Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.

The TATA-box binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked Dystonia-Parkinsonism, a neurodegenerative disorder. However, this field has suffered from the lack of a genetic mouse model of TAF1 disease to explore mammalian mechanism and treatments. Here, we generated and validated a conditional cre-lox allele, and the first ubiquitous Taf1 knock-out mouse. We discovered that Taf1 deletion in males was embryonically lethal, which may explain why no human null-variants have been identified. In the brains of Taf1 heterozygous females, no differences were found in gross structure, overall expression, and protein localization, suggesting extreme skewed X-inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting a small subset of neurons has been negatively impacted by Taf1 loss. Finally, this new mouse may be a future platform for the development of TAF1 disease therapeutics.

Noninvasive and Multiplex Self-Test of Kidney Disease Biomarkers with Graphene-Based Lab-on-a-Chip (G-LOC): Toward Digital Diagnostics in the Hands of Patients.

Chronic kidney disease is one of the major health issues worldwide. However, diagnosis is now highly centralized in large laboratories, resulting in low access to patient monitoring and poor personalized treatments. This work reports the development of a graphene-based lab-on-a-chip (G-LOC) for the digital testing of renal function biomarkers in serum and saliva samples. G-LOC integrates multiple bioelectronic sensors with a microfluidic system that enables multiplex self-testing of urea, potassium, sodium, and chloride. The linearity, limit of detection (LOD), accuracy, and coefficient of variability (CV) were studied. Accuracy values higher than 95.5% and CV lower than 9% were obtained for all of the biomarkers. The analytical performance was compared against three reference lab benchtop analyzers by measuring healthy- and renal-failure-level samples of serum. From receiver operating characteristic (ROC) plots, sensitivities (%) of 99.7, 97.6, 99.1, and 89.0 were obtained for urea, potassium, sodium, and chloride, respectively. Then, the test was evaluated in noninvasive saliva samples and compared against reference methods. Correlation and Bland-Altman plots showed good correlation and agreement of the G-LOC with the reference methods. It is noteworthy that the precision of G-LOC was similar to better than benchtop lab analyzers, with the advantage of being highly portable. Finally, a user testing study was conducted. The analytical performance obtained with untrained volunteers was similar to that obtained with trained chemists. Additionally, based on a user experience survey, G-LOC was found to have very simple usability and would be suitable for at-home diagnostics.

An urgent call to address work-related psychosocial hazards and improve worker well-being.

Work-related psychosocial hazards are on the verge of surpassing many other occupational hazards in their contribution to ill-health, injury, disability, direct and indirect costs, and impact on business and national productivity. The risks associated with exposure to psychosocial hazards at work are compounded by the increasing background prevalence of mental health disorders in the working-age population. The extensive and cumulative impacts of these exposures represent an alarming public health problem that merits immediate, increased attention. In this paper, we review the linkage between work-related psychosocial hazards and adverse effects, their economic burden, and interventions to prevent and control these hazards. We identify six crucial societal actions: (1) increase awareness of this critical issue through a comprehensive public campaign; (2) increase etiologic, intervention, and implementation research; (3) initiate or augment surveillance efforts; (4) increase translation of research findings into guidance for employers and workers; (5) increase the number and diversity of professionals skilled in preventing and addressing psychosocial hazards; and (6) develop a national regulatory or consensus standard to prevent and control work-related psychosocial hazards.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

Modelling Alzheimer's disease in a dish: dissecting amyloid-ß metabolism in human neurons.

This scientific commentary refers to 'Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-ß deposition' by Rowland et al. (https://doi.org/10.1042/NS20230016). Insulin-degrading enzyme (IDE) and neprilysin (NEP) have been proposed as two Aß-degrading enzymes supported by human genetics and in vivo data. Rowland et al. provide complementary evidence of a key role for IDE in Aß metabolism in human-induced pluripotent stem cell (iPSC)-derived cortical neurons.

Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Systemic Arterial Oxygen Levels Differentiate Pre- and Post-capillary Predominant Hemodynamic Abnormalities During Exercise in Undifferentiated Dyspnea on Exertion.

