Exploring dysfunctional barrier phenotypes associated with glaucoma using a human pluripotent stem cell-based model of the neurovascular unit.

Glaucoma is a neurodegenerative disease that results in the degeneration of retinal ganglion cells (RGCs) and subsequent loss of vision. While RGCs are the primary cell type affected in glaucoma, neighboring cell types selectively modulate RGCs to maintain overall homeostasis. Among these neighboring cell types, astrocytes, microvascular endothelial cells (MVECs), and pericytes coordinate with neurons to form the neurovascular unit that provides a physical barrier to limit the passage of toxic materials from the blood into neural tissue.

Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction.

The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants.

Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models.

Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression.

A highly reproducible and efficient method for retinal organoid differentiation from human pluripotent stem cells.

Human pluripotent stem cell (hPSC)-derived retinal organoids are three-dimensional cellular aggregates that differentiate and self-organize to closely mimic the spatial and temporal patterning of the developing human retina. Retinal organoid models serve as reliable tools for studying human retinogenesis, yet limitations in the efficiency and reproducibility of current retinal organoid differentiation protocols have reduced the use of these models for more high-throughput applications such as disease modeling and drug screening. To address these shortcomings, the current study aimed to standardize prior differentiation protocols to yield a highly reproducible and efficient method for generating retinal organoids.

Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.

Objective: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis.

Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of Aβ plaques and neurofibrillary tangles, resulting in synaptic loss and neurodegeneration. The retina is an extension of the central nervous system within the eye, sharing many structural similarities with the brain, and previous studies have observed AD-related phenotypes within the retina. Three-dimensional retinal organoids differentiated from human pluripotent stem cells (hPSCs) can effectively model some of the earliest manifestations of disease states, yet early AD-associated phenotypes have not yet been examined.

Modelling spatiotemporal dynamics of cerebral blood flow using multiple-timepoint arterial spin labelling MRI.

Cerebral blood flow (CBF) is an important physiological parameter that can be quantified non-invasively using arterial spin labelling (ASL) imaging. Although most ASL studies are based on single-timepoint strategies, multi-timepoint approaches (multiple-PLD) in combination with appropriate model fitting strategies may be beneficial not only to improve CBF quantification but also to retrieve other physiological information of interest. In this work, we tested several kinetic models for the fitting of multiple-PLD pCASL data in a group of 10 healthy subjects.

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism.

Background And Aims: There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.

Methods: Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks.

The influence of astrocytic leaflet motility on ionic signalling and homeostasis at active synapses.

Astrocytes display a highly complex, spongiform morphology, with their fine terminal processes (leaflets) exercising dynamic degrees of synaptic coverage, from touching and surrounding the synapse to being retracted from the synaptic region. In this paper, a computational model is used to reveal the effect of the astrocyte-synapse spatial relationship on ionic homeostasis. Specifically, our model predicts that varying degrees of astrocyte leaflet coverage influences concentrations of K, Na and Ca, and results show that leaflet motility strongly influences Ca uptake, as well as glutamate and K to a lesser extent.

Autophagy disruption reduces mTORC1 activation leading to retinal ganglion cell neurodegeneration associated with glaucoma.

Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs.

EFFECT OF AUTOGENOUS BONE GRAFT SITE ON DENTAL IMPLANT SURVIVAL AND DONOR SITE COMPLICATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Objectives: This systematic review and meta-analysis was undertaken to answer the following focus questions: Is the implant survival in augmented bone utilizing iliac crest bone grafts the same as while using intraoral autologous bone grafts? Is the incidence of postoperative donor site complications the same when using iliac crest bone grafts as opposed to intraoral grafts?

Methods: Systematic searches of electronic databases (PubMed, Embase, CENTRAL) were performed to identify studies which reported on implant survival and postoperative complications for dental implants placed in grafted partially/completely edentulous human jaws. Studies were included if: they reported on 2-piece micro-rough surface root form dental implants placed in bone-augmented completely or partially edentulous human jaws, and the jaws must have been augmented with autologous bone graft materials. Time and nature of postoperative complications must have been reported.

Image-based computer modeling assessment of microwave ablation for treatment of adrenal tumors.

Purpose: To assess the feasibility of delivering microwave ablation for targeted treatment of aldosterone producing adenomas using image-based computational models.

Methods: We curated an anonymized dataset of diagnostic C-metomidate PET/CT images of 14 patients with aldosterone producing adenomas (APA). A semi-automated approach was developed to segment the APA, adrenal gland, and adjacent organs within 2 cm of the APA boundary.

Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells.

Although the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls.

Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates.

A Computational Study of Astrocytic GABA Release at the Glutamatergic Synapse: EAAT-2 and GAT-3 Coupled Dynamics.

Neurotransmitter dynamics within neuronal synapses can be controlled by astrocytes and reflect key contributors to neuronal activity. In particular, Glutamate (Glu) released by activated neurons is predominantly removed from the synaptic space by perisynaptic astrocytic transporters EAAT-2 (GLT-1). In previous work, we showed that the time course of Glu transport is affected by ionic concentration gradients either side of the astrocytic membrane and has the propensity for influencing postsynaptic neuronal excitability.

Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids.

The development of the visual system involves the coordination of spatial and temporal events to specify the organization of varied cell types, including the elongation of axons from retinal ganglion cells (RGCs) to post-synaptic targets in the brain. Retinal organoids recapitulate many features of retinal development, yet have lacked downstream targets into which RGC axons extend, limiting the ability to model projections of the human visual system. To address these issues, retinal organoids were generated and organized into an in vitro assembloid model of the visual system with cortical and thalamic organoids.

Hardware acceleration of genomics data analysis: challenges and opportunities.

The significant decline in the cost of genome sequencing has dramatically changed the typical bioinformatics pipeline for analysing sequencing data. Where traditionally, the computational challenge of sequencing is now secondary to genomic data analysis. Short read alignment (SRA) is a ubiquitous process within every modern bioinformatics pipeline in the field of genomics and is often regarded as the principal computational bottleneck.

Why having a voice is important to children who are involved in family support services.

Background: Having a voice in family matters is considered a protective factor from harm, and key to promoting children's wellbeing. However, since the adoption of the United Nations Convention on the Rights of the Child (1989) and specifically Article 12 pertaining to children's participation, research reveals that children's voices often remain invisible in child protection and family welfare services.

Objective: While there is renewed interest in hearing children's voices about their experiences in out-of-home care, there remains little awareness and knowledge of children's voices in family support services.

Case Study-Spiking Neural Network Hardware System for Structural Health Monitoring.

This case study provides feasibility analysis of adapting Spiking Neural Networks (SNN) based Structural Health Monitoring (SHM) system to explore low-cost solution for inspection of structural health of damaged buildings which survived after natural disaster that is, earthquakes or similar activities. Various techniques are used to detect the structural health status of a building for performance benchmarking, including different feature extraction methods and classification techniques (e.g.

Assessing the impact of posture on diaphragm morphology and function using an open upright MRI system-A pilot study.

Purpose: The diaphragm is the most important muscle of respiration. Disorders of the diaphragm can have a deleterious impact on respiratory function. We aimed to evaluate the use of an open-configuration upright low-field MRI system to assess diaphragm morphology and function in patients with bilateral diaphragm weakness (BDW) and chronic obstructive pulmonary disease (COPD) with hyperinflation.

GABA Regulation of Burst Firing in Hippocampal Astrocyte Neural Circuit: A Biophysical Model.

It is now widely accepted that glia cells and gamma-aminobutyric acidergic (GABA) interneurons dynamically regulate synaptic transmission and neuronal activity in time and space. This paper presents a biophysical model that captures the interaction between an astrocyte cell, a GABA interneuron and pre/postsynaptic neurons. Specifically, GABA released from a GABA interneuron triggers in astrocytes the release of calcium ( ) from the endoplasmic reticulum via the inositol 1, 4, 5-trisphosphate ( ) pathway.

HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure.

Aims: To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium.

Methods And Results: Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5-13.

Calcium Microdomain Formation at the Perisynaptic Cradle Due to NCX Reversal: A Computational Study.

It has recently been proposed using a multi-compartmental mathematical model that negatively fixed charged membrane-associated sites constrain the flow of cations in perisynaptic astroglial processes. This restricted movement of ions between the perisynaptic cradle (PsC), principal astroglial processes and the astrocyte soma gives rise to potassium (K) and sodium (Na) microdomains at the PsC. The present paper extends the above model to demonstrate that the formation of an Na microdomain can reverse the Na/Ca exchanger (NCX) thus providing an additional source of calcium (Ca) at the PsC.

Low Cost Interconnected Architecture for the Hardware Spiking Neural Networks.

A novel low cost interconnected architecture (LCIA) is proposed in this paper, which is an efficient solution for the neuron interconnections for the hardware spiking neural networks (SNNs). It is based on an all-to-all connection that takes each paired input and output nodes of multi-layer SNNs as the source and destination of connections. The aim is to maintain an efficient routing performance under low hardware overhead.