CAIRNS: The Cluster And Infall Region Nearby Survey I. Redshifts and Mass Profiles

The CAIRNS (Cluster And Infall Region Nearby Survey) project is a spectroscopic survey of the infall regions surrounding eight nearby, rich, X-ray luminous clusters of galaxies. We collect 15665 redshifts (3471 new or remeasured) within \sim 5-10 Mpc of the centers of the clusters, making it the largest study of the infall regions of clusters. We determine cluster membership and the mass profiles of the clusters based on the phase space distribution of the galaxies. All of the clusters display decreasing velocity dispersion profiles. The mass profiles are fit well by functional forms based on numerical simulations but exclude an isothermal sphere. Specifically, NFW and Hernquist models provide good descriptions of cluster mass profiles to their turnaround radii. Our sample shows that the predicted infall pattern is ubiquitous in rich, X-ray luminous clusters over a large mass range. The caustic mass estimates are in excellent agreement with independent X-ray estimates at small radii and with virial estimates at intermediate radii. The mean ratio of the caustic mass to the X-ray mass is 1.03\pm0.11 and the mean ratio of the caustic mass to the virial mass (when corrected for the surface pressure term) is 0.93\pm0.07. We further demonstrate that the caustic technique provides reasonable mass estimates even in merging clusters.Comment: 54 pages, 18 figures, to appear in The Astronomical Journa

P-624: Changes in plasma renin match the antihypertensive effects of aliskiren in patients with hypertension: Placebo/irbesartan-controlled trial with the orally active renin inhibitor aliskiren

For several decades, the lack of oral availability and poor antihypertensive effects of renin inhibitors (RI), despite seemingly powerful inhibition of conventionally measured plasma renin activity (PRA), have discredited RI as cardiovascular drugs. Aliskiren is a novel orally effective RI with antihypertensive potency comparable to losartan or irbesartan. The present study investigated the effects of aliskiren and irbesartan on PRA, measured by the reliable antibody trapping technique, as well as on plasma active renin concentration (ARC) and sitting systolic blood pressure (SBP). In 569 patients with mild to moderate hypertension (baseline sphygmomanometric sitting blood pressure 152±12/99±4 mmHg, mean±SD), PRA and ARC, as well as SBP were measured before and after 8 weeks of treatment with once daily oral doses of aliskiren (150, 300 or 600mg), irbesartan 150mg or placebo. The effects of study treatments on PRA, ARC and SBP are summarized in the Table. Treatment N PRA (ng/mL/h) ARC (pg/mL) SBP (mmHg) Baseline Week 8 Baseline Week 8 Baseline Week 8 Placebo 111 0.72 0.64 6.2 5.6 152 ± 12 147 ± 18 Aliskiren 150mg 112 0.66 0.20 6.0 15.3 151 ± 11 140 ± 14 Aliskiren 300mg 115 0.59 0.17 6.1 21.0 152 ± 10 137 ± 14 Aliskiren 600mg 113 0.64 0.16 5.8 34.9 153 ± 12 137 ± 16 Irbesartan 150mg 118 0.64 1.33 5.5 11.3 153 ± 11 140 ± 16 PRA and ARC values are geometric means; SBP values are mean ± SD Aliskiren reduced PRA by 69%, 71% and 75% at 150, 300 and 600mg respectively, while irbesartan doubled PRA. Most of the antihypertensive effect of aliskiren was obtained with the lowest dose, but higher doses slightly further decreased SBP. Aliskiren 150mg and irbesartan 150mg provided similar increases in ARC and hence comparably blocked the renin-angiotensin system (RAS), and the achieved SBP was also the same. Aliskiren 300mg and 600mg caused greater increases in ARC compared with irbesartan 150mg (p<0.05), and further decreases in SBP. The dose-dependent increases in ARC observed with aliskiren document increasing blockade of the RAS. In conclusion, aliskiren provides a parallel reduction in PRA and SBP, a dose-dependent blockade of the RAS and is at least as effective as irbesartan at comparable dosages (150mg

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Focus, Vol. 1 No. 1

A literary magazine of student writing published by the Department of English of Stephen F. Austin State College.https://scholarworks.sfasu.edu/focus/1000/thumbnail.jp

Albumin enhanced morphometric image analysis in CLL.

