Miracle-dz/UniFAR-FTUs huggingface dataset:
Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes

Accurate modelling type 2 diabetes and diabetic complications in rodents has proven a challenge, largely as a result of the long‐time course of disease development in humans. In the present study, we aimed to develop and comprehensively characterise a new rodent model of type 2 diabetes. To do this, we fed Sprague–Dawley rats a high fat/high sugar diet (HFD) to induce obesity and dyslipidaemia. After 3 weeks, we s.c. implanted osmotic mini pumps to enable a 14 day, slow infusion of streptozotocin (STZ; lower dose = 100 mg kg−1; higher dose = 120 mg kg−1) to dose‐dependently reduce pancreatic beta cell mass. After removing the mini pumps, we monitored animals for 4 months using a battery of tests to assess both metabolic and neurodegenerative changes across time. Our data demonstrate the combination of the HFD and lower dose STZ leads to induction of early‐stage type 2 diabetes defined by moderate hyperglycaemia, hyperinsulinaemia and impaired glucose tolerance, at the same time as the retention of an obese phenotype. By contrast, combining the HFD and higher dose STZ leads to induction of later‐stage type 2 diabetes defined by frank hyperglycaemia, hypoinsulinaemia (but not insulin depletion) and severely impaired glucose tolerance, at the same time as retaining an obese phenotype. Regardless of dose of STZ (and level of hyperglycaemia), all diabetic rats exhibited signs of peripheral neurodegeneration in the skin and muscle. Thus, this model recapitulates many of the complex metabolic disturbances seen in type 2 diabetes and provides an excellent platform for investigating the pathophysiological mechanisms that lead to diabetic complications such as peripheral neuropathy.
Correlation between cumulative mammographic density and age‐specific incidence of breast cancer: A biethnic study in Israel

Women with the most extensive breast density, have a 4‐ to 6‐fold higher cancer risk than women with the lowest density. This cross‐sectional study evaluated associations of cumulative mammographic density in two distinct ethnic groups with the respective age‐specific breast cancer incidences in the population. The study compared four cohorts of 200 women each aged 35 to 49 and 50 to 74, representing Jewish and Arab ethnicity. Breast density measures were calculated from screening mammograms, using a thresholding software (Cumulus). Breast cancer specific incidence values were obtained from the National Cancer Registry. The percent mammographic density was lower for women aged 50 to 74 than 35 to 49 years, both for Jews: 11.7 vs 23.1 and for Arabs: 11.6 vs 18.3. In contrast, the cumulative density increased with age, from 37.30 to 181.24 in Jews, compared to 21.26 to 108.03 in Arabs. Similar trends in breast cancer incidence rates per 100 000 in the Israeli population were apparent, with an increase from 92.95 to 381.91 in Jews, compared to 48.6 to 244.44 in Arabs. Comparing cumulative density of the cohort with respective age‐specific breast cancer incidence in the population yielded a highly significant correlation: Jews; r = . 97, P < . 0001 and Arabs: r = . 86, P = . 007. A strong association was found between the log of cumulative density and the log of cancer incidence, as well. Our study identified correlations between cumulative mammographic density and breast cancer incidence in two distinct populations. The findings should prompt research to enhance our understanding of the pathogenesis of breast cancer, and lead to novel insights into measures of prevention.
Outcomes of Visceral Arterial Reconstruction: A Systematic Review

Aims: The study aimed to review the use of synthetic grafts (SGs) and autologous vein grafts (AVGs) in visceral arterial reconstruction (VAR) in chronic visceral ischaemia. Methods: Systematic review methodology was employed. Results: Six studies were included (218 patients and 281 vessels). Two studies had data about AVG only, 3 had data about SG only and 1 had both AVG and SG data. Three studies reported outcomes for AVG (117 patients and 132 vessels revascularized). One-year primary patency was 87% (95% CI 71%, 97%). Graft thrombosis rate was 6% (95% CI 0%, 16%). Pooled stenosis rate at one-year was 11% (95% CI 1%, 28%). The 30-day (n = 96), one-year (n = 72) and 5-year mortality (n = 30) were 0%, 0% and 12%, respectively. Four studies reported outcomes for SGs (106 patients and 147 vessels). The pooled primary patency at one year was 100% (95% CI 99%, 100%). Pooled primary 5-year patency rate was 88% (95% CI 69%, 100%). There was no graft infection in 2 of the 3 studies. Overall pooled percentage of graft thrombosis and stenosis at one year was 0%. Jimenez et al. (2002) reported one graft thrombosis at 20 months and graft stenosis in 2 patients at 46 and 49 months. Illuminati et al (2017) reported graft thrombosis in 2/24 patients at 22 and 52 months. Thirty days, one-year and 5-year mortality was 1% (95% CI 0%, 6), 7% (95% CI 0%, 20%) and 39% (95% CI 11%), respectively. Conclusion: Patency was better with SG compared with AVG. Mortality was higher in the SG group. Graft dilatation does occur with vein grafts, but in this review no intervention was found necessary. Poorly designed studies, incomplete reporting and absence of morbidity and mortality indices preclude emphatic conclusions.
In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family

Abstract Background Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22–31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging. Methods We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal–Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational. Results Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex. Conclusions In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.
The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment

Background: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia. Objective: The objective was to evaluate the effectiveness of the cognitive rehabilitation program “GRADIOR” in people with mild cognitive impairment and mild dementia. Method: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0: baseline, T1: at 4 months, T2: at 12 months were compared within and between-groups. Results: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage’s Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between “time and group” for MMSE (F = 8.971; p = 0.03; η2 = 0.019) and the GDS (F = 3.414; p = 0.04; η2 = 0.041), as well as small effect sizes for TMT-A-time (F = 1.641; p = 0.21; η2 = 0.021) and TMT-A-mistakes (F = 0.908; p = 0.41; η2 = 0.019). Conclusion: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788).
Diagnosis of poult enteritis complex (PEC) and molecular detection of avian coronaviruses in some commercial turkey flocks in Iran.

Background Enteritis syndromes, also known as poult enteritis complex (PEC) with diverse etiologies, can affect turkey production. An avian coronavirus (AvCoV), turkey coronavirus (TCoV), is one of the most important viral causes of PEC in turkeys. Aims In the present study, the occurrence of PEC and the presence of AvCoV in some commercial turkey flocks were investigated. Methods PEC was diagnosed based on the history, clinical, and necropsy findings. A reverse transcriptase-polymerase chain reaction (RT-PCR) targeting the AvCoV nucleoprotein (N) gene was applied to detect the virus in the tissue samples. Cloacal swabs were collected from 11 flocks without a known history of PEC. Results PEC was diagnosed in six (16.2%) out of 37 investigated turkey flocks. The daily mortality rate in affected flocks ranged from 0.2 to 1.2%. Samples from 8 flocks out of 18 (44.4%) were positive for AvCoV. Four PEC affected flocks were positive for AvCoV. Seven positive samples were sequenced and phylogenetic analysis revealed the close relationship with previously characterized avian infectious bronchitis viruses (IBV). Conclusion The results suggested that PEC should be considered as a significant syndrome in the Iranian turkey industry. According to this preliminary study, it was shown that avian coronavirus infection is prevalent in commercial turkey farms of Iran. However, no causative association could be concluded between PEC occurrence and AvCoV infection in turkey flocks.
Empowering Future Women Leaders Through GATE: The Way Forward

The underlying premise of the human capital theory in education is that higher education and training are costly but there are concomitant tangible and intangible benefits to the microcosm and macrocosm. The aforementioned theoretical underpinning of this study set the tone for this qualitative research project which encompasses informal face-to-face interviews with 61 full-time and part-time-female students at the University of the West Indies School of Business and Applied Studies Limited (trading as ROYTEC) concerning their experiences with Government Assistance for Tuition Expenses (GATE). The positive impact of GATE on each female student's life is unquestionable as her empowerment, development, and commitment are reflected in her answers to three open-ended questions. Further expenditure in higher education would be of benefit to any country seeking to improve its citizen's quality of life and standard of living.
A‐to‐I RNA editing of Filamin A regulates cellular adhesion, migration and mechanical properties

A‐to‐I RNA editing by ADARs is an abundant epitranscriptomic RNA‐modification in metazoa. In mammals, Flna pre‐mRNA harbours a single conserved A‐to‐I RNA editing site that introduces a Q‐to‐R amino acid change in Ig repeat 22 of the encoded protein. Previously, we showed that FLNA editing regulates smooth muscle contraction in the cardiovascular system and affects cardiac health. The present study investigates how ADAR2‐mediated A‐to‐I RNA editing of Flna affects actin crosslinking, cell mechanics, cellular adhesion and cell migration. Cellular assays and AFM measurements demonstrate that the edited version of FLNA increases cellular stiffness and adhesion but impairs cell migration in both, mouse fibroblasts and human tumour cells. In vitro, edited FLNA leads to increased actin crosslinking, forming actin gels of higher stress resistance. Our study shows that Flna RNA editing is a novel regulator of cytoskeletal organisation, affecting the mechanical property and mechanotransduction of cells.
Ontogenetic Changes in Blood Osmolality During the Postembryonic Development of Zebrafish (Danio rerio)

The zebrafish Danio rerio is a teleost model species widely used in developmental genetics, biomedical studies, toxicology, and drug screening. Despite the interest of this species in research, little is known through indirect observations about its blood osmolality, which is a key parameter for diverse experiments. In this study, we directly measured blood osmolality using nano-osmometry at different stages of zebrafish postembryonic development. We found that blood osmolality is close to 240 mOsm·kg−1 in early larvae. It progressively increased to ∼270 mOsm·kg−1 during the larval development before reaching ∼300 mOsm·kg−1 after metamorphosis in juveniles and later in adults. These ontogenetic changes in blood osmolality illustrate the physiological changes in osmoregulation associated with postembryonic development, including metamorphosis. These values are of practical interest for adjusting the osmolality of fixatives and cell and tissue culture media for research using zebrafish as a model.
HIV clinic‐based extended‐release naltrexone versus treatment as usual for people with HIV and opioid use disorder: a non‐blinded, randomized non‐inferiority trial

Abstract Background and aim Opioid agonist medications for treatment of opioid use disorder (OUD) can improve human immunodeficiency virus (HIV) outcomes and reduce opioid use. We tested whether outpatient antagonist treatment with naltrexone could achieve similar results. Design Open‐label, non‐inferiority randomized trial. Setting Six US HIV primary care clinics. Participants A total of 114 participants with untreated HIV and OUD (62% male; 56% black, 12% Hispanic; positive for fentanyl (62%), other opioids (47%) and cocaine (60%) at baseline). Enrollment halted early due to slow recruitment. Intervention HIV clinic‐based extended‐release naltrexone (XR‐NTX; n = 55) versus treatment as usual (TAU) with buprenorphine or methadone (TAU; n = 59). Measurements Treatment group differences were compared for the primary outcome of viral suppression (HIV RNA ≤ 200 copies/ml) at 24 weeks and secondary outcomes included past 30‐day use of opioids at 24 weeks. Findings Fewer XR‐NTX participants initiated medication compared with TAU participants (47 versus 73%). The primary outcome of viral suppression was comparable for XR‐NTX (52.7%) and TAU (49.2%) [risk ratio (RR) = 1.064; 95% confidence interval (CI) = 0.748, 1.514] at 24 weeks. Non‐inferiority could not be demonstrated, as the lower confidence limit of the RR did not exceed the pre‐specified margin of 0.75 in intention‐to‐treat (ITT) analysis. The main secondary outcome of past 30‐day opioid use was comparable for XR‐NTX versus TAU (11.7 versus 14.8 days; mean difference = −3.1; 95% CI = –8.7, 1.1) in ITT analysis. Among those initiating medication, XR‐NTX resulted in fewer days of opioid use compared with TAU in the past 30 days (6.0 versus 13.6, mean difference = −7.6; 95% CI = –13.8, −0.2). Conclusions A randomized controlled trial found supportive, but not conclusive, evidence that human immunodeficiency virus clinic‐based extended‐release naltrexone is not inferior to treatment as usual for facilitating human immunodeficiency virus viral suppression. Participants who initiated extended‐release naltrexone used fewer opioids than those who received treatment as usual.
Pilus proteins from Streptococcus pyogenes stimulate innate immune responses through Toll‐like receptor 2

