenia and are not significantly shared with depression or a lack of psychopathology. This suggests the possibility of identifying specific genetic variants that contribute to this correlation and to these important individual differences among schizophrenia patients. (PsycINFO Database Record