TUDCA modulates drug bioavailability to regulate resistance to acute ER stress in .

Cells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA), has been described as a chemical chaperone.

Molecular basis of neurodegeneration in a mouse model of -related disease.

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of -related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of -related disease pathogenesis is unknown.

Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity.

Background: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts.

Molecular basis of neurodegeneration in a mouse model of -related disease.

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of -related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of -related disease pathogenesis is unknown.

"No One Manages It; We Just Sign Them Up and Do It": A Whole System Analysis of Access to Healthcare in One Remote Australian Community.

Objective: To assess the accessibility, availability and utilisation of a comprehensive range of community-based healthcare services for Aboriginal people and describe contributing factors to providing effective healthcare services from the provider perspective.

Setting: A remote community in New South Wales, Australia.

Participants: Aboriginal and non-Aboriginal health and education professionals performing various roles in healthcare provision in the community.

Defective myelination in an RNA polymerase III mutant leukodystrophic mouse.

RNA polymerase (Pol) III synthesizes abundant short noncoding RNAs that have essential functions in protein synthesis, secretion, and other processes. Despite the ubiquitous functions of these RNAs, mutations in Pol III subunits cause Pol III-related leukodystrophy, an early-onset neurodegenerative disease. The basis of this neural sensitivity and the mechanisms of disease pathogenesis are unknown.

Enablers and Barriers to Accessing Healthcare Services for Aboriginal People in New South Wales, Australia.

Background: Australia's healthcare system is complex and fragmented which can create challenges in healthcare, particularly in rural and remote areas. Aboriginal people experience inequalities in healthcare treatment and outcomes. This study aimed to investigate barriers and enablers to accessing healthcare services for Aboriginal people living in regional and remote Australia.

A graduate oral health therapist program to support dental service delivery and oral health promotion in Aboriginal communities in New South Wales, Australia.

Introduction: The early closure of the Voluntary Dental Graduate Year Program and the Oral Health Therapy Graduate Year Program by the Australian Government adversely impacted New South Wales (NSW) Aboriginal Community Controlled Health Services (ACCHSs). This led to the co-design of a small-scale oral health therapy graduate year program for ACCHSs known as the Dalang Project, which enabled oral health therapists to engage with local Aboriginal communities and implement culturally competent, practical and evidence-based oral health promotion activities. This article provides an overview of the Dalang Project and its evaluation.

Functional characterization of Polr3a hypomyelinating leukodystrophy mutations in the S. cerevisiae homolog, RPC160.

Mutations in RNA polymerase III (Pol III) cause hypomeylinating leukodystrophy (HLD) and neurodegeneration in humans. POLR3A and POLR3B, the two largest Pol III subunits, together form the catalytic center and carry the majority of disease alleles. Disease-causing mutations include invariant and highly conserved residues that are predicted to negatively affect Pol III activity and decrease transcriptional output.

MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse.

Maf1 mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined.

In Vivo Quasi-Elastic Light Scattering Eye Scanner Detects Molecular Aging in Humans.

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo.

Structural basis for RNA polymerase III transcription repression by Maf1.

Maf1 is a conserved inhibitor of RNA polymerase III (Pol III) that influences phenotypes ranging from metabolic efficiency to lifespan. Here, we present a 3.3-Å-resolution cryo-EM structure of yeast Maf1 bound to Pol III, establishing that Maf1 sequesters Pol III elements involved in transcription initiation and binds the mobile C34 winged helix 2 domain, sealing off the active site.

The oral health of Indigenous pregnant women: A mixed-methods systematic review.

Background: Western models of care to improve the oral health of pregnant women have been successfully implemented in the healthcare setting across various developed countries. Even though Indigenous women experience poorer pregnancy and birth outcomes compared to other women, these models have not been developed with Indigenous communities to address the oral health needs of Indigenous pregnant women. This review aimed to understand the oral health knowledge, practices, attitudes and challenges of Indigenous pregnant women globally.

The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis.

Recessive mutations in the ubiquitously expressed POLR3A and POLR3B genes are the most common cause of POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), a rare childhood-onset disorder characterized by deficient cerebral myelin formation and cerebellar atrophy. POLR3A and POLR3B encode the two catalytic subunits of RNA Polymerase III (Pol III), which synthesizes numerous small non-coding RNAs. We recently reported that mice homozygous for the Polr3a mutation c.

Low Evolutionary Selection Pressure in Senescence Does Not Explain the Persistence of Aβ in the Vertebrate Genome.

The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer's disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide's elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review if evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide's expression in senescence.

Annexin II Light Chain p11 Interacts With ENaC to Increase Functional Activity at the Membrane.

The epithelial Na channel (ENaC) provides for Na absorption in various types of epithelia including the kidney, lung, and colon where ENaC is localized to the apical membrane to enable Na entry into the cell. The degree of Na entry via ENaC largely depends on the number of active channels localized to the cell membrane, and is tightly controlled by interactions with ubiquitin ligases, kinases, and G-proteins. While regulation of ENaC endocytosis has been well-studied, relatively little is understood of the proteins that govern ENaC exocytosis.

Metabolic programming a lean phenotype by deregulation of RNA polymerase III.

As a master negative regulator of RNA polymerase (Pol) III, Maf1 modulates transcription in response to nutrients and stress to balance the production of highly abundant tRNAs, 5S rRNA, and other small noncoding RNAs with cell growth and maintenance. This regulation of Pol III transcription is important for energetic economy as mice lacking are lean and resist weight gain on normal and high fat diets. The lean phenotype of knockout (KO) mice is attributed in part to metabolic inefficiencies which increase the demand for cellular energy and elevate catabolic processes, including autophagy/lipophagy and lipolysis.

The antimicrobial protection hypothesis of Alzheimer's disease.

Objective: We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β-amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune-mediated inflammation propagates AD neurodegeneration.

Background: AD pathology is characterized by cerebral deposition of amyloid-β protein (Aβ) as β-amyloid.

Results of a two year dental health education program to reduce dental caries in young Aboriginal children in New South Wales, Australia.

Objective: To assess the effectiveness of a dental health education program, 'Smiles not Tears' in preventing Early Childhood Caries in young Aboriginal children.

Basic Research Design: Community trial.

Clinical Setting: Aboriginal Community Controlled Health Services in rural, remote and metropolitan areas in New South Wales, Australia.

Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.

Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities.

Enhanced Isotopic Ratio Outlier Analysis (IROA) Peak Detection and Identification with Ultra-High Resolution GC-Orbitrap/MS: Potential Application for Investigation of Model Organism Metabolomes.

Identifying non-annotated peaks may have a significant impact on the understanding of biological systems. In silico methodologies have focused on ESI LC/MS/MS for identifying non-annotated MS peaks. In this study, we employed in silico methodology to develop an Isotopic Ratio Outlier Analysis (IROA) workflow using enhanced mass spectrometric data acquired with the ultra-high resolution GC-Orbitrap/MS to determine the identity of non-annotated metabolites.

Signaling to and from the RNA Polymerase III Transcription and Processing Machinery.

RNA polymerase (Pol) III has a specialized role in transcribing the most abundant RNAs in eukaryotic cells, transfer RNAs (tRNAs), along with other ubiquitous small noncoding RNAs, many of which have functions related to the ribosome and protein synthesis. The high energetic cost of producing these RNAs and their central role in protein synthesis underlie the robust regulation of Pol III transcription in response to nutrients and stress by growth regulatory pathways. Downstream of Pol III, signaling impacts posttranscriptional processes affecting tRNA function in translation and tRNA cleavage into smaller fragments that are increasingly attributed with novel cellular activities.