The group A Streptococcus (GAS) pilus is a long, flexible, hair‐like structure anchored to the cell surface that facilitates the adherence of GAS to host cells, thus playing a critical role in initiating infections. Because of its important role in GAS virulence, the pilus has become an attractive target for vaccine development. While current research mainly focuses on pilus function and its potential as a vaccine component, there is a lack of knowledge on how the host immune system recognizes and responds to this abundant surface structure. Here we show that both assembled GAS pili and individual pilus proteins induce a potent release of the proinflammatory cytokines tumor necrosis factor and interleukin‐8. We further show that the surface‐exposed backbone pilin and ancillary pilin 1 subunits are Toll‐like receptor 2 (TLR2) agonists. Using reporter cell lines coexpressing human TLR2 in combination with either TLR1 or TLR6, we determined that activation was mediated by the TLR2/TLR6 heterodimer. Finally, we used solid‐phase and flow cytometry binding assays to illustrate a direct interaction between the pilus subunits and TLR2. These results provide further support for the suitability of the pilus as a vaccine component and opens potential avenues for using GAS pili as an adjuvant or immune‐modulation agent.
Associations of combining paid work and family care with gender-specific differences in depressive symptoms among older workers and the role of work characteristics

Objectives This study aims to provide insight into (i) how the combination of paid work and family care is longitudinally associated with gender-related differences in depressive symptoms and (ii) the role of work characteristics in this association. Methods Data were derived from STREAM, a Dutch prospective cohort study of older workers aged 45–64 years. Respondents were included if they were employed in at least one measurement between 2015 and 2017 (N=12 447). Mixed-models were applied to disentangle between-person (BP) and within-person (WP) effects of family caregiving on depressive symptoms. Analyses were stratified by gender. Work characteristics (social support, autonomy, emotional and mental workload) were separately added to the multivariable models. Results For older employees, family caregiving was positively associated with depressive symptoms between and within persons for both women [BP B=0.80, 95% confidence interval (CI) 0.52–1.08; WP B=0.32, 95% CI 0.08–0.56] and men (BP B=0.75, 95% CI 0.45–1.05; WP B=0.25, 95% CI 0.01–0.48). Social support at work reduced the adverse effect of family care on depressive symptoms for women (BP) and men (BP and WP). Emotional workload partly explained the effect of family care for both women and men (BP). Conclusions The longitudinal association between family care and mental health was similar for male and female employees. Resources at work (ie, social support) could protect caregiving employees against depressive symptoms. More research is needed regarding the relative impact of the care context compared to the work context of working family caregivers.
Optimisation of shaft voltage based condition monitoring in generators using a Bayesian approach

This paper presents a framework for the optimisation of shaft voltage based condition monitoring in synchronous generators utilising Bayesian classification. With machines involved in critical processes such as power generation, it is preferable to determine faults well in advance. The proposed system uses shaft voltage signals as an online method for diagnosis of incipient faults in synchronous machines. A Naive Bayes classifier is used in conjunction with frequency spectrum estimation in order to optimise the shaft voltage condition monitoring technique. A Finite Element (FE) model and an experimental machine are used to train, test and validate the fault classification system.
Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival

Supplemental Digital Content is available in the text. Rationale: The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. Objective: To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. Methods and Results: Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. Conclusions: Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.