Alzheimer's disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 ...participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.
Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the canonical androgen production ...pathway and is essential for normal masculinisation and testis function. Disruption to androgen production can result in disorders of sexual development (DSD). In the canonical pathway, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is viewed as a critical enzyme in the production of testosterone, performing the final conversion required. HSD17B3 deficiency in humans is associated with DSD due to low testosterone concentration during development. Individuals with
mutations have poorly masculinised external genitalia that can appear as ambiguous or female, whilst having internal Wolffian structures and testes. Recent studies in mice deficient in HSD17B3 have made the surprising finding that testosterone production is maintained, male mice are masculinised and remain fertile, suggesting differences between mice and human testosterone production exist. We discuss the phenotypic differences observed and the possible other pathways and enzymes that could be contributing to testosterone production and male development. The identification of alternative testosterone synthesising enzymes could inform the development of novel therapies to endogenously regulate testosterone production in individuals with testosterone deficiency.
Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various ...inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production. However, endogenous glucocorticoids are produced by the adrenal and within the testis, but whether their action on GR in Leydig cells regulates steroidogenesis is unknown. This study aimed to define the role of endogenous GR signalling in adult Leydig cells. We developed and compared two models; an inducible Cre transgene driven by expression of the
steroidogenic gene (
-iCre) that depletes GR during development and a viral vector-driven Cre (AAV9-Cre) to deplete GR in adulthood. The delivery of AAV9-Cre ablated GR in adult mouse Leydig cells depleted Leydig cell GR more efficiently than the
-iCre model. Importantly, adult depletion of GR in Leydig cells caused reduced expression of luteinising hormone receptor (
) and of steroidogenic enzymes required for normal androgen production. These findings reveal that Leydig cell GR signalling plays a physiological role in the testis and highlight that a normal balance of glucocorticoid activity in the testis is important for steroidogenesis.
Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary ...microvascular blood flow (PMBF) in early chronic lung disease.
To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.
PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below -950 Hounsfield units (-950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.
Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema-950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.
PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.
Curcumin has been shown to reduce exercise-induced oxidative stress (OS) and inflammation. The purpose of this investigation was to examine the effects of curcumin supplementation on OS, ...inflammation, muscle damage, and muscle soreness. Nineteen males participated in a randomized, double-blinded, placebo-controlled trial to examine the effects of curcumin supplementation (1.5 g/day) compared to a placebo (PLA) following a muscle-damaging protocol (MDP) on OS, inflammation, muscle damage, and soreness. Participants were randomized to two groups, curcumin or placebo group. The MDP was performed before and after supplementation (28 days). Blood was sampled pre- and postexercise and 60 min, 24 h, and 48 h postexercise and analyzed for total antioxidant capacity (TAC), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and creatine kinase (CK). In addition, a visual analog scale (VAS) was used on each blood sample to measure perceived muscle soreness. After supplementation, curcumin significantly blunted CK levels (199.62 U/L) compared to the placebo (287.03 U/L), overall (p < 0.0001). In addition, curcumin resulted in decreased muscle soreness, overall (VAS scale 2.88), when compared to the placebo (VAS scale 3.36) (p = 0.0120). There were no differences found in TAC, TNF-α, or MDA. Curcumin may reduce muscle damage and perceived muscle soreness without negatively impacting a natural inflammatory response following exercise. Future research should investigate chronic curcumin supplementation and its mechanistic effects on muscle recovery from exercise.
Abstract
Background
The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model given its similarity in size, anatomy, physiology, metabolism, pathology, and ...pharmacology to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete, and unresolved redundancies, short-range order and orientation errors, and associated misassembled genes limited its utility.
Results
We present 2 annotated highly contiguous chromosome-level genome assemblies created with more recent long-read technologies and a whole-genome shotgun strategy, 1 for the same Duroc female (Sscrofa11.1) and 1 for an outbred, composite-breed male (USMARCv1.0). Both assemblies are of substantially higher (>90-fold) continuity and accuracy than Sscrofa10.2.
Conclusions
These highly contiguous assemblies plus annotation of a further 11 short-read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs.
Here we describe the development of the London Hybrid Exposure Model (LHEM), which calculates exposure of the Greater London population to outdoor air pollution sources, in-buildings, in-vehicles, ...and outdoors, using survey data of when and where people spend their time. For comparison and to estimate exposure misclassification we compared Londoners LHEM exposure with exposure at the residential address, a commonly used exposure metric in epidemiological research. In 2011, the mean annual LHEM exposure to outdoor sources was estimated to be 37% lower for PM2.5 and 63% lower for NO2 than at the residential address. These decreased estimates reflect the effects of reduced exposure indoors, the amount of time spent indoors (∼95%), and the mode and duration of travel in London. We find that an individual’s exposure to PM2.5 and NO2 outside their residential address is highly correlated (Pearson’s R of 0.9). In contrast, LHEM exposure estimates for PM2.5 and NO2 suggest that the degree of correlation is influenced by their exposure in different transport modes. Further development of the LHEM has the potential to increase the understanding of exposure error and bias in time-series and cohort studies and thus better distinguish the independent effects of NO2 and PM2.5.
Controlling the assembly and disassembly of nanoscale protein cages for the capture and internalization of protein or non-proteinaceous components is fundamentally important to a diverse range of ...bionanotechnological applications. Here, we study the reversible, pressure-induced dissociation of a natural protein nanocage, E. coli bacterioferritin (Bfr), using synchrotron radiation small-angle X-ray scattering (SAXS) and circular dichroism (CD). We demonstrate that hydrostatic pressures of 450 MPa are sufficient to completely dissociate the Bfr 24-mer into protein dimers, and the reversibility and kinetics of the reassembly process can be controlled by selecting appropriate buffer conditions. We also demonstrate that the heme B prosthetic group present at the subunit dimer interface influences the stability and pressure lability of the cage, despite its location being discrete from the interdimer interface that is key to cage assembly. This indicates a major cage-stabilizing role for heme within this family of ferritins.
We have produced an Fc conjugate of colony-stimulating factor (CSF) 1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce ...proinflammatory cytokines in vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-enhanced green fluorescent protein (EGFP) reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, tumor necrosis factor, and interleukin 6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.
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