Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amyloid-β (Aβ) in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβ appears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβ also increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS). Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1), CD36, and RAGE (receptor for advanced glycation end products). SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβ and propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD

Linking the chemical speciation of cerium to its bioavailability in water for a freshwater alga

Over the past decade, researchers have begun to use metals of the lanthanide family for numerous applications, including liquid crystal display (LCD) screens, optical fibers, and laser technology. Unfortunately, little is presently known about their bioavailability or the mechanisms by which they might cause toxicity. The present study focuses on cerium (Ce), one of the most widely used lanthanides, and on validating the biotic ligand model as a means to predict Ce bioaccumulation. Short-term exposures to Ce were performed using the unicellular alga Chlamydomonas reinhardtii, to better relate Ce bioavailability to its chemical speciation in solution. Maximum uptake fluxes (Jmax) and affinity constants for the binding of Ce to the biological uptake sites (KS) were established at pH 5.0 and pH 7.0. An apparent affinity constant of 1.8 × 107 M–1 was observed at pH 5.0, with a larger value obtained at pH 7.0 (6 × 107 M–1), albeit under conditions where equilibrium could not be confirmed. By evaluating Ce speciation using centrifugal ultrafiltration and single-particle inductively coupled plasma spectrometry, it could be concluded that very little (∼30%) Ce was truly dissolved at pH 7.0, with the majority of the metal being present in colloidal species. Speciation was also monitored by fluorescence to evaluate Ce complexation by natural organic matter (NOM). The presence of NOM decreased Ce bioaccumulation in line with free Ce concentrations. Finally, competition with calcium for the metal uptake sites was shown to result in a decrease in Ce uptake by C. reinhardtii

Reproducibility of Facial Soft Tissue Thickness Measurements Using Cone-Beam CT Images According to the Measurement Methods

The purpose of this study was to establish the reproducibility of facial soft tissue (ST) thickness measurements by comparing three different measurement methods applied at 32 landmarks on three-dimensional cone-beam computed tomography (CBCT) images. Two observers carried out the measurements of facial ST thickness of 20 adult subjects using CBCT scan data, and inter- and intra-observer reproducibilities were evaluated. The measurement method of “perpendicular to bone” resulted in high inter- and intra-observer reproducibility at all 32 landmarks. In contrast, the “perpendicular to skin” method and “direct” method, which measures a distance between one point on bone and the other point on skin, presented low reproducibility. The results indicate that reproducibility could be increased by identifying the landmarks on hard tissue images, rather than on ST images, and the landmark description used in this study can be used in the establishment of reliable tissue depth data using CBCT images

Chemical master equation and Langevin regimes for a gene transcription model

Gene transcription models must take account of intrinsic stochasticity. The Chemical Master Equation framework is based on modelling assumptions that are highly appropriate for this context, and the Stochastic Simulation Algorithm (also known as Gillespie's algorithm) allows for practical simulations to be performed. However, for large networks and/or fast reactions, such computations can be prohibitatively expensive. The Chemical Langevin regime replaces the massive ordinary dierential equation system with a small stochastic dierential equation system that is more amenable to computation. Although the transition from Chemical Master Equation to Chemical Langevin Equation can be justied rigorously in the large system size limit, there is very little guidance available about how closely the two models match for a xed system. Here, we consider a transcription model from the recent literature and show that it is possible to compare rst and second moments in the two stochastic settings. To analyse the Chemical Master Equation we use some recent work of Gadgil, Lee and Othmer, and to analyse the Chemical Langevin Equation we use Ito's Lemma. We nd that there is a perfect match|both modelling regimes give the same means, variances and correlations for all components in the system. The model that we analyse involves 'unimolecular reactions', and we nish with some numerical simulations involving dimerization to show that the means and variances in the two regimes can also be close when more general 'bimolecular reactions' are involved

Prostaglandin insert dinoprostone versus trans-cervical balloon catheter for outpatient labour induction: a randomised controlled trial of feasibility (PROBIT-F)

Background The aim was to assess the feasibility of conducting a randomised controlled trial (RCT) of induction of labour comparing use of two methods in the outpatient setting. Methods An open-label feasibility RCT was conducted in two UK maternity units from October 2017 to March 2019. Women aged ≥ 16 years, undergoing induction of labour (IOL) at term, with intact membranes and deemed suitable for outpatient IOL according to local guidelines were considered eligible. They were randomised to cervical ripening balloon catheter (CRB) or vaginal dinoprostone (Propess). The participants completed a questionnaire and a sub-group underwent detailed interview. Service use and cost data were collected via the Adult Service Use Schedule (AD-SUS). Women who declined to participate were requested to complete a decliners’ questionnaire. Results During the study period, 274 eligible women were identified. Two hundred thirty (83.9%) were approached for participation of whom 84/230 (36.5%) agreed and 146 did not. Of these, 38 were randomised to Propess (n = 20) and CRB (n = 18). Decliner data were collected for 93 women. The reasons for declining were declining IOL (n = 22), preference for inpatient IOL (n = 22) and preference for a specific method, Propess (n = 19). The intended sample size of 120 was not reached due to restrictive criteria for suitability for outpatient IOL, participant preference for Propess and shortage of research staff. The intervention as randomised was received by 29/38 (76%) women. Spontaneous vaginal delivery was observed in 9/20 (45%) women in the dinoprostone group and 11/18 (61%) women in the CRB group. Severe maternal adverse events were recorded in one woman in each group. All babies were born with good condition and all except one (37/38, 97.4%) remained with the mother after delivery. No deaths were recorded. − 21% of women in the dinoprostone group were re-admitted prior to diagnosis of active labour compared to 12% in the CRB group. Conclusions A third of the approached eligible women agreed for randomisation. An RCT is not feasible in the current service context. Modifications to the eligibility criteria for outpatient IOL, better information provision and round the clock availability of research staff would be needed to reach sufficient numbers

Social preferences and agricultural innovation: An experimental case study from Ethiopia

We run an experiment in Ethiopia where farmers can use their own money to decrease the money of others (money burning). The data support the prediction from an inequality aversion model based on absolute income differences; but there is no support for an inequality aversion model based on comparison with mean payoff of others. Experimentally measured money burning on the village level is negatively correlated to real-life agricultural innovations. This result is robust even when data from another independent survey than the current research are used. This underscores the importance of social preferences in agricultural innovations in developing countries

Role of the community pharmacist in emergency contraception counseling and delivery in the United States: current trends and future prospects

Women and couples continue to experience unintended pregnancies at high rates. In the US, 45% of all pregnancies are either mistimed or unwanted. Mishaps with contraceptives, such as condom breakage, missed pills, incorrect timing of patch or vaginal ring application, contraceptive nonuse, forced intercourse, and other circumstances, place women at risk of unintended pregnancy. There is a critical role for emergency contraception (EC) in preventing those pregnancies. There are currently three methods of EC available in the US. Levonorgestrel EC pills have been available with a prescription for over 15 years and over-the-counter since 2013. In 2010, ulipristal acetate EC pills became available with a prescription. Finally, the copper intrauterine device remains the most effective form of EC. Use of EC is increasing over time, due to wider availability and accessibility of EC methods. One strategy to expand access for both prescription and nonprescription EC products is to include pharmacies as a point of access and allow pharmacist prescribing. In eight states, pharmacists are able to prescribe and provide EC directly to women: levonorgestrel EC in eight states and ulipristal acetate in seven states. In addition to access with a prescription written by a pharmacist or other health care provider, levonorgestrel EC is available over-the-counter in pharmacies and grocery stores. Pharmacists play a critical role in access to EC in community pharmacies by ensuring product availability in the inventory, up-to-date knowledge, and comprehensive patient counseling. Looking to the future, there are opportunities to expand access to EC in pharmacies further by implementing legislation expanding the pharmacist scope of practice, ensuring third-party reimbursement for clinical services delivered by pharmacists, and including EC in pharmacy education and training

RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF

What is the optimum time to start antiretroviral therapy in people with HIV and tuberculosis coinfection? A systematic review and meta-analysis

Background: HIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of tuberculosis treatment start, at any CD4 count. We aimed to assess whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis. Methods: We did a systematic review by searching nine database for for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studied published from database inception to 12 March 2021. We compared ART within four weeks vs. ART more than four weeks after TB treatment, and ART within two weeks vs. ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS-defining events. We used random effects meta-analysis to pool effect estimates. Results: 2468 abstracts were screened, from which we identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤ 4 week) vs. later ART (> 4 week) (risk difference [RD] 0%; 95% confidence interval [CI] -2% to +1%). Among people with CD4 count ≤50 cells/mm3, earlier ART (≤4 weeks) reduced risk of death (RD -6%; -10% to -1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS defining events (RD -2%, 95% CI -4% to 0%). Results were similar when trials were restricted to the five trials which permitted comparison of ART within two weeks to ART between two and eight weeks. Discussion: Earlier ART did not alter risk of death overall among people living with HIV who had TB disease. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase inhibitors in ART regimens. For logistical and patient preference reasons, earlier ART initiation for everyone with TB and HIV may be preferred to later ART