Tarikul Islam

The melanocortin 4 receptor (MC4R) is a key component of the leptin–melanocortin system. Recent studies have started to expand our understanding of the role of MC4R beyond energy balance and sexual behaviour, exploring its potential influence on respiratory function, particularly in the context of obesity hypoventilation syndrome and obstructive sleep apnoea. The MC4R pathway is implicated in respiratory control. MC4R is expressed on the CO ₂ ‐sensing neurons of the retrotrapezoid nucleus, and activation of the MC4R ⁺ neurons in the retrotrapezoid nucleus augments the hypercapnic ventilatory response. MC4R is present at other sites of the neural respiratory network, where this receptor might also be involved in ventilatory control. The US Food and Drug Administration approved the MC4R agonist setmelanotide, which has been used effectively for the treatment of obesity involving the leptin–melanocortin pathway. Setmelanotide is also a promising treatment option for obesity hypoventilation syndrome and obstructive sleep apnoea, particularly in people with obesity caused by specific genetic disorders, including POMC , LEPR ^b , MC4R and other associated gene mutations. image

The neuromodulator dopamine plays a critical role in orchestrating behavior by signaling actions and rewards. Dopamine signaling in the hippocampus is necessary for the formation of long-term memories but the functional correlates, anatomical organization, and spatiotemporal scale of hippocampal dopamine release remain largely unknown. Using high-resolution, two-photon imaging of optical sensors in the hippocampus of male and female mice, we identified dopamine release in two closely apposed spatial domains. In pavlovian conditioning, there was no significant dopamine release in early training but over days to weeks of experience, dopamine transients appeared at rewards in the “deep” domain of CA1 (basal dendritic layer). Surprisingly these transients did not strongly encode reward. The act of stopping and licking, used to collect reward, was sufficient to produce deep dopamine transients even without the conditioned stimulus or reward. Similarly, hippocampal dopamine transients showed no reward prediction error at surprise rewards. In a spatial goal-directed task, deep dopamine domain transients at rewards persisted but dopamine ramps now appeared, ramping up in the superficial domain (cell body and apical dendrites) during reward approach while ramping down in the deep domain. Our results reveal anatomically segregated hippocampal dopamine release domains with dynamic signaling that is distinct from striatal dopamine. Rather than a unitary volume and function of dopamine, we identify multiple spatial domains and functional signals that likely play distinct and dissociable roles in hippocampal-dependent learning and memory.

TPO (Thyroid Peroxidase) is known to be one of the major genes involved in congenital hypothyroid patients with thyroid dyshormonogenesis. The present study aims to validate high-resolution melting (HRM) curve analysis as a substitute method for Sanger sequencing, focusing on the frequently observed non-synonymous mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in patients from Bangladesh. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood specimens were collected, and DNA was extracted followed by PCR and Sanger sequencing. Among the 36 specimens, 20 were pre-sequenced, and variants were characterized through Sanger sequencing. Following pre-sequencing, the 20 pre-sequenced specimens underwent real-time PCR-HRM curve analysis to determine the proper HRM condition for separating the three variations from the wild-type state into heterozygous and homozygous states. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method demonstrated a sensitivity and specificity of 100 percent in accurately discerning wild-type alleles from both homozygous and heterozygous states of c.1117G>T (23/36; 63.8%), c.1193G>C (30/36; 83.3%), and c.2173A>C (23/36; 63.8%) variants frequently encountered among 36 Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene variant detection. In conclusion, HRM-based molecular technique targeting variants c.1117G>T, c.1193G>C, and c.2173A>C could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.

Jellyfish (JF) are essential to marine ecosystems. However, JF that increases rapidly can have negative effects. On 3-4 August 2022, a significant JF (Lobonemoides robustus Stiasny, 1920) bloom was observed along Cox’s Bazar coast (from Najdirartek to Sabrang) in Bangladesh. The goal of the current investigation was to identify the fatty acids (FAs) and amino acids (AAs) of L. robustus. The AAs were determined using liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, while the FAs were determined using a gas chromatographic system with a flame ionisation detector. The most prevalent AA was glycine. The most common FA was linoleic acid (C18:3) (0.43%), followed by myristic acid (0.12%), cis-9-oleic acid (0.18%), gamma-linolenic acid (0.24%), and heptadecanoic acid (0.29%). Based on its AA and FA contents, L. robustus can be a great candidate for the potentially sustainable manufacture of nutraceutical, cosmeceutical, and biomedical natural products to improve health and well-being. In addition, the edible L. robustus could be exported to other countries, thus way it can play a major role in achieving a blue economy.

Thyroid Peroxidase ( TPO ) is known to be the major gene involved in Congenital hypothyroid patients with thyroid dyshormonogenesis. This present study aimed to establish high-resolution melting (HRM) curve analysis as a supplementary mutation detection approach of Sanger sequencing targeting commonly found mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in Bangladeshi patients. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood samples were collected, and genomic DNA was isolated for molecular techniques. Among the 36 specimens, 20 were pre-sequenced, and mutations were characterized through Sanger sequencing. The pre-sequenced specimens (n=20) were then subjected to real-time PCR-HRM curve analysis to get the appropriate HRM condition capable of differentiating heterozygous and homozygous states for the three mutations from the wild-type state. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method showed 100 percent sensitivity and specificity to distinguish wild-type alleles from homozygous or heterozygous states (c.1117G>T, c.1193G>C, and c.2173A>C) of alleles commonly found in Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene mutation. In conclusion, the established HRM-based molecular technique targeting c.1117G>T, c.1193G>C, and c.2173A>C mutations could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.

