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Psychosis constitutes a cardinal component of schizophrenia and affects nearly fifty percent of those with bipolar disorder. We sought to molecularly characterize psychosis segregating in consanguineous families. Participants from eight multiplex families were evaluated using standardized testing tools. DNA was subjected to exome sequencing followed by Sanger sequencing. Effects of variants were modeled using in-silico tools, while cDNA from a patient’s blood sample was analyzed to evaluate the effect of a splice-site variant. Twelve patients in six families were diagnosed with schizophrenia, whereas four patients from two families had psychotic bipolar disorder. Two homozygous rare deleterious variants in INSR (c.2232-7T>G) and NFXL1 (c.1322G>A; p.Cys441Tyr) were identified, which segregated with severe treatment-resistant psychosis/schizophrenia in two families. There were none, or ambiguous findings in the other six families. The predicted deleterious missense variant affected a conserved amino acid, while the intronic variant was predicted to affect splicing. However, cDNA analysis from a patient’s blood sample did not reveal an aberrant transcript. Our results indicate that INSR and NFXL1 variants may have a role in psychosis that requires to be investigated further. Lack of molecular diagnosis in some patients suggests the need for genome sequencing to pinpoint the genetic causes.

Schizophrenia is characterized by hallucinations, delusions and disorganized behaviour. Recessive or X-linked transmissions are rarely described for common psychiatric disorders. We examined the genetics of psychosis to identify rare large-effect variants in patients with extreme schizophrenia. We recruited 2 consanguineous families, each with patients affected by early-onset, severe, treatment-resistant schizophrenia. We performed exome sequencing for all participants. We checked variant rarity in public databases and with ethnically matched controls. We performed in silico analyses to assess the effects of the variants on proteins. Structured clinical evaluations supported diagnoses of schizophrenia in all patients and phenotypic absence in the unaffected individuals. Data analyses identified multiple variants. Only 1 variant per family was predicted as pathogenic by prediction tools. A homozygous c.649C > T:p.(Arg217Cys) variant in RGS3 and a hemizygous c.700A > G:p.(Thr234Ala) variant in IL1RAPL1 affected evolutionary conserved amino acid residues and were the most likely causes of phenotype in the patients of each family. Variants were ultra-rare in publicly available databases and absent from the DNA of 400 ethnically matched controls. RGS3 is implicated in modulating sensory behaviour in Caenorhabditis elegans. Variants of IL1RAPL1 are known to cause nonsyndromic X-linked intellectual disability with or without human behavioural dysfunction. Each variant is unique to a particular family’s patients, and findings may not be replicated. Our work suggests that some rare variants may be involved in causing inherited psychosis or schizophrenia. Variant-specific functional studies will elucidate the pathophysiology relevant to schizophrenias and motivate translation to personalized therapeutics.

Background Psychiatric disorders are characterized by alteration in emotions, mood and behavior. Genetics is known to play a significant role in the development of psychiatric disorders. Genome-wide association studies have identified several loci associated with psychiatric illnesses. We hypothesize the existence of rare variants following Mendelian recessive mode of inheritance. These variants can be identified in families with multiple affected individuals born to unaffected consanguineous parents. Methods We visited psychiatric outpatient departments of multiple hospitals in Lahore, Pakistan. We focused on psychosis, as it can occur in several DSM disorders such as schizophrenia, dementia and bipolar disorder. After clinical diagnosis by an American trained psychiatrist, detailed clinical assessments using Diagnostic Interview for Genetic Studies (DIGS), Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD), Positive and Negative Syndrome Scale (PANSS), Hamilton Depression and Anxiety Rating Scale (HAM-D; HAM-A) were administered to all willing affected and unaffected participants. Results We identified eight pedigrees with two or more psychotic individuals in each family. Clinical diagnoses determined by their psychiatrists included ten individuals with schizophrenia; four individuals with psychosis and bipolar disorder; and two patients with “unspecified psychosis.” The rating instruments rigorously confirmed the diagnosis of psychosis in the affected patients from the six families as well as the absence of psychotic disorders in unaffected individuals from the six families. We obtained DNA samples from willing members of all eight families for future genetic analyses. Conclusion Our research highlights an alternative approach to discovery of rare recessively inherited genetic variants causing psychiatric disorders that have remained unidentified to date. These findings could illuminate underlying biological mechanisms leading toward development of targeted therapies in future.

Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)−5] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1–3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia.

ABSTRACT To assess iron overload, disturbed liver and hematological profile and secondary complications in β thalassemia major (BTM) patients, the current study was carried on 408 subjects including 204 patients and 204 controls. For all 408 individuals; complete blood count (CBC), blood group, serum ferritin level and liver function tests were performed. Secondary complications were assessed by physical examination of pallor, splenomegaly, ascites, and hepatomegaly. The average±SD values of patients' CBCs and liver enzymes were: red blood cells 3.07x 1012±0.769x 1012/L, white blood cells 8.89x 109±2.849x 109/L, hemoglobin 8.01± 1.027 g/dL, platelets 321.68x 109±1.027x 109/L, serum ferritin 2773.3±1071.9ng/mL, alanine transaminase 117.12±32.001U/L, aspartate transaminase 84.77±18.223U/L and bilirubin 1.02±0.139mg/dL. CBC of control group revealed that all of the studied parameters were normal in them and BTM patients showed significant deviation from control in both hematological and hepatic profile (P < 0.05). Examination for secondary complications revealed that Pallor sign was observed in 79.6% of patients, followed by splenomegaly (64.9%) and hepatomegaly (9%). As far as the control group is concerned no complication was found in that group. Current study provides sufficient evidence to justify advanced therapies to overcome secondary complications, iron overload, disturbed hepatic and hematological profile of patients and overall offers insight into improving the quality of treatment for β-thalassemia major patients.

The purpose of this study is to examine the relationship between renewable energy sources and sustainable economic growth of the South Asian Association for Regional Cooperation (SAARC) countries. This study uses three main renewable energy sources such as geothermal, hydro and wind. This study collects dataset from SAARC countries from 1995 to 2018. This study applies a fixed-effect test and panel vector error correction model (PVECM) test for data analysis. The overall results show that all three renewable energy sources have positively significant impacts on economic development among SAARC countries’ economies. Moreover, the hydropower renewable energy source has more effects and influences on economic growth as relatively compared with the rest of the two individual sources of renewable energy.

Purpose The particle distribution in a fluid is mostly not homogeneous. The inhomogeneous dispersion of solid particles affects the velocity profile as well as the heat transfer of fluid. This study aims to highlight the effects of varying density of particles in a fluid. The fluid flows through a wavy curved passage under an applied magnetic field. Heat transfer is discussed with variable thermal conductivity. Design/methodology/approach The mathematical model of the problem consists of coupled differential equations, simplified using stream functions. The results of the time flow rate for fluid and solid granules have been derived numerically. Findings The fluid and dust particle velocity profiles are being presented graphically to analyze the effects of density of solid particles, magnetohydrodynamics, curvature and slip parameters. Heat transfer analysis is also performed for magnetic parameter, density of dust particles, variable thermal conductivity, slip parameter and curvature. As the number of particles in the fluid increases, heat conduction becomes slow through the fluid. Increase in temperature distribution is noticed as variable thermal conductivity parameter grows. The discussion of variable thermal conductivity is of great concern as many biological treatments and optimization of thermal energy storage system’s performance require precise measurement of a heat transfer fluid’s thermal conductivity. Originality/value This study of heat transfer with inhomogeneous distribution of the particles in a fluid has not yet been reported.