BACKGROUND: Whether systemic oxygen levels (SaO2) during exercise can provide a window into invasively derived exercise hemodynamic profiles in patients with undifferentiated dyspnea on exertion is unknown. METHODS: We performed cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial blood gas sampling in individuals referred for dyspnea on exertion. Receiver operator analysis was performed to distinguish heart failure with preserved ejection fraction from pulmonary arterial hypertension. RESULTS: Among 253 patients (mean ± SD, age 63 ± 14 years, 55% female, arterial O2 [PaO2] 87 ± 14 mmHg, SaO2 96% ± 4%, resting pulmonary capillary wedge pressure [PCWP] 18 ± 4mmHg, and pulmonary vascular resistance [PVR] 2.7 ± 1.2 Wood units), there was no exercise PCWP threshold, measured up to 49 mmHg, above which hypoxemia was consistently observed. Exercise PaO2 was not correlated with exercise PCWP (rho = 0.04; P = 0.51) but did relate to exercise PVR (rho = -0.46; P < 0.001). Exercise PaO2 and SaO2 levels distinguished left-heart-predominant dysfunction from pulmonary-vascular-predominant dysfunction with an area under the curve of 0.89 and 0.89, respectively. CONCLUSION: Systemic O2 levels during exercise distinguish relative pre- and post-capillary pulmonary hemodynamic abnormalities in patients with undifferentiated dyspnea. Hypoxemia during upright exercise should not be attributed to isolated elevation in left heart filling pressures and should prompt consideration of pulmonary vascular dysfunction.

Reimagining Thriving Ethics Programs without Ethics Committees.

With the increasing professionalization of clinical ethics, some hospitals and health systems utilize both ethics committees and professional clinical ethicists to address their ethics needs. Drawing upon historical critiques of ethics committees and their own experiences, the authors argue that, in ethics programs with one or more professional clinical ethicists, ethics committees should be dissolved when they fail to meet minimum standards of effectiveness. The authors outline several criteria for assessing effectiveness, describe the benefits of a model that places primary responsibility for ethics work with professional clinical ethicists-the PCE-primary model, and offer suggestions for alternative ethics program structures that empower healthcare professionals to contribute to ethics work in ways more tailored to their strengths and skills while minimizing the shortcomings of ethics committees.

Vital Signs: Health Worker-Perceived Working Conditions and Symptoms of Poor Mental Health - Quality of Worklife Survey, United States, 2018-2022.

Introduction: Health workers faced overwhelming demands and experienced crisis levels of burnout before the COVID-19 pandemic; the pandemic presented unique challenges that further impaired their mental health. Methods: Data from the General Social Survey Quality of Worklife Module were analyzed to compare self-reported mental health symptoms among U.S. adult workers from 2018 (1,443 respondents, including 226 health workers) and 2022 (1,952, including 325 health workers). Logistic regression was used to examine associations between health workers' reported perceptions of working conditions and anxiety, depression, and burnout. Results: From 2018 to 2022, health workers reported an increase of 1.2 days of poor mental health during the previous 30 days (from 3.3 days to 4.5 days); the percentage who reported feeling burnout very often (11.6% to 19.0%) increased. In 2022, health workers experienced a decrease in odds of burnout if they trusted management (odds ratio [OR] = 0.40), had supervisor help (OR = 0.26), had enough time to complete work (OR = 0.33), and felt that their workplace supported productivity (OR = 0.38), compared with those who did not. Harassment at work was associated with increased odds of anxiety (OR = 5.01), depression (OR = 3.38), and burnout (OR = 5.83). Conclusions and implications for public health practice: Health workers continued to face a mental health crisis in 2022. Positive working conditions were associated with less burnout and better mental health. CDC's National Institute for Occupational Safety and Health has developed a national campaign, Impact Wellbeing, to provide employers of health workers with resources to improve the mental health of these workers.

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.

Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.

A staffing perspective on barriers to and facilitators of temporary worker safety and health.

BACKGROUND: Research has documented occupational health disparities, including higher rates of work-related injuries, among temporary workers compared with workers in standard employment arrangements. According to guidance from the Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH), both staffing companies and host employers are responsible for protecting the occupational safety and health (OSH) of temporary workers. To date, there has been little qualitative research on temporary worker OSH in the United States and a lack of evidence-based OSH programs designed to meet the needs of temporary workers. The aim of this study was to better understand the barriers to and facilitators of temporary worker OSH from the perspective of US staffing companies. METHODS: In-depth interviews were conducted with a convenience sample of representatives from 15 US staffing companies. Interviews were audio recorded, transcribed verbatim, and analyzed through a three-step process. RESULTS: Commonly mentioned barriers to temporary worker OSH include differential treatment of temporary workers by host employers; lack of understanding among host employers and staffing companies of joint OSH responsibilities; and workers' fear of job loss or other negative repercussions if they report an injury or illness or voice OSH concerns. Commonly mentioned facilitators of temporary worker OSH include conducting client assessments and site visits and fostering strong communication and relationships with both host employers and temporary workers. CONCLUSIONS: These findings can help inform the tailoring of OSH programs to promote health equity in temporary workers.

Opinion: more mouse models and more translation needed for ALS.

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions.

Aortic valve leaflets are asymmetric and correlated with the origin of coronary arteries.

Background: Asymmetry of the aortic valve leaflets has been known since Leonardo Da Vinci, but the relationship between size and shape and origin of the coronary arteries has never been examined. Our aim was to evaluate this anatomy in a population of pediatric patients using a cross-sectional study design. Methods: Consecutive pediatric patients with trans-esophageal echocardiography (TEE), with or without trans-thoracic echocardiography (TTE), were included in our study. Exclusion criteria: (I) bicuspid aortic valve; (II) aortic valve stenosis; (III) hypoplasia of aortic valve annulus, or aortic root; (IV) truncal valve; (V) coronary artery atresia; (VI) previous surgery on aortic valve and/or coronary arteries. In pre-operative TTE and intra-operative TEE inter-commissural distance and length of aortic valve leaflets were measured in short axis view in the isovolumic phase of systole. Echocardiography investigations, anonymized and randomly coded, were independently reviewed by at least two readers. Echocardiography, angiography, cardiac computed tomography (CT) scan and magnetic resonance imaging (MRI), and operative notes were reviewed to identify origin of coronary arteries. Results: Two hundred sixty-one pediatric patients were identified, 93 excluded per our criteria, leaving 168 patients, age 2.6±4.3 years, weight 12.87±17.34 kg, 128 (76%) with normal and 40 (24%) with abnormal coronary arteries. In TTE and TEE measurements the non-coronary leaflet had larger area (P<0.001), while the right and left had equal areas, but different shape, with the left leaflet longer (P<0.001) and narrower (P=0.005) than the right. With the major source of blood flow from the right coronary sinus, the non-coronary leaflet was still the longest. However, there was no statically significant difference between the size and shape previously observed between the right and left leaflets. Conclusions: Our study showed asymmetry of size and shape among aortic valve leaflets, and a relationship with coronary artery origin. The complex aortic root anatomy must be approximated to optimize function of any surgical repair. These findings also may prove useful in the pre-operative definition of coronary artery anatomy and in the recognition of coronary artery anomalies.

Becoming Inclusive: Actionable Steps to Diversify the Field of Clinical Ethics.

At the 2022 Clinical Ethics Unconference, the authors perceived a significant lack of racial and ethnic diversity, which was consistent with their experiences in other clinical ethics settings. As a result, they convened a working group to address the pervasive lack of diversity present in the field of clinical ethics and to propose strategies to increase the representation of people from racial and ethnic minority populations. This article identifies the harms associated with the lack of diversity in the healthcare setting and translates these to the field of clinical ethics. The article then proposes a framework that may be used to help diversify the field of clinical ethics. Specifically, the authors identify existing barriers to appropriate diversity, actionable steps to increase diversity, and tools the field can utilize to systematically assess its progress with respect to achieving diversity.

Introducing a new themed collection on emerging technologies for research models of human neuronal disorders in vivo and in vitro.

This themed collection of articles was prompted by a collaboration between Neuronal Signaling and the British Neuroscience Association. The Biochemical Society and Portland Press organised a symposium at the BNA Festival of Neuroscience in 2021, focused on the development and use of experimental models of human neuronal disorders. One aspect dealt with how new technologies are being (or could be) used both as a substitute for, or to complement, research that uses whole animal models. Another aspect discussed factors that need to be considered when appraising the validity of animal models of complex, multifactorial neuronal disorders. Given its relevance to the scope of Neuronal Signaling, the journal's Editorial Board developed a themed collection of content around this symposium entitled Emerging technologies for research models of human neuronal disorders in vivo and in vitro. We were delighted that speakers from the symposium and other experts working in this field agreed to submit reviews for the collection, which offers an invaluable resource both for researchers who are already experts in this field and those who need merely to learn about its scope and potential.

A case-control study of polychlorinated biphenyl association with metabolic and hormonal outcomes in polycystic ovary syndrome.

Polychlorinated biphenyls (PCBs) are a class of environmental pollutants with a long half-life that sequester in fat. Women with polycystic ovarian syndrome (PCOS) may represent a sensitive subgroup to endogenous exposure to PCBs because of associated weight gain. Seven PCB congeners were compared in age, ethnicity, and BMI matched women with (n = 29) and without (n = 30) PCOS and related to metabolic outcomes, and steroid and thyroid hormone levels. PCB118, PCB138, PCB153, and PCB180 were detected in all serum samples but geometric mean did not differ between cases and controls. PCBs correlated with increasing concentrations of each other (p < .01), increasing age (p < .01) and decreasing lneGFR (p < .05). lnPCB118 correlated with increasing Free-T4 (p = .028). lnPCB158, lnPCB180, and ln∑PCB correlated with increasing lnSHBG (p = .044). In regression modeling, although not significant, PCB118 positively associated with lnSHBG in controls (p = .0504) but not in cases; estradiol inversely associated with PCB138 in controls (p = .055) and ∑PCB in cases (p = .051). No significant associations were observed between metabolic endpoints, and steroid and thyroid hormone levels. The results presented do not suggest the PCOS cases in this cohort are at adverse risk compared to age, ethnicity, and BMI matched controls.