The disorder of thyroid gland development or thyroid dysgenesis accounts for 80–85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the TSHR gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR_368-764 protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR_368-764MT2 and MS438-TSHR_368-764MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR_368-764MT1 exhibited much more variations than TSHR_368-764WT and TSHR_368-764MT2, emphasizing a more damaging pattern in TSHR_368-764MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis.

The disorder of thyroid gland development or thyroid dysgenesis (TH) accounts for 80-85% cases of congenital hypothyroidism (CH). Hence, the understanding of molecular etiology of TH is prerequisite. Mutations in TSHR gene is mostly associated with thyroid dysgenesis, prevent or disrupt normal development of the gland. The current study detects two nonsynonymous mutations (p.Ser508Leu, p.Asp727Glu) in transmembrane (TM)-region (Exon 10) of TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, transmembrane (TM)-region of TSHR protein is modelled by homology modeling. Transmembrane (TM)-region of TSHR protein is targeted by small molecules thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants were envisaged by molecular docking and interactions. The binding affinity of wild type protein was much higher than the mutant cases for both of the ligands (MS437 and MS438). Molecular dynamics simulates dynamic behavior of wild type and mutant complexes. MS437-TSHR _368-764 MT2 and MS438-TSHR _368-764 MT1 show stable conformations in biological environments. Finally, PCA reveals structural and energy profile discrepancies. TSHR _368-764 MT1 exhibits much variations than TSHR _368-764 WT and TSHR _368-764 MT2, emphasizing more damaging pattern in TSHR _368-764 MT1. The study might be helpful to understand molecular etiology of thyroid dysgenesis (TH) exploring the mutational impact on TSHR protein to the interaction with agonists.

Self-grooming plays an essential role in hygiene maintenance, thermoregulation, and stress response. However, the neural populations involved in self-grooming remain largely unknown. The paraventricular hypothalamic nucleus (PVH) has been implicated in the regulation of self-grooming. Arginine vasopressin-producing neurons are among the major neuronal populations in the PVH (PVH^AVP), which play important roles in water homeostasis, blood pressure regulation, feeding, and stress response. Here, we report the critical role of PVH^AVP neurons in the induction of self-grooming. Optogenetic activation of PVH^AVP neurons immediately induced self-grooming in freely moving mice. Chemogenetic activation of these neurons also increased time spent self-grooming. In contrast, their chemogenetic inhibition significantly reduced naturally occurring self-grooming, suggesting that PVH^AVP-induced grooming has physiological relevance. Notably, optogenetic activation of PVH^AVP neurons triggered self-grooming over other adaptive behaviors, such as voracious feeding induced by fasting and social interaction with female mice. Thus, our study proposes the novel role of PVH^AVP neurons in regulating self-grooming behavior and, consequently, hygiene maintenance and stress response. Furthermore, uncontrolled activation of these neurons may be potentially relevant to diseases characterized by compulsive behaviors and impaired social interaction, such as autism, obsessive–compulsive disorder, and anorexia nervosa.

The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABA_A receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca²⁺ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks. Significance In mammals, the suprachiasmatic nucleus (SCN) functions as the master circadian clock to orchestrate multiple circadian biological rhythms in the body. Although almost all SCN neurons contain γ-aminobutyric acid (GABA) as a neurotransmitter, the physiological roles of GABA in the SCN network are poorly understood. We show that mice lacking GABA release specifically from arginine vasopressin (AVP)-producing neurons, one of the major neuron types in the SCN, retain an SCN that progresses normally at the clock gene level but fires aberrantly with bimodal rhythm. Accordingly, the mice demonstrate locomotor activity at inappropriate times with respect to the clock gene-based SCN clock. GABAergic transmission from AVP neurons may regulate SCN firing rhythm to modulate when SCN molecular clocks enable daily behavior.

Transfusion transmitted infections have remained a major deterrent to public health, particularly among the patients with transfusion-dependent Beta thalassemia in developing countries. Although proper donor selection through adoption of WHO-advised infection panel has lowered the rate of infections, the multi-transfused patients are not free of risk. In this study, we screened 148 transfusion-dependent Beta thalassemia patients to determine the frequency of Hepatitis C Virus (HCV), Hepatitis B Virus (HBV) and Human Immunodeficiency Virus (HIV) using the ELISA method. Among them, infected cases with HCV, HBV and HIV were 13.51%, 3.37% and 0%, respectively. Moreover, 2% of the patients were found to be co-infected with both HBV and HCV. The percentage of infections in the patients with frequent transfusion interval (≤30 days) was significantly higher (p < 0.0005) than that in the patients with less frequent transfusion intervals (>30 days). Immunochromatography (ICT)-based rapid test kits are usually used to screen and confirm these infections in the blood of the patients. However, ICT-based tests are not sensitive enough to detect the infections. So, a combination of both Nucleic Acid testing (NAT) and serological testing are suggested to significantly reduce the risk of viral infections during blood transfusion.