An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy

Regulation of the Arf6 Signal Transduction System at Excitatory Synapses

Archival abstract submitte

Detection of TEM and CTX-M Genes in Escherichia coli Isolated from Clinical Specimens at Tertiary Care Heart Hospital, Kathmandu, Nepal

Background: Antimicrobial resistance (AMR) among Gram-negative pathogens, predominantly ESBL-producing clinical isolates, are increasing worldwide. The main aim of this study was to determine the prevalence of ESBL-producing clinical isolates, their antibiogram, and the frequency of ESBL genes (blaTEM and blaCTX-M) in the clinical samples from patients. Methods: A total of 1065 clinical specimens from patients suspected of heart infections were collected between February and August 2019. Bacterial isolates were identified on colony morphology and biochemical properties. Thus, obtained clinical isolates were screened for antimicrobial susceptibility testing (AST) using modified Kirby–Bauer disk diffusion method, while ESBL producers were identified by using a combination disk diffusion method. ESBL positive isolates were further assessed using conventional polymerase chain reaction (PCR) to detect the ESBL genes blaTEM and blaCTX-M. Results: Out of 1065 clinical specimens, 17.8% (190/1065) showed bacterial growth. Among 190 bacterial isolates, 57.4% (109/190) were Gram-negative bacteria. Among 109 Gram-negative bacteria, 40.3% (44/109) were E. coli, and 30.2% (33/109) were K. pneumoniae. In AST, 57.7% (n = 63) Gram-negative bacterial isolates were resistant to ampicillin and 47.7% (n = 52) were resistant to nalidixic acid. Over half of the isolates (51.3%; 56/109) were multidrug resistant (MDR). Of 44 E. coli, 27.3% (12/44) were ESBL producers. Among ESBL producer E. coli isolates, 58.4% (7/12) tested positive for the blaCTX-M gene and 41.6% (5/12) tested positive for the blaTEM gene. Conclusion: Half of the Gram-negative bacteria in our study were MDR. Routine identification of an infectious agent followed by AST is critical to optimize the treatment and prevent antimicrobial resistance

COVID-19 and the World with Co-Morbidities of Heart Disease, Hypertension and Diabetes

Newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) pandemic has now spread across the globe in past few months while affecting 26 million people and leading to more than 0.85 million deaths as on 2nd September, 2020. Severity of SARS-CoV-2 infection increases in COVID-19 patients due to pre-existing health co-morbidities. This mini-review has focused on the three significant co-morbidities viz., heart disease, hypertension, and diabetes, which are posing high health concerns and increased mortality during this ongoing pandemic. The observed co-morbidities have been found to be associated with the increasing risk factors for SARS-CoV-2 infection and COVID-19 critical illness as well as to be associated positively with the worsening of the health condition of COVID-19 suffering individuals resulting in the high risk for mortality. SARS-CoV-2 enters host cell via angiotensin-converting enzyme 2 receptors. Regulation of crucial cardiovascular functions and metabolisms like blood pressure and sugar levels are being carried out by ACE2. This might be one of the reasons that contribute to the higher mortality in COVID-19 patients having co-morbidities. Clinical investigations have identified higher levels of creatinine, cardiac troponin I, alanine aminotransferase, NT-proBNP, creatine kinase, D-dimer, aspartate aminotransferase and lactate dehydrogenase in patients who have succumbed to death from COVID-19 as compared to recovered individuals. More investigations are required to identify the modes behind increased mortality in COVID-19 patients having co-morbidities of heart disease, hypertension, and diabetes. This will enable us to design and develop suitable therapeutic strategies for reducing the mortality. More attention and critical care need to be paid to such high risk patients suffering from co-morbidities during COVID-19 pandemic