SON-dependent nuclear speckle rejuvenation alleviates proteinopathies.

Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as a pivotal membrane-less organelle responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON.

Sulforaphane prevents the reactivation of HIV-1 by suppressing NFκB signaling.

Despite more than 20 years of combination antiretroviral therapy (cART), complete eradication of HIV remains a daunting task. While cART has been very effective in limiting new cycles of infection and keeping viral load below detectable levels with partial restoration of immune functions, it cannot provide a cure. Evidently, the interruption of cART leads to a quick rebound of the viral load within a few weeks.

Impact of sequential capacity building on emergency department organisational flow during COVID-19 pandemic: a quasi-experimental study in a low-resource, tertiary care centre.

Introduction: A quasi-experimental study was conducted to estimate the impact of sequential emergency department (ED) capacity building interventions on key performance indicators such as patients' length of stay (LOS) and wait time (WT) during the COVID-19 pandemic. This was achieved through augmenting personnel education and head count, space restructuring and workflow reorganisation.

Setting And Participants: This study included 268 352 patients presenting from January 2019 to December 2020 at Indus Hospital and Health network Karachi, a philanthropic tertiary healthcare facility in a city of 20 million residents.

Multiple sclerosis in Kenya: Demographic and clinical characteristics of a registry cohort.

Background: Multiple Sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults. There is limited literature regarding the burden of MS in sub-Saharan Africa (SSA).

Objective: To describe the demographic and clinical characteristics of patients with MS (PwMS) presenting to a tertiary referral hospital in Nairobi.

Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments.

Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury.

Inter-hospital communication and transfer practices during COVID-19 Pandemic in Karachi, Pakistan. A brief overview.

Objective: To discuss the referral mechanisms established for safe and expeditious inter-facility transfer of COVID 19 positive patients to ensure their referrals through establishing proper communication channels.

Methods: Mobile phone and WhatsApp based groups, administrated by The Indus Hospital were established in April 2020. Through detailed reports and frequent communication, factors like bed and ventilator availability across these facilities are shared.

Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood.

Topoisomerase 1 inhibitor topotecan delays the disease progression in a mouse model of Huntington's disease.

Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan.

Environmental Enrichment Improves Behavioral Abnormalities in a Mouse Model of Angelman Syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder largely caused by the loss of function of maternally inherited UBE3A. UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood. Here, we demonstrate that rearing of AS mice in the enriched environment for prolonged period significantly improved their cognitive and motor dysfunction.

Deficiency of Ube3a in Huntington's disease mice brain increases aggregate load and accelerates disease pathology.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of CAG repeats in the gene encoding huntingtin. Mutant huntingtin undergoes proteolytic processing and its N-terminal fragment containing polyglutamine repeat accumulates as inclusion not only in nucleus but also in cytoplasm and neuronal processes. Here, we demonstrate that removal of ubiquitin ligase Ube3a selectively from HD mice brain resulted in accelerated disease phenotype and shorter lifespan in comparison with HD mice.