BACKGROUND: The heterogeneity of lymphocytes from patients with chronic lymphocytic leukemia (CLL) and blood film artifacts make morphologic subclassification of this disease difficult. METHODS: We reviewed paired blood films prepared from ethylene-diamine-tetraacetic acid (ETDA) samples with and without bovine serum albumin (BSA) from 82 CLL patients. Group 1 adhered to NCCLS specifications for the preparations of EDTA blood films. Group 2 consisted of blood films containing EDTA and a 1:12 dilution of 22% BSA. Eight patients were selected for digital photomicroscopy and statistical analysis. Approximately 100 lymphocytes from each slide were digitally captured. RESULTS: The mean cell area +/- standard error was 127.8 microm(2) +/- 1.42 for (n = 793) for group 1 versus 100.7 microm(2) +/- 1.39 (n = 831) for group 2. The nuclear area was 88.9 microm(2) +/- 0.85 for group 1 versus 76.4 microm(2) +/- 0.83 for group 2. For the nuclear transmittance, the values were 97.6 +/- 0.85 for group 1 and 104.1 +/- 0.83 for group 2. The nuclear:cytoplasmic ratios were 0.71 +/- 0.003 for group 1 and 0.78 +/- 0.003 for group 2. All differences were statistically significant (P \u3c 0.001). CONCLUSIONS: BSA addition results in the reduction of atypical lymphocytes and a decrease in smudge cells. BSA also decreases the lymphocyte area and nuclear area, whereas nuclear transmittance and nuclear:cytoplasmic ratio are increased. A standardized method of slide preparation would allow accurate interlaboratory comparison. The use of BSA may permit better implementation of the blood film-based subclassification of CLL and lead to a better correlation of morphology with cytogenetics and immunophenotyping. Published 2003 Wiley-Liss, Inc

Identification of novel small molecule inhibitors of adenovirus gene transfer using a high throughput screening approach

Due to many favourable attributes adenoviruses (Ads) are the most extensively used vectors for clinical gene therapy applications. However, following intravascular administration, the safety and efficacy of Ad vectors are hampered by the strong hepatic tropism and induction of a potent immune response. Such effects are determined by a range of complex interactions including those with neutralising antibodies, blood cells and factors, as well as binding to native cellular receptors (coxsackie adenovirus receptor (CAR), integrins). Once in the bloodstream, coagulation factor X (FX) has a pivotal role in determining Ad liver transduction and viral immune recognition. Due to difficulties in generating a vector devoid of multiple receptor binding motifs, we hypothesised that a small molecule inhibitor would be of value. Here, a pharmacological approach was implemented to block adenovirus transduction pathways. We developed a high throughput screening (HTS) platform to identify the small molecule inhibitors of FX-mediated Ad5 gene transfer. Using an in vitro fluorescence and cell-based HTS, we evaluated 10,240 small molecules. Following sequential rounds of screening, three compounds, T5424837, T5550585 and T5660138 were identified that ablated FX-mediated Ad5 transduction with low micromolar potency. The candidate molecules possessed common structural features and formed part of the one pharmacophore model. Focused, mini-libraries were generated with structurally related molecules and in vitro screening revealed novel hits with similar or improved efficacy. The compounds did not interfere with Ad5:FX engagement but acted at a subsequent step by blocking efficient intracellular transport of the virus. In vivo, T5660138 and its closely related analogue T5660136 significantly reduced Ad5 liver transgene expression at 48 h post-intravenous administration of a high viral dose (1 × 10&lt;sup&gt;11&lt;/sup&gt; vp/mouse). Therefore, this study identifies novel and potent small molecule inhibitors of the Ad5 transduction which may have applications in the Ad gene therapy setting

Ionizable lipid nanoparticles for in utero mRNA delivery.

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing

Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis

Defining and unpacking the core concepts of pharmacology : A global initiative

The authors acknowledge the contribution of the expert group members who contributed their expertise to the study and Professor Martin Kingsbury for his invaluable guidance on concept mapping.Peer reviewe

A Critical Review of the \u3csup\u3e15\u3c/sup\u3eN\u3csub\u3e2\u3c/sub\u3e Tracer Method to Measure Diazotrophic Production in Pelagic Ecosystems

Dinitrogen (N2) fixation is an important source of biologically reactive nitrogen (N) to the global ocean. The magnitude of this flux, however, remains uncertain, in part because N2 fixation rates have been estimated following divergent protocols and because associated levels of uncertainty are seldom reported—confounding comparison and extrapolation of rate measurements. A growing number of reports of relatively low but potentially significant rates of N2 fixation in regions such as oxygen minimum zones, the mesopelagic water column of the tropical and subtropical oceans, and polar waters further highlights the need for standardized methodological protocols for measurements of N2 fixation rates and for calculations of detection limits and propagated error terms. To this end, we examine current protocols of the 15N2 tracer method used for estimating diazotrophic rates, present results of experiments testing the validity of specific practices, and describe established metrics for reporting detection limits. We put forth a set of recommendations for best practices to estimate N2 fixation rates using 15N2 tracer, with the goal of fostering transparency in reporting sources of uncertainty in estimates, and to render N2 fixation rate estimates intercomparable among studies