Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.

Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.

Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease.

Virtual Education Program to Support Providers Caring for People With Intellectual and Developmental Disabilities During the COVID-19 Pandemic: Rapid Development and Evaluation Study.

Background: People with intellectual and developmental disabilities are at increased health-related risk due to the COVID-19 pandemic. Virtual training programs that support providers in caring for the physical and mental health needs of this population, as well provide psychological support to the providers themselves, are needed during the pandemic.

Objective: This paper describes the design, delivery, and evaluation of a virtual educational COVID-19-focused Extension for Community Healthcare Outcomes program to support providers during the COVID-19 pandemic in caring for the mental health of people with intellectual and developmental disabilities.

Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer's disease.

Cognitive decline in early-stage Alzheimer's disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years.

Similar Methanogenic Shift but Divergent Syntrophic Partners in Anaerobic Digesters Exposed to Direct versus Successive Ammonium Additions.

During anaerobic digestion (AD) of protein-rich wastewater, ammonium (NH) is released by amino acid degradation. High NH concentrations disturb the AD microbiome balance, leading to process impairments. The sensitivity of the AD microbiome to NH and the inhibition threshold depend on multiple parameters, especially the previous microbial acclimation to ammonium stress.

Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis.

Background: International asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective β-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective β-agonist in acute asthma.

Deorphanizing Caspase-3 and Caspase-9 Substrates In and Out of Apoptosis with Deep Substrate Profiling.

Caspases are a family of enzymes that regulate biological processes such as inflammation and programmed cell death, through proteolysis. For example, in the intrinsic pathway of apoptosis, cell death signaling involves cytochrome release from the mitochondria, which leads to the activation of caspase-9 and eventually the executioners caspase-3 and -7. One key step in our understanding of these proteases is to identify their respective protein substrates.

Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1.

Doublecortin-like kinase 1 (DCLK1) is an understudied bi-functional kinase with a proven role in tumour growth and development. However, the presence of tissue-specific spliced DCLK1 isoforms with distinct biological functions have challenged the development of effective strategies to understand the role of DCLK1 in oncogenesis. Recently, DCLK1-IN-1 was reported as a highly selective DCLK1 inhibitor, a powerful tool to dissect DCLK1 biological functions.

SORL1 mutation in a Greek family with Parkinson's disease and dementia.

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.

A Review of the Clinical Pharmacology of Pelacarsen: A Lipoprotein(a)-Lowering Agent.

Patients with genetically associated elevated lipoprotein(a) [Lp(a)] levels are at greater risk for coronary artery disease, heart attack, stroke, and peripheral arterial disease. To date, there are no US FDA-approved drug therapies that are designed to target Lp(a) with the goal of lowering the Lp(a) level in patients who have increased risk. The American College of Cardiology (ACC) has provided guidelines on how to use traditional lipid profiles to assess the risk of atherosclerotic cardiovascular disease (ASCVD); however, even with the emergence of statin add-on therapies such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, some populations with elevated Lp(a) biomarkers remain at an increased risk for cardiovascular (CV) disease.

Standing flank laparotomy for colic: 37 cases.

Background: Standing flank laparotomy can be an alternative to ventral midline laparotomy in horses with colic. Standing flank laparotomy avoids general anaesthesia, provides excellent access to some regions of the abdominopelvic cavity and costs less than ventral midline laparotomy.

Objective: To report a series of cases of peritoneal and intestinal diseases other than SC diseases managed with standing flank laparotomy.

Caspase-9 Activation of Procaspase-3 but Not Procaspase-6 Is Based on the Local Context of Cleavage Site Motifs and on Sequence.

Studying the interactions between a protease and its protein substrates at a molecular level is crucial for identifying the factors facilitating selection of particular proteolytic substrates and not others. These selection criteria include both the sequence and the local context of the substrate cleavage site where the active site of the protease initially binds and then performs proteolytic cleavage. Caspase-9, an initiator of the intrinsic apoptotic pathway, mediates activation of executioner procaspase-3 by cleavage of the intersubunit linker (ISL) at site IETD↓S.

Exogenous Introduction of Initiator and Executioner Caspases Results in Different Apoptotic Outcomes.

The balance of pro-apoptotic and pro-survival proteins defines a cell's fate. These processes are controlled through an interdependent and finely tuned protein network that enables survival or leads to apoptotic cell death. The caspase family of proteases is central to this apoptotic network, with initiator and executioner caspases, and their interaction partners, regulating and executing apoptosis.

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation.

The Amyloid-β Pathway in Alzheimer's Disease.

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics.

White matter abnormalities in active elite adult rugby players.

The recognition, diagnosis and management of mild traumatic brain injuries are difficult and confusing. It is unclear how the severity and number of injuries sustained relate to brain injuries, such as diffuse axonal injury, diffuse vascular injury and progressive neurodegeneration. Advances in neuroimaging techniques enable the investigation of neuropathologies associated with acute and long-term effects of injury.

Annular lipoatrophy of the ankle: Four new pediatric cases and a review of the literature.

Annular lipoatrophy of the ankle is a rare and unique acquired lipoatrophic panniculitis that mainly affects children. There is no consensus on treatment, and the long-term course is not well known. We present four new pediatric cases that contribute to the understanding of this rare disease.

Development of the Butterfly Agility Test.

Objectives: To develop a PPT that incorporates multiple components of athletic ability and to assess its reliability.

Design: Test-retest experimental design.

Setting: Indoor basketball court in southern Alabama, USA.

Effectiveness of booster BCG vaccination in preventing Covid-19 infection.

The evidence that BCG (bacille Calmette-Guerin) vaccine may increase the ability of the immune system to fight off pathogens other than tuberculosis has been studied in the past. This nonspecific immunity gained our interest, especially after initial reports of less cases in countries with universal BCG vaccination. In hopes of possible protective immunity, all staff of the Emirates International Hospital (United Arab Emirates) were offered a booster BCG vaccine in early March 2020.

Towards the translation of electroconductive organic materials for regeneration of neural tissues.

Carbon-based conductive and electroactive materials (e.g., derivatives of graphene, fullerenes, polypyrrole, polythiophene, polyaniline) have been studied since the 1970s for use in a broad range of applications.

Aducanumab: a new phase in therapeutic development for Alzheimer's disease?

On 7 June the FDA approved aducanumab, the first new drug for Alzheimer's disease in almost 20 years-and notably, the first drug with a putative disease-modifying mechanism for the treatment of this devastating disorder, namely the removal of β-amyloid (or Aβ) plaques from the brain.

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases.

Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs.