The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.

While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity.

Posttranscriptional Regulation of Gcr1 Expression and Activity Is Crucial for Metabolic Adjustment in Response to Glucose Availability.

The transcription factor Gcr1 controls expression of over 75% of the genes in actively growing yeast. Yet despite its widespread effects, regulation of Gcr1 itself remains poorly understood. Here, we show that posttranscriptional Gcr1 regulation is nutrient dependent. Moreover, GCR1 RNA contains a long, highly conserved intron, which allows the cell to generate multiple RNA and protein isoforms whose levels change upon glucose depletion. Intriguingly, an isoform generated by intron retention is exported from the nucleus, and its translation is initiated from a conserved, intronic translation start site. Expression of gene products from both the spliced and unspliced RNAs is essential, as cells expressing only one isoform cannot adjust their metabolic program in response to environmental changes. Finally, we show that the Gcr1 proteins form dimers, providing an elegant mechanism by which this one gene, through its regulation, can perform the repertoire of transcriptional activities necessary for fine-tuned environmental response.

The Global Leadership Mentoring Community: An evaluation of its impact on nursing leadership.

AIM: To evaluate a year-long mentorship program, pairing nurses from different regions across the world to support their global leadership capability, and identifying additional consequences of their participation. BACKGROUND: Investment in developing nurse leaders continues as a strategic global imperative. Building on the first cohort's recommendations, this second program illustrates continued progress. PROGRAM EVALUATION: Using the logic model of program evaluation, this non-empirical paper uses data collected from anonymized questionnaires and participants' stories to help improve the program, illustrating innovative practices to develop the confidence and competence of emerging and established nurse leaders globally. DISCUSSION: The value of mentorship was recognized, and there were gains for both mentors and mentees in the development of leadership confidence and competence. Through engagement and collaboration with the whole community, participants were encouraged to understand their own and others' cultures avoiding assumptions and stereotypes. CONCLUSION: This evaluation illustrates that in addition to helping improve future programs, mentorship has enabled the growth of individuals' skill sets and the confidence to reach out to peers across the world to understand the meaning of global health and to make a meaningful contribution to the challenges they face. IMPLICATIONS FOR NURSING PRACTICE: Nurse managers should be encouraged to develop and formalize a mentoring culture to benefit the leadership competence and well-being of their workforce. IMPLICATIONS FOR NURSING POLICY: Every nurse has a responsibility to invest in nursing leadership for themselves and others. Mentorship can assist nurse leaders to build workforce capability to lead and contribute to the policy agenda locally, nationally, and internationally. Starting early and at the individual level, global mentorship programs can develop leadership expertise to help nurses find their voice and strengthen their confidence and competence to lead and therefore build the strategic leaders of the future.

Exploring neuropeptide signalling through proteomics and peptidomics.

INTRODUCTION: Neuropeptides are neuro-endocrine signaling molecules capable of signaling as neurotransmitters, neuromodulators or neurohormones. Studying how neuropeptide signaling is integrated in endocrine pathways and how neuropeptides regulate endogenous processes is crucial to understanding how multicellular organisms respond to environmental and internal cues. Areas covered: This review will cover proteomics and peptidomics approaches used in researching peptide signaling systems and breakthroughs that were achieved in this field. Both differential mass spectrometry and reverse genetic approaches are commonly used to study neuropeptidergic signaling. The field of proteomics quickly developed in the past decades and expanded from gel-based approaches to include advanced liquid chromatography and mass spectrometry. We explore how proteomics is used to reveal neuropeptide maturation and identify downstream targets of neuropeptide signaling pathways. We show how peptidomics differs from standard proteomics approaches and how it is used to study both neuropeptide processing and signal pathway identification. Expert commentary: Thanks to recent advancements in isolation techniques and increased sensitivity of equipment, proteomics and peptidomics studies of neuropeptide signaling are contributing increasingly to elucidating functional implications of endocrine signaling. Further technical progress should allow for full peptidomic profiling of single neurons, eventually providing us with a complete comprehension of endocrine signaling.

Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening.

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ2=16.98, P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (χ2=0.21, P=0.644), and more tested (76.0%) than not-tested (66.7%) women (χ2=6.35, P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not-tested than tested women (uncertainty: χ2=18.51, P<0.001 and χ2=43.11, P<0.001, respectively; regret: χ2=6.61, P<0.037 and χ2=35.54, P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling.

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

Genetic Counselling Needs for Reproductive Genetic Carrier Screening: A Scoping Review.

Reproductive genetic carrier screening provides individuals and couples with information regarding their risk of having a child affected by an autosomal recessive or X-linked recessive genetic condition. This information allows them the opportunity to make reproductive decisions in line with their own beliefs and values. Traditionally, carrier screening has been accessed by family members of affected individuals. In recent years, improvements to accessibility and updates to recommendations suggest that all women planning or in early pregnancy should be offered reproductive genetic carrier screening. As uptake moves towards the population scale, how can the genetic counselling needs of such large-scale screening be met? A scoping review of the literature was performed to ascertain what the genetic counselling needs of reproductive genetic carrier screening are, and what future research is needed. Four broad themes were identified in the existing literature: (1) The offer-when and in what context to offer screening; (2) Information-the importance of and what to include in education, and pre- and post-test counselling; (3) Who and how-who the genetic counselling is performed by and how; (4) Personalization-how do we find the balance between standardized and individualized approaches? Based on the existing literature, we present a set of recommendations for consideration in implementing population-scale reproductive genetic carrier screening as well as suggested areas for future research.

The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission): Design and Implementation.

Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie's Mission­the Australian Reproductive Genetic Carrier Screening Project. Mackenzie's Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

Gene selection for the Australian Reproductive Genetic Carrier Screening Project ("Mackenzie's Mission").

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for gene-phenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement.

Frequency and prevalence of obesity and related comorbidities in West Texas.

The aim of this cross-sectional study was to estimate the frequency and prevalence of obesity and its association with diabetes mellitus, systemic hypertension, hyperlipidemia, coronary artery disease, myocardial infarction, and obstructive sleep apnea in West Texas adults. Data were extracted from 9528 clinic patients: 2287 (24.4%) were normal weight or underweight, and 7057 (75.5%) were overweight or obese (28.9% and 46.6%, respectively). We observed a lower prevalence of any degree of obesity in men compared to women (43.8% vs 48.6%). Diabetes mellitus (odds ratio [OR] = 2.56; 95% confidence interval [CI], 2.30-2.85), hypertension (OR = 2.28; 95% CI, 2.06-2.53), hyperlipidemia (OR = 1.90; 95% CI, 1.71-2.10), and obstructive sleep apnea (OR = 7.18; 95% CI, 5.84-8.83) were associated with obesity. The association of coronary artery disease (OR = 1.17; 95% CI, 1.03-1.33) with obesity was small, and myocardial infarction did not show any association with weight status. The frequency and prevalence of obesity are progressively increasing in West Texas adults and are linked to significant comorbidities, especially in low-income areas. Access to preventive interventions and further investigations are needed to slow the rising prevalence of obesity and its comorbidities.

The Impact of Next-Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorders.

The impact of high-throughput sequencing in genetic neuromuscular disorders cannot be overstated. The ability to rapidly and affordably sequence multiple genes simultaneously has enabled a second golden age of Mendelian disease gene discovery, with flow-on impacts for rapid genetic diagnosis, evidence-based treatment, tailored therapy development, carrier-screening, and prevention of disease recurrence in families. However, there are likely many more neuromuscular disease genes and mechanisms to be discovered. Many patients and families remain without a molecular diagnosis following targeted panel sequencing, clinical exome sequencing, or even genome sequencing. Here we review how massively parallel, or next-generation, sequencing has changed the field of genetic neuromuscular disorders, and anticipate future benefits of recent technological innovations such as RNA-seq implementation and detection of tandem repeat expansions from short-read sequencing.

Tumor-associated antigens and their antibodies in the screening, diagnosis, and monitoring of esophageal cancers.

Despite the advances in the treatment and management, esophageal cancers continue to carry a dismal prognosis with an overall 5-year survival rate ranging from 15 to 25%. Delayed onset of symptoms and lack of effective screening methods and guidelines for diagnosis of the early disease contribute to the high mortality rate of esophageal cancers. Detection of esophageal cancer at their early stage is really a challenge for physicians including primary care physicians, gastroenterologists and oncologists. Although imaging, endoscopy and biopsy have been proved to be useful diagnostic tools for esophageal cancers, their diagnostic accuracy is unsatisfactory. In addition, expensive costs, invasiveness and special training operator have limited the clinical application of these tools. Recently, tumor-associated antigens (TAAs) and their antibodies have been reported to be potential markers in esophageal cancer screening, diagnosis, monitoring and prognostication. Because TAAs and their antibodies have the advantages of inexpensive cost, noninvasiveness and easy access, they have attracted much attention as an affordable option for early esophageal cancer diagnosis. In this review, we summarized the advances in TAAs and their antibodies in esophageal cancer screening, diagnosis, monitoring and prognostication.

Study protocol of a multicentre cohort pilot study implementing an expanded preconception carrier-screening programme in metropolitan and regional Western Australia.

INTRODUCTION: Preconception carrier screening (PCS) identifies couples at risk of having children with recessive genetic conditions. New technologies have enabled affordable sequencing for multiple disorders simultaneously, including identifying carrier status for many recessive diseases. The aim of the study was to identify the most effective way of delivering PCS in Western Australia (WA) through the public health system. METHODS AND ANALYSIS: This is a multicentre cohort pilot study of 250 couples who have used PCS, conducted at three sites: (1) Genetic Services of Western Australia, (2) a private genetic counselling practice in Perth and (3) participating general practice group practices in the Busselton region of WA. The primary outcome of the pilot study was to evaluate the feasibility of implementing the comprehensive PCS programme in the WA healthcare system. Secondary outcome measures included evaluation of the psychosocial impact of couples, such as reproductive autonomy; identification of areas within the health system that had difficulties in implementing the programme and evaluation of tools developed during the study. ETHICS AND DISSEMINATION: Approval was provided by the Women and Newborn Health Service Human Research Ethics Committee (HREC) at King Edward Memorial Hospital for Women (RGS0000000946) and the University of Western Australia (UWA) HREC (RA/4/20/4258). Participants may choose to withdraw at any time. Withdrawal will in no way affect participating couples' medical care. Study couples will be redirected to another participating health professional for consultation or counselling in the event of a health professional withdrawing. All evaluation data will be deidentified and stored in a password-protected database in UWA. In addition, all hard copy data collected will be kept in a locked cabinet within a secure building. All electronic data will be stored in a password-protected, backed-up location in the UWA Institutional Research Data Store. All evaluative results will be published as separate manuscripts, and selected results will be presented at conferences.

Clinical, social and ethical issues associated with non-invasive prenatal testing for aneuploidy.

Non-invasive prenatal testing (NIPT), based on analysis of cell-free foetal DNA, is rapidly becoming a preferred method to screen for chromosomal aneuploidy with the technology now available in over 90 countries. This review provides an up-to-date discussion of the key clinical, social and ethical implications associated with this revolutionary technology. Stakeholders are positive about a test that is highly accurate, safe, can be perfomed early in pregnancy, identifies affected pregnancies that might otherwise have been missed and reduces the need for invasive testing. Nevertheless, professional societies currently recommend it as an advanced screening test due to the low false positive rate (FPR). Despite the practical and psychological benefits, a number of concerns have been raised which warrant attention. These include the potential for routinisation of testing and subsequent impact on informed decision-making, an "easy" blood test inadvertently contributing to women feeling pressured to take the test, fears NIPT will lead to less tolerance and support for those living with Down syndrome and the heightened expectation of having "perfect babies". These issues can be addressed to some extent through clinician education, patient information and establishing national and international consensus in the development of comprehensive and regularly updated guidelines. As the number of conditions we are able to test for non-invasively expands it will be increasingly important to ensure pre-test counselling can be delivered effectively supported by knowledgeable healthcare professionals.

Identification of Endogenous Neuropeptides in the Nematode C. elegans Using Mass Spectrometry.

The nematode Caenorhabditis elegans lends itself as an excellent model organism for peptidomics studies. Its ease of cultivation and quick generation time make it suitable for high-throughput studies. Adult hermaphrodites contain 959 somatic nuclei that are ordered in defined, differentiated tissues. The nervous system, with its 302 neurons, is probably the most known and studied endocrine tissue. Moreover, its neuropeptidergic signaling pathways display a large number of similarities with those observed in other metazoans. However, various other tissues have also been shown to express several neuropeptides. This includes the hypodermis, gonad, gut, and even muscle. Hence, whole mount peptidomics of C. elegans cultures provides an integral overview of peptidergic signaling between the different tissues of the entire organism. Here, we describe a peptidomics approach used for the identification of endogenous (neuro)peptides in C. elegans. Starting from a detailed peptide extraction procedure, we will outline the setup for an online liquid chromatography-mass spectrometry (LC-MS) analysis and describe subsequent data analysis approaches.

Beyond ROS clearance: Peroxiredoxins in stress signaling and aging.

Antioxidants were long predicted to have lifespan-promoting effects, but in general this prediction has not been well supported. While some antioxidants do seem to have a clear effect on longevity, this may not be primarily as a result of their role in the removal of reactive oxygen species, but rather mediated by other mechanisms such as the modulation of intracellular signaling. In this review we discuss peroxiredoxins, a class of proteinaceous antioxidants with redox signaling and chaperone functions, and their involvement in regulating longevity and stress resistance. Peroxiredoxins have a clear role in the regulation of lifespan and survival of many model organisms, including the mouse, Caenorhabditis elegans and Drosophila melanogaster. Recent research on peroxiredoxins - in these models and beyond - has revealed surprising new insights regarding the interplay between peroxiredoxins and longevity signaling, which will be discussed here in detail. As redox signaling is emerging as a potentially important player in the regulation of longevity and aging, increased knowledge of these fascinating antioxidants and their mode(s) of action is paramount.

The family impact of caring for a child with juvenile dermatomyositis.

Background Juvenile dermatomyositis (JDM), a rare autoimmune disease, accounts for more than 80% of idiopathic inflammatory myopathy childhood cases, making it the most common idiopathic inflammatory myopathy among children. The average age of onset is approximately 7 years and commonly leads a chronic course. Symptoms of JDM include cutaneous features (Gottron's rash, heliotrope rash, or nail fold capillary changes), musculoskeletal features, calcinosis and lipodystrophy (a symmetrical deficit of subcutaneous fatty tissue), and acanthosis (thickening of the skin). Despite improvement in treatment regimens and the lowering of mortality rates, some children still lose their lives to JDM. This study assessed the effects of caring for a child diagnosed with JDM on the family system. Methods Participants included 36 mothers and 3 fathers of a child diagnosed with JDM. Parents were administered self-report measures, which assessed the overall family functioning (PedsQL-Family Impact Module), and the parents' mood and level of distress (profile of mood states). Additionally, parents were administered a semi-structured interview that included background information, psychosocial information, and sources of support. Results and conclusion Families of children with JDM reported difficulties in family functioning, communication problems, and an increased number of conflicts. Parents appeared to be experiencing higher than average levels of worry, worse physical functioning, and family relationships when compared to normative populations. Parents would benefit from psychosocial support due to the many challenges associated with caring for a child with JDM.

Time-to-contact estimation errors among older drivers with useful field of view impairments.

Previous research indicates that useful field of view (UFOV) decline affects older driver performance. In particular, elderly drivers have difficulty estimating oncoming vehicle time-to-contact (TTC). The objective of this study was to evaluate how UFOV impairments affect TTC estimates in elderly drivers deciding when to make a left turn across oncoming traffic. TTC estimates were obtained from 64 middle-aged (n=17, age=46±6years) and older (n=37, age=75±6years) licensed drivers with a range of UFOV abilities using interactive scenarios in a fixed-base driving simulator. Each driver was situated in an intersection to turn left across oncoming traffic approaching and disappearing at differing distances (1.5, 3, or 5s) and speeds (45, 55, or 65mph). Drivers judged when each oncoming vehicle would collide with them if they were to turn left. Findings showed that TTC estimates across all drivers, on average, were most accurate for oncoming vehicles travelling at the highest velocities and least accurate for those travelling at the slowest velocities. Drivers with the worst UFOV scores had the least accurate TTC estimates, especially for slower oncoming vehicles. Results suggest age-related UFOV decline impairs older driver judgment of TTC with oncoming vehicles in safety-critical left-turn situations. Our results are compatible with national statistics on older driver crash proclivity at intersections.