Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes

The mass evolution of the first galaxies: stellar mass functions and star formation rates at 4<z<74 < z < 7 in the CANDELS GOODS-South field

We measure new estimates for the galaxy stellar mass function and star formation rates for samples of galaxies at $z \sim 4,~5,~6~\&~7$ using data in the CANDELS GOODS South field. The deep near-infrared observations allow us to construct the stellar mass function at $z \geq 6$ directly for the first time. We estimate stellar masses for our sample by fitting the observed spectral energy distributions with synthetic stellar populations, including nebular line and continuum emission. The observed UV luminosity functions for the samples are consistent with previous observations, however we find that the observed $M_{UV}$ - M$_{*}$ relation has a shallow slope more consistent with a constant mass to light ratio and a normalisation which evolves with redshift. Our stellar mass functions have steep low-mass slopes ($\alpha \approx -1.9$), steeper than previously observed at these redshifts and closer to that of the UV luminosity function. Integrating our new mass functions, we find the observed stellar mass density evolves from $\log_{10} \rho_{*} = 6.64^{+0.58}_{-0.89}$ at $z \sim 7$ to $7.36\pm0.06$ $\text{M}_{\odot} \text{Mpc}^{-3}$ at $z \sim 4$. Finally, combining the measured UV continuum slopes ($\beta$) with their rest-frame UV luminosities, we calculate dust corrected star-formation rates (SFR) for our sample. We find the specific star-formation rate for a fixed stellar mass increases with redshift whilst the global SFR density falls rapidly over this period. Our new SFR density estimates are higher than previously observed at this redshift.Comment: 28 pages, 23 figures, 2 appendices. Accepted for publication in MNRAS, August 7 201

Publishing and sharing multi-dimensional image data with OMERO

Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO’s Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org

Distribution of ancestral proto-Actinopterygian chromosome arms within the genomes of 4R-derivative salmonid fishes (Rainbow trout and Atlantic salmon)

Comparative genomic studies suggest that the modern day assemblage of ray-finned fishes have descended from an ancestral grouping of fishes that possessed 12-13 linkage groups. All jawed vertebrates are postulated to have experienced two whole genome duplications (WGD) in their ancestry (2R duplication). Salmonids have experienced one additional WGD (4R duplication event) compared to most extant teleosts which underwent a further 3R WGD compared to other vertebrates. We describe the organization of the 4R chromosomal segments of the proto-rayfinned fish karyotype in Atlantic salmon and rainbow trout based upon their comparative syntenies with two model species of 3R ray-finned fishes. Results: Evidence is presented for the retention of large whole-arm affinities between the ancestral linkage groups of the ray-finned fishes, and the 50 homeologous chromosomal segments in Atlantic salmon and rainbow trout. In the comparisons between the two salmonid species, there is also evidence for the retention of large whole-arm homeologous affinities that are associated with the retention of duplicated markers. Five of the 7 pairs of chromosomal arm regions expressing the highest level of duplicate gene expression in rainbow trout share homologous synteny to the 5 pairs of homeologs with the greatest duplicate gene expression in Atlantic salmon. These regions are derived from proto-Actinopterygian linkage groups B, C, E, J and K. Conclusion: Two chromosome arms in Danio rerio and Oryzias latipes (descendