Structure of the human autophagy factor EPG5 and the molecular basis of its conserved mode of interaction with Atg8-family proteins.

The multi-step macroautophagy/autophagy process ends with the cargo-laden autophagosome fusing with the lysosome to deliver the materials to be degraded. The metazoan-specific autophagy factor EPG5 plays a crucial role in this step by enforcing fusion specificity and preventing mistargeting. How EPG5 exerts its critical function and how its deficiency leads to diverse phenotypes of the rare multi-system disorder Vici syndrome are not fully understood.

Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity.

The heterodimeric Rab3GAP complex is a guanine nucleotide exchange factor (GEF) for the Rab18 GTPase that regulates lipid droplet metabolism, ER-to-Golgi trafficking, secretion, and autophagy. Why both subunits of Rab3GAP are required for Rab18 GEF activity and the molecular basis of how Rab3GAP engages and activates its cognate substrate are unknown. Here we show that human Rab3GAP is conformationally flexible and potentially autoinhibited by the C-terminal domain of its Rab3GAP2 subunit.

Structure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A.

Phosphatidylinositol 4-kinase alpha (PI4KA) maintains the phosphatidylinositol 4-phosphate (PI4P) and phosphatidylserine pools of the plasma membrane. A key regulator of PI4KA is its association into a complex with TTC7 and FAM126 proteins. This complex can be regulated by the CNAβ1 isoform of the phosphatase calcineurin.

The Hong Kong version of Montreal Cognitive Assessment for the Visually Impaired (HKMoCA-VI): Proposed cut-off and cognitive functioning survey of visually impaired elderly in residential homes.

Background: Visual impairment has been strongly associated with the incidence of dementia. Appropriate cognitive screening for the elderly with visual impairment is crucial for early identification of dementia and its management. Due to challenges in processing visually presented stimuli among participants, the cut-off score of the Hong Kong version of the Montreal Cognitive Assessment for the Visually Impaired (HKMoCA-VI), also known as MoCA-BLIND or MoCA-22, was unknown.

Molecular basis for plasma membrane recruitment of PI4KA by EFR3.

The lipid kinase phosphatidylinositol 4 kinase III alpha (PI4KIIIa/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B.

Examining the longitudinal associations between activity limitations, instrumental supports and social participation in osteoarthritis: A CLSA population-based study.

Objective: In osteoarthritis (OA) research, disability is largely studied within the context of activities of daily living. Broader consequences for social participation are often overlooked. In prior work, instrumental supports received and their perceived availability were shown to play a role in the maintenance of social participation.

Molecular structures and function of the autophagosome-lysosome fusion machinery.

Macroautophagy (also known as autophagy) plays a pivotal role in maintaining cellular homeostasis. The terminal step of the multi-step autophagy degradation pathway involves fusion between the cargo-laden, double-membraned autophagosome and the lytic organelle lysosome/vacuole. Over the past decade, various core components of the molecular machinery that execute this critical terminal autophagy event have been identified.

Clinical effectiveness of mindfulness-based music therapy on improving emotional regulation in blind older women: A randomized controlled trial.

Background: This study aimed to investigate clinical effectiveness of a structured eight-week mindfulness-based music therapy (MBMT) program on improving mood regulation in older women with blindness. This investigation compared a MBMT group with a mindfulness intervention (MI) group and a control group.

Methods: Ninety-two older females with blindness from a residential setting in Hong Kong were recruited and randomly allocated to a MBMT ( = 31), MI ( = 30), or control ( = 31) group.

Novel Genetic and Phenotypic Expansion in -Related Progressive Myoclonus Epilepsy.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene () have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a -related disorder and novel genetic and clinical findings.

Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.

PI3Kγ is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCβ activated by the IgE receptor, and Gβγ subunits released from activated GPCRs. PI3Kγ can form two distinct complexes, with the p110γ catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here, using a combination of cryo electron microscopy, HDX-MS, and biochemical assays, we have identified novel roles of the helical domain of p110γ in regulating lipid kinase activity of distinct PI3Kγ complexes.

Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.

PI3Kγ is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCβ activated by the IgE receptor, and Gβγ subunits released from activated GPCRs. PI3Kγ can form two distinct complexes, with the p110γ catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here using a combination of cryo electron microscopy, HDX-MS, and biochemical assays we have identified novel roles of the helical domain of p110γ in regulating lipid kinase activity of distinct PI3Kγ complexes.

Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs.

Class IB phosphoinositide 3-kinase (PI3Kγ) is activated in immune cells and can form two distinct complexes (p110γ-p84 and p110γ-p101), which are differentially activated by G protein-coupled receptors (GPCRs) and Ras. Using a combination of X-ray crystallography, hydrogen deuterium exchange mass spectrometry (HDX-MS), electron microscopy, molecular modeling, single-molecule imaging, and activity assays, we identify molecular differences between p110γ-p84 and p110γ-p101 that explain their differential membrane recruitment and activation by Ras and GPCRs. The p110γ-p84 complex is dynamic compared with p110γ-p101.

A Comprehensive Assessment Protocol for Swallowing (CAPS): Paving the Way towards Computer-Aided Dysphagia Screening.

Dysphagia is one of the most common problems among older adults, which might lead to aspiration pneumonia and eventual death. It calls for a feasible, reliable, and standardized screening or assessment method to prompt rehabilitation measures and mitigate the risks of dysphagia complications. Computer-aided screening using wearable technology could be the solution to the problem but is not clinically applicable because of the heterogeneity of assessment protocols.

Swallow Detection with Acoustics and Accelerometric-Based Wearable Technology: A Scoping Review.

Swallowing disorders, especially dysphagia, might lead to malnutrition and dehydration and could potentially lead to fatal aspiration. Benchmark swallowing assessments, such as videofluoroscopy or endoscopy, are expensive and invasive. Wearable technologies using acoustics and accelerometric sensors could offer opportunities for accessible and home-based long-term assessment.

Rational Generation of Monoclonal Antibodies Selective for Pathogenic Forms of Alpha-Synuclein.

Misfolded toxic forms of alpha-synuclein (α-Syn) have been implicated in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The α-Syn oligomers and soluble fibrils have been shown to mediate neurotoxicity and cell-to-cell propagation of pathology. To generate antibodies capable of selectively targeting pathogenic forms of α-Syn, computational modeling was used to predict conformational epitopes likely to become exposed on oligomers and small soluble fibrils, but not on monomers or fully formed insoluble fibrils.

A balancing act: interactions within NuA4/TIP60 regulate picNuA4 function in Saccharomyces cerevisiae and humans.

The NuA4 lysine acetyltransferase complex acetylates histone and nonhistone proteins and functions in transcription regulation, cell cycle progression, and DNA repair. NuA4 harbors an interesting duality in that its catalytic module can function independently and distinctly as picNuA4. At the molecular level, picNuA4 anchors to its bigger brother via physical interactions between the C-terminus of Epl1 and the HSA domain of Eaf1, the NuA4 central scaffolding subunit.

Conformational landscape of the yeast SAGA complex as revealed by cryo-EM.

Spt-Ada-Gcn5-Acetyltransferase (SAGA) is a conserved multi-subunit complex that activates RNA polymerase II-mediated transcription by acetylating and deubiquitinating nucleosomal histones and by recruiting TATA box binding protein (TBP) to DNA. The prototypical yeast Saccharomyces cerevisiae SAGA contains 19 subunits that are organized into Tra1, core, histone acetyltransferase, and deubiquitination modules. Recent cryo-electron microscopy studies have generated high-resolution structural information on the Tra1 and core modules of yeast SAGA.

Predictors of response following standardized education and self-management recommendations for low back pain stratified by dominant pain location.

Background: Low back pain (LBP) is a leading cause of disability globally. Risk-stratification systems (e.g.

Biochemical and Structural Characterization of Human Core Elongator and Its Subassemblies.

Conserved from yeast to humans and composed of six core subunits (Elp1-Elp6), Elongator is a multiprotein complex that catalyzes the modification of the anticodon loop of transfer RNAs (tRNAs) and in turn regulates messenger RNA decoding efficiency. Previous studies showed that yeast Elongator consists of two subassemblies (yElp1/2/3 and yElp4/5/6) and adopts an asymmetric overall architecture. Yet, much less is known about the structural properties of the orthologous human Elongator.

Cardiovascular Risk Profile and Osteoarthritis-Considering Sex and Multisite Joint Involvement: A Canadian Longitudinal Study on Aging.

Objective: The objective of this study was to investigate a profile of cardiovascular disease (CVD) risk factors by sex among individuals with and without osteoarthritis (OA) and to consider single-site and multisite joint OA.

Methods: Data were sourced from Cycle 1, Comprehensive Cohort, Canadian Longitudinal Study on Aging, a national sample of individuals ages 45 to 85 years. Systemic inflammatory/metabolic CVD risk factors collected were high-sensitivity C-reactive protein (hsCRP) level, high-density lipoprotein, triglycerides, total cholesterol, body mass index (BMI), systolic blood pressure, and hemoglobin A1c.

Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation.

The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein-coupled receptors. Here, we report the cryo-electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-p101.

HDX-MS-optimized approach to characterize nanobodies as tools for biochemical and structural studies of class IB phosphoinositide 3-kinases.

There is considerable interest in developing antibodies as modulators of signaling pathways. One of the most important signaling pathways in higher eukaryotes is the phosphoinositide 3-kinase (PI3K) pathway, which plays fundamental roles in growth, metabolism, and immunity. The class IB PI3K, PI3Kγ, is a heterodimeric complex composed of a catalytic p110γ subunit bound to a p101 or p84 regulatory subunit.