Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort.

Background And Aims: Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3.

Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene Associated with Reduced Migraine Risk.

Dysfunction in ion channels or processes involved in maintaining ionic homeostasis is thought to lower the threshold for cortical spreading depression (CSD), and plays a role in susceptibility to associated neurological disorders, including pathogenesis of a migraine. Rare pathogenic variants in specific ion channels have been implicated in monogenic migraine subtypes. In this study, we further examined the channelopathic nature of a migraine through the analysis of common genetic variants in three selected ion channel or transporter genes: , , and .

Heparan sulfate proteoglycans: Mediators of cellular and molecular Alzheimer's disease pathogenic factors via tunnelling nanotubes?

Neurological disorders impact around one billion individuals globally (15 % approx.), with significant implications for disability and mortality with their impact in Australia currently amounts to 6.8 million deaths annually.

CpG methylation changes in human mesenchymal and neural stem cells in response to in vitro niche modifications.

Stem cell therapies hold promise in addressing the burden of neurodegenerative diseases with human embryonic neural stem cells (hNSC-H9s) and bone marrow-derived human mesenchymal stem cells (hMSCs) as viable candidates. The induction of hMSC neurospheres (hMSC-IN) generate a more lineage-restricted common neural progenitor-like cell population, potentially tunable by heparan sulfate proteoglycans (HSPGs). We examined CpG (5 mC) site methylation patterns using Illumina Infinium 850 K EPIC arrays in hNSC-H9, hMSCs and hMSC-IN cultures with HSPG agonist heparin at early and late phases of growth.

Improving the strategy to identify historical military remains: a literature review and Y-STR meta-analysis.

Unlabelled: The identification of historical military remains by Unrecovered War Casualties-Army (UWC-A) currently relies on Y-chromosome Short Tandem Repeat (Y-STR) testing when maternal relatives are not available, or when a mitochondrial DNA match does not provide sufficient certainty of identification. However, common Y-STR profiles (using Yfiler™) between sets of remains or families often prevent identification. To resolve these cases, an investigation of additional Y-DNA markers is needed for their potential inclusion into the DNA identification strategy.

Exploring Heparan Sulfate Proteoglycans as Mediators of Human Mesenchymal Stem Cell Neurogenesis.

Alzheimer's disease (AD) and traumatic brain injury (TBI) are major public health issues worldwide, with over 38 million people living with AD and approximately 48 million people (27-69 million) experiencing TBI annually. Neurodegenerative conditions are characterised by the accumulation of neurotoxic amyloid beta (Aβ) and microtubule-associated protein Tau (Tau) with current treatments focused on managing symptoms rather than addressing the underlying cause. Heparan sulfate proteoglycans (HSPGs) are a diverse family of macromolecules that interact with various proteins and ligands and promote neurogenesis, a process where new neural cells are formed from stem cells.

The effects of OPRM1 118A>G on methadone response in pain management in advanced cancer at end of life.

Cancer pain is the most feared symptom at end of life. Methadone has advantages over other opioids but is associated with significant variability in clinical response, making dosing challenging in practice. OPRM1 is the most studied pharmacogene associated with the pharmacodynamics of opioids, however reports on the association of the A118G polymorphism on opioid dose requirements are conflicting, with no reports including methadone as the primary intervention.

Association Study of a Comprehensive Panel of Neuropeptide-Related Polymorphisms Suggest Potential Roles in Verbal Learning and Memory.

Neuropeptides are mostly expressed in regions of the brain responsible for learning and memory and are centrally involved in cognitive pathways. The majority of neuropeptide research has been performed in animal models; with acknowledged differences between species, more research into the role of neuropeptides in humans is necessary to understand their contribution to higher cognitive function. In this study, we investigated the influence of genetic polymorphisms in neuropeptide genes on verbal learning and memory.

Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.

Background: Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication.

Exploring the Functional Basis of Epigenetic Aging in Relation to Body Fat Phenotypes in the Norfolk Island Cohort.

DNA methylation is an epigenetic factor that is modifiable and can change over a lifespan. While many studies have identified methylation sites (CpGs) related to aging, the relationship of these to gene function and age-related disease phenotypes remains unclear. This research explores this question by testing for the conjoint association of age-related CpGs with gene expression and the relation of these to body fat phenotypes.

Sex differences in muscle protein expression and DNA methylation in response to exercise training.

Background: Exercise training elicits changes in muscle physiology, epigenomics, transcriptomics, and proteomics, with males and females exhibiting differing physiological responses to exercise training. However, the molecular mechanisms contributing to the differing adaptations between the sexes are poorly understood.

Methods: We performed a meta-analysis for sex differences in skeletal muscle DNA methylation following an endurance training intervention (Gene SMART cohort and E-MTAB-11282 cohort).

Exonic mutations in cell-cell adhesion may contribute to CADASIL-related CSVD pathology.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15-23% of individuals clinically suspected of CADASIL have mutations in NOTCH3.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown.

Diagnosing sepsis in the ICU: Comparison of a gene expression signature to pre-existing biomarkers.

Purpose: We aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers.

Methods: 91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers.

GSTM1 and GSTT1 polymorphisms associated with pain in a chemotherapy-induced peripheral neuropathy cohort.

Purpose: Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN.

MicroRNA-Target Identification: A Combinatorial In Silico Approach.

Contemporary computational target prediction tools with their distinctive properties and stringency have been playing a vital role in pursuing putative targets for a solitary miRNA or a subcategory of miRNAs. These tools utilize a defined set of probabilistic algorithms, machine learning techniques, and information of experimentally validated miRNA targets to provide the best selection. However, there are numerous false-positive predictions, and a method to choose an archetypal approach and put the data provided by the prediction tools into context is still lacking.

Data on 2D culture characterisation of potential markers in human HER2-positive breast cancer cell lines.

To obtain this dataset, two human HER2-positive breast cancer cell lines (SKBR3 and MDA-MB-453 cell lines) were cultured in basal growth media to 80% confluence. Cells were passaged and total RNA extracted, RNA converted to cDNA and diluted to a working concentration of 40 ng/µL. Gene expression panels of cancer markers including Fibroblast growth factors (), FGF receptors (), cyclin-dependent kinases, cytokeratins, and WNT pathway components were then examined using Q-PCR.

Global reported impacts of COVID-19 on lymphoma patients and the emerging clinical management approaches in response to the ongoing pandemic.

The Coronavirus disease 2019 (COVID-19) pandemic has dramatically impacted the health risk and management of patients with lymphoma. Clinical evaluations on the impact of COVID-19 on lymphoma patients are currently limited however, reports have shown a correlation with specific variants and more severe COVID-19 complications and higher mortality rates relative to other disease states and age-matched populations. During peak pandemic periods this created a concerning management problem for clinicians and raised the question of how different immunocompromised states increase COVID-19-associated risk and provided insights into how immunity interacts with the circulating variant, including the effects of low virulent variants in vaccinated lymphoma populations.

Exploring the Potential of PEG-Heparin Hydrogels to Support Long-Term Ex Vivo Culture of Patient-Derived Breast Explant Tissues.

Breast cancer is a complex, highly heterogenous, and dynamic disease and the leading cause of cancer-related death in women worldwide. Evaluation of the heterogeneity of breast cancer and its various subtypes is crucial to identify novel treatment strategies that can overcome the limitations of currently available options. Explant cultures of human mammary tissue have been known to provide important insights for the study of breast cancer structure and phenotype as they include the context of the surrounding microenvironment, allowing for the comprehensive exploration of patient heterogeneity.

Syndecan-4 regulates the HER2-positive breast cancer cell proliferation cells via CK19/AKT signalling.

Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20-30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation.

An Alzheimer's Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition.

An early symptom of Alzheimer's disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways.

Investigating a Genetic Link Between Alzheimer's Disease and CADASIL-Related Cerebral Small Vessel Disease.

Monogenic forms of Alzheimer's disease (AD) have been identified through mutations in genes such as APP, PSEN1, and PSEN2, whilst other genetic markers such as the APOE ε carrier allele status have been shown to increase the likelihood of having the disease. Mutations in these genes are not limited to AD, as APP mutations can also cause an amyloid form of cerebral small vessel disease (CSVD) known as cerebral amyloid angiopathy, whilst PSEN1 and PSEN2 are involved in NOTCH3 signalling, a process known to be dysregulated in the monogenic CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The overlap between AD genes and causes of CSVD led to the hypothesis that mutations in other genes within the PANTHER AD-presenilin pathway may be novel causes of CSVD in a cohort of clinically suspicious CADASIL patients without a pathogenic NOTCH3 mutation.

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk.

In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair.

Investigation of Cav3.3 Dysfunction in Hemiplegic Migraine.

Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, , , and , have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the gene encoding the T-type calcium channel Cav3.