Explore the vast range of titles available.

A fundamental question in hematopoietic stem cell (HSC) biology is how self-renewal is controlled. Here we show that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and we identify Notch signaling as a key factor in inhibiting differentiation. Using transgenic Notch reporter mice, we found that Notch signaling was active in HSCs in vivo and downregulated as HSCs differentiated. Inhibition of Notch signaling led to accelerated differentiation of HSCs in vitro and depletion of HSCs in vivo . Finally, intact Notch signaling was required for Wnt-mediated maintenance of undifferentiated HSCs but not for survival or entry into the cell cycle in vitro . These data suggest that Notch signaling has a dominant function in inhibiting differentiation and provide a model for how HSCs may integrate multiple signals to maintain the stem cell state.

Background Previous studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, although it has been suggested that hormonal factors may play a role. Methods The aim was to determine the association between sleep duration, sleep quality and frailty, and to determine whether testosterone influenced this association. Males aged 40–79 years were recruited from eight European centres to the European Male Aging Study (EMAS). Subjects completed an interviewer-assisted questionnaire including questions regarding sleep quality and duration. Sleep quality was scored 0–20 and categorised as 0–4, 5–9, 10–14, and 15–20, with higher scores indicating poorer quality. A 39-component frailty index (FI) was constructed. Total testosterone levels were measured. The association between sleep duration, sleep quality and the FI was assessed using negative binomial regression, with adjustment for putative confounders including testosterone level. Results Two thousand three hundred ninety-three participants contributed data to the analysis. The mean age was 63.3 years and mean sleep duration was 7.01 h. The mean frailty index was 0.15. Mean testosterone levels declined with decreasing sleep quality. After adjustment, compared to those with a sleep score of 0–4, the FI was 57% (95% CI 38%, 78%) higher among those with a sleep score of 15–20. After adjustment compared to those with normal sleep duration (6–9 h) , those with a short (< 6 h) and long (≥ 9 h) sleep duration had a 16% (95% CI 6%, 28%) and 11% (95% CI 0%, 23%) higher FI, respectively. Adjustment for testosterone did not influence the strength of either association. Conclusion Frailty is associated with impaired sleep quality and sleep duration. The association cannot, however, be explained by variation in testosterone levels.

Lyme borreliosis is increasing rapidly in many parts of the world and is the most commonly occurring vector-borne disease in Europe and the USA. The disease is transmitted by ticks of the genus Ixodes. They require a blood meal at each stage of their life cycle and feed on a wide variety of wild and domestic animals as well as birds and reptiles. Transmission to humans is incidental and can occur during visits to a vector habitat, when host mammals and their associated ticks migrate into the urban environment, or when companion animals bring ticks into areas of human habitation. It is frequently stated that the risk of infection is very low if the tick is removed within 24-48 hours, with some claims that there is no risk if an attached tick is removed within 24 hours or 48 hours. A literature review has determined that in animal models, transmission can occur in <16 hours, and the minimum attachment time for transmission of infection has never been established. Mechanisms for early transmission of spirochetes have been proposed based on their presence in different organs of the tick. Studies have found systemic infection and the presence of spirochetes in the tick salivary glands prior to feeding, which could result in cases of rapid transmission. Also, there is evidence that spirochete transmission times and virulence depend upon the tick and Borrelia species. These factors support anecdotal evidence that Borrelia infection can occur in humans within a short time after tick attachment.

A fixed-target approach to high-throughput room-temperature serial synchrotron crystallography with oscillation is described. Patterned silicon chips with microwells provide high crystal-loading density with an extremely high hit rate. The microfocus, undulator-fed beamline at CHESS, which has compound refractive optics and a fast-framing detector, was built and optimized for this experiment. The high-throughput oscillation method described here collects 1–5° of data per crystal at room temperature with fast (10° s −1 ) oscillation rates and translation times, giving a crystal-data collection rate of 2.5 Hz. Partial datasets collected by the oscillation method at a storage-ring source provide more complete data per crystal than still images, dramatically lowering the total number of crystals needed for a complete dataset suitable for structure solution and refinement – up to two orders of magnitude fewer being required. Thus, this method is particularly well suited to instances where crystal quantities are low. It is demonstrated, through comparison of first and last oscillation images of two systems, that dose and the effects of radiation damage can be minimized through fast rotation and low angular sweeps for each crystal.

Background Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power—which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross‐sectional muscle area (CSMA) with bone outcomes at the radius and tibia. Methods White European, Black Afro‐Caribbean, and South Asian men aged 40–79 years were recruited from Manchester, UK. Cortical bone mineral content, cross‐sectional area, cortical area, cross‐sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two‐legged jump performed on a ground‐reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. Results Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P < 0.0001). There was a significant age–ethnicity interaction for jump power (P = 0.039); after adjustments, this was attenuated (P = 0.088). For every 10 year increase in age, grip strength decreased by 11%. Jump force was positively associated with tibial bone outcomes: a 1 standard deviation greater jump force was associated with significantly higher cortical bone mineral content 3.1%, cross‐sectional area 4.2%, cortical area 3.4%, and cross‐sectional moment of inertia 6.8% (all P < 0.001). Cross‐sectional muscle area of the lower leg was not associated with tibial bone outcomes. Both grip strength and CSMA of the arm were positively associated, to a similar extent, with radius diaphyseal bone outcomes. Conclusions Jump force and power are negatively associated with age in UK men. In the lower limb, the measurement of jump force is more strongly related to bone outcomes than CSMA. It is important to consider jump force and power when understanding the aetiology of bone loss and mobility in ageing men.

Osteoarthritis is a painful, disabling condition which is increasing in prevalence as a result of an ageing population. With no recognized disease-limiting therapeutics, arthroplasty of the hip and knee is the most common and effective treatment for lower limb osteoarthritis, however lower limb arthroplasty has a finite life-span and a proportion of patients will require revision arthroplasty. With increasing life expectancy and an increasing proportion of younger (<65 years) patients undergoing arthroplasty, the demand for revision arthroplasty after implant failure is also set to increase. Statins are cholesterol-modulating drugs widely used for cardiovascular risk reduction which have been noted to have pleiotropic effects including potentially influencing arthroplasty survival. In vitro studies have demonstrated pleiotropic effects in human bone cells, including enhancement of osteoblastogenesis following simvastatin exposure, and in vivo studies have demonstrated that intraperitoneal simvastatin can increase peri-implant bone growth in rats following titanium tibial implant insertion. There is evidence that statins may also influence osseointegration, enhancing bone growth at the bone–implant interface, subsequently improving the functional survival of implants. Data from the Danish Hip Arthroplasty Registry and the Clinical Practice Research Datalink in the UK suggest a reduction in the risk of lower limb revision arthroplasty in statin ever-users versus never-users, and a time-dependent effect of statins in reducing the risk of revision. In this article we review the clinical and experimental evidence linking statins and risk of revision arthroplasty.

Solution-processed films of 1,4,8,11,15,18,22,25-octakis(hexyl) copper phthalocyanine (CuPc 6 ) were utilized as an active semiconducting layer in the fabrication of organic field-effect transistors (OFETs) in the bottom-gate configurations using chemical vapour deposited silicon dioxide (SiO 2 ) as gate dielectrics. The surface treatment of the gate dielectric with a self-assembled monolayer of octadecyltrichlorosilane (OTS) resulted in values of 4×10 −2 cm 2 V −1 s −1 and 10 6 for saturation mobility and on/off current ratio, respectively. This improvement was accompanied by a shift in the threshold voltage from 3 V for untreated devices to -2 V for OTS treated devices. The trap density at the interface between the gate dielectric and semiconductor decreased by about one order of magnitude after the surface treatment. The transistors with the OTS treated gate dielectrics were more stable over a 30-day period in air than untreated ones.

Introduction: Epidemiological modelling of infectious diseases plays an important role in driving public health policy. Commonly used models are described, including those based on exponential growth (Laplace and related distributions); susceptible-infected-removed; the Gompertz distribution; and the skew-reflected-Gompertz distribution. These are all sensitive to the timing of peak infection. The development of a novel method for forecasting the number of deaths occurring during epidemics of infectious diseases is described. Methods: The mathematical development of the authors' novel asymmetric difference model is detailed in this paper. Its predictions for mortality rates associated with the COVID-19 pandemic for 14 countries were compared with the corresponding published mortality data. Results: Forecasts by the asymmetric difference model of deaths from SARS-CoV-2 in different countries, actual recorded deaths to 30th June 2020, and corresponding errors included UK (42,700; 55,904; -24%); Poland (1490; 1444; +3%); Denmark (580; 605; -4%); Netherlands (6510; 6189; +5%); France (34,280; 29,836; +15%); Canada (1500; 8591; -78%); USA (44,540; 124,734; -64%); and Italy (22,020; 34,980; -37%). The model output was dependent upon forecast date accuracy for the peak of the disease outbreak. For Spain, the forecast date was one day early and for 10 (71%) countries the forecast peak occurred within seven days (inclusive) of the actual date. Discussion: Mortality prediction by the asymmetric difference model is relatively accurate. Furthermore, this new model does not appear to be as unduly sensitive to the timing of peak infection as other models. Indeed, its prediction of peak infection also appears to be relatively accurate. Keywords: COVID-19, coronavirus, infectious disease modelling, SARS-CoV-2, epidemic forecasting, pandemic forecasting

Human babesiosis is caused when erythrocytes are invaded by . Infection can occur from the bite of an infected tick, blood transfusion or congenitally. Issues related to the infecting species, symptomology and testing technology are discussed and the implications of accurate incidence and prevalence of the disease discussed. Human babesiosis is considered to be relatively rare in the UK. With a considerable number of non-specific symptoms and diagnostic testing limitations, it is probable that true positives are being missed. Based on co-infection data for and from Rhode Island and Connecticut, and on seropositivity data from northeastern France, the prevalence of babesiosis in those aged under 35 years, 35 to 44 years, 45 to 54 years and 55 years and over would be expected to be 0.6%, 1.8%, 2.8% and 3.5%, respectively. Based on the prevalence of infections in ticks and canines and a disease model previously published, it is estimated that the UK incidence of human babesiosis is likely to be approximately 18,500 cases per year.

The clinical diagnosis of Lyme borreliosis can be supported by various test methodologies; test kits are available from many manufacturers. Literature searches were carried out to identify studies that reported characteristics of the test kits. Of 50 searched studies, 18 were included where the tests were commercially available and samples were proven to be positive using serology testing, evidence of an erythema migrans rash, and/or culture. Additional requirements were a test specificity of ≥85% and publication in the last 20 years. The weighted mean sensitivity for all tests and for all samples was 59.5%. Individual study means varied from 30.6% to 86.2%. Sensitivity for each test technology varied from 62.4% for Western blot kits, and 62.3% for enzyme-linked immunosorbent assay tests, to 53.9% for synthetic C6 peptide ELISA tests and 53.7% when the two-tier methodology was used. Test sensitivity increased as dissemination of the pathogen affected different organs; however, the absence of data on the time from infection to serological testing and the lack of standard definitions for \"early\" and \"late\" disease prevented analysis of test sensitivity versus time of infection. The lack of standardization of the definitions of disease stage and the possibility of retrospective selection bias prevented clear evaluation of test sensitivity by \"stage\". The sensitivity for samples classified as acute disease was 35.4%, with a corresponding sensitivity of 64.5% for samples from patients defined as convalescent. Regression analysis demonstrated an improvement of 4% in test sensitivity over the 20-year study period. The studies did not provide data to indicate the sensitivity of tests used in a clinical setting since the effect of recent use of antibiotics or steroids or other factors affecting antibody response was not factored in. The tests were developed for only specific species; sensitivities for other species could not be calculated.