Electric Signals Regulate the Directional Migration of Oligodendrocyte Progenitor Cells (OPCs) via ß1 Integrin.

The guided migration of neural cells is essential for repair in the central nervous system (CNS). Oligodendrocyte progenitor cells (OPCs) will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric fields (EFs) are known to influence cell migration in vivo, and have been utilised in this study to direct the migration of OPCs isolated from neonatal Sprague-Dawley rats. The OPCs were exposed to physiological levels of electrical stimulation, and displayed a marked electrotactic response that was dependent on ß1 integrin, one of the key subunits of integrin receptors. We also observed that F-actin, an important component of the cytoskeleton, was re-distributed towards the leading edge of the migrating cells, and that this asymmetric rearrangement was associated with ß1 integrin function.

GATA2 mitotic bookmarking is required for definitive haematopoiesis.

In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.

The impact of working in academia on researchers' mental health and well-being: A systematic review and qualitative meta-synthesis.

OBJECTIVE: To understand how researchers experience working in academia and the effects these experiences have on their mental health and well-being, through synthesizing published qualitative data. METHOD: A systematic review and qualitative meta-synthesis was conducted to gain a comprehensive overview of what is currently known about academic researchers' mental health and well-being. Relevant papers were identified through searching electronic databases, Google Scholar, and citation tracking. The quality of the included studies was assessed and the data was synthesised using reflexive thematic analysis. RESULTS: 26 papers were identified and included in this review. Academic researchers' experiences were captured under seven key themes. Job insecurity coupled with the high expectations set by the academic system left researchers at risk of poor mental health and well-being. Access to peer support networks, opportunities for career progression, and mentorship can help mitigate the stress associated with the academic job role, however, under-represented groups in academia are at risk of unequal access to resources, support, and opportunities. CONCLUSION: To improve researchers' well-being at work, scientific/academic practice and the system's concept of what a successful researcher should look like, needs to change. Further high-quality qualitative research is needed to better understand how systemic change, including tackling inequality and introducing better support systems, can be brought about more immediately and effectively. Further research is also needed to better understand the experiences and support needs of post-doctoral and more senior researchers, as there is a paucity of literature in this area. TRIAL REGISTRATION: The review protocol was registered on PROSPERO (CRD42021232480).

Obstructive sleep apnoea in women with idiopathic intracranial hypertension: a sub-study of the idiopathic intracranial hypertension weight randomised controlled trial (IIH: WT).

OBJECTIVE: Obesity is a risk factor for idiopathic intracranial hypertension (IIH) and obstructive sleep apnoea (OSA). We aimed to determine the prevalence of OSA in IIH and evaluate the diagnostic performance of OSA screening tools in IIH. Additionally, we evaluated the relationship between weight loss, OSA and IIH over 12 months. METHODS: A sub-study of a multi-centre, randomised controlled parallel group trial comparing the impact of bariatric surgery vs. community weight management intervention (CWI) on IIH-related outcomes over 12 months (IIH:WT). OSA was assessed using home-based polygraphy (ApneaLink Air, ResMed) at baseline and 12 months. OSA was defined as an apnoea-hypopnoea index (AHI) ≥ 15 or ≥ 5 with excessive daytime sleepiness (Epworth Sleepiness Scale ≥11 ). RESULTS: Of the 66 women in the IIH: WT trial, 46 were included in the OSA sub-study. OSA prevalence was 47% (n = 19). The STOP-BANG had the highest sensitivity (84%) compared to the Epworth Sleepiness Scale (69%) and Berlin (68%) to detect OSA. Bariatric surgery resulted in greater reductions in AHI vs. CWI (median [95%CI] AHI reduction of - 2.8 [ - 11.9, 0.7], p = 0.017). Over 12 months there was a positive association between changes in papilloedema and AHI (r = 0.543, p = 0.045), despite adjustment for changes in the body mass index (R2 = 0.522, p = 0.017). CONCLUSION: OSA is common in IIH and the STOP-BANG questionnaire was the most sensitive screening tool. Bariatric surgery improved OSA in patients with IIH. The improvement in AHI was associated with improvement in papilloedema independent of weight loss. Whether OSA treatment has beneficial impact on papilloedema warrants further evaluation. TRIAL REGISTRATION NUMBER: IIH: WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 (28/04/2014).

The impact of sleep disorders on microvascular complications in patients with type 2 diabetes (SLEEP T2D): the protocol of a cohort study and feasibility randomised control trial.

BACKGROUND: Obstructive sleep apnoea (OSA) is very common in patients with type 2 diabetes (T2D). We and others have shown that OSA was associated with diabetes-related microvascular complications in patients with T2D in cross-sectional and longitudinal studies and that compliance with continuous positive airway pressure (CPAP) reduced the progression of microvascular complications. Hence, we hypothesised that adequate CPAP reduces the development of microvascular complication in patients with T2D. METHODS: SLEEP T2D is a cohort study with embedded feasibility, open-label, parallel-arm, randomised control trial (RCT) over 2 years. The primary aim is the feasibility of conducting a definitive RCT assessing the impact of CPAP on chronic kidney disease and other microvascular complications in patients with T2D. The main parameters are to assess willingness of participants to be randomised, follow-up rates, CPAP adherence/compliance, to optimise the choice of outcome measures for a substantive trial, and to identify the parameters for sample size calculations. The secondary aims of the study are related to the impact of CPAP, sleep-related disorders, and sleep chronotype on a variety of diabetes-related end points. The study participants were recruited from the T2D services in multiple NHS trusts across England. The main exclusion criteria for the cohort study are as follows: T1D, eGFR < 15 mL/min/1.73 m2, known OSA, active malignancy or chronic kidney disease from reasons other than diabetes, pregnancy, professional drivers, and a history of falling asleep whilst driving within last 2 years. The main exclusion criteria from the RCT were as follows: Apnoea-Hypopnoea Index < 10 and Epworth Sleepiness Score ≥ 11. Study participants were extensively phenotyped clinically and biochemically. The OSA diagnosis was based on multichannel portable device (ApneaLink AirTM, Resmed). DISCUSSION: The feasibility RCT will help us design the future RCT to assess the impact of CPAP on diabetes-related microvascular complications. The cohort study will generate preliminary data regarding the impact of sleep quality, duration, and chronotype on diabetes-related outcomes which could lead to further mechanistic and interventional studies. TRIAL REGISTRATION: ISRCTN, ISRCTN12361838 . Registered 04 April 2018, Protocol version: v5.0 02.12.19.

Cognitive performance in idiopathic intracranial hypertension and relevance of intracranial pressure.

Cognitive impairments have been reported in idiopathic intracranial hypertension; however, evidence supporting these deficits is scarce and contributing factors have not been defined. Using a case-control prospective study, we identified multiple domains of deficiency in a cohort of 66 female adult idiopathic intracranial hypertension patients. We identified significantly impaired attention networks (executive function) and sustained attention compared to a body mass index and age matched control group of 25 healthy female participants. We aimed to investigate how cognitive function changed over time and demonstrated that deficits were not permanent. Participants exhibited improvement in several domains including executive function, sustained attention and verbal short-term memory over 12-month follow-up. Improved cognition over time was associated with reduction in intracranial pressure but not body weight. We then evaluated cognition before and after a lumbar puncture with acute reduction in intracranial pressure and noted significant improvement in sustained attention to response task performance. The impact of comorbidities (headache, depression, adiposity and obstructive sleep apnoea) was also explored. We observed that body mass index and the obesity associated cytokine interleukin-6 (serum and cerebrospinal fluid) were not associated with cognitive performance. Headache severity during cognitive testing, co-morbid depression and markers of obstructive sleep apnoea were adversely associated with cognitive performance. Dysregulation of the cortisol generating enzyme 11ß hydroxysteroid dehydrogenase type 1 has been observed in idiopathic intracranial hypertension. Elevated cortisol has been associated with impaired cognition. Here, we utilized liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and cerebrospinal fluid in idiopathic intracranial hypertension patients. We noted that reduction in the serum cortisol:cortisone ratio in those undergoing bariatric surgery at 12 months was associated with improving verbal working memory. The clinical relevance of cognitive deficits was noted in their significant association with impaired reliability to perform visual field tests, the cornerstone of monitoring vision in idiopathic intracranial hypertension. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of idiopathic intracranial hypertension and impairs the ability to perform visual field testing reliably. Importantly, cognitive deficits can improve over time and with reduction of intracranial pressure. Treating comorbid depression, obstructive sleep apnoea and headache could improve cognitive performance in idiopathic intracranial hypertension.

The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition.

Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1-/- mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1-/- cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.

The relationship between obstructive sleep apnoea and quality of life in women with polycystic ovary syndrome: a cross-sectional study.

BACKGROUND: Obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS) are associated with significant comorbidities and commonly coexist. The primary aim of this study was to examine the relationship between OSA and quality of life (QoL) in women with PCOS. METHODS: We conducted an observational cross-sectional study. PCOS was diagnosed according to the Rotterdam criteria. Women with increased risk of OSA, based on the Berlin questionnaire or the Epworth Sleepiness Scale (ESS), had home-based polysomnography performed (ALICE PDx). Participants were divided into two groups: (a) PCOS only: women with normal ESS and low-risk Berlin questionnaire (no sleep studies performed), or women with normal sleep studies [oxygen desaturation index (ODI) < 5 events/hour]; and (b) PCOS+OSA: women with PCOS and OSA ODI ⩾ 5. QoL was assessed using the World Health Organization QoL questionnaire (WHOQOL-BREF) and the PCOS health-related quality of life questionnaire (PCOSQ). RESULTS: A total of 39 women were included; age (mean ± SD) was 32.2 ± 8.9 years, weight 92.5 ± 23.7 kg and body mass index (BMI) 34.1 ± 7.9 kg/m2; 38.5% (n = 15) had OSA. Compared with women with PCOS only, women with PCOS+OSA had higher BMI, HbA1c, C-reactive protein and low-density lipoprotein. ODI was independently associated with impaired QoL. Excessive daytime sleepiness (EDS) was independently associated with anxiety, depression and impaired QoL. CONCLUSIONS: OSA is highly prevalent and is associated with impaired QoL and worse metabolic profile in women with PCOS. Interventional studies are needed to examine the impact of OSA in women with PCOS. CLINICALTRIALSGOV IDENTIFIER: NCT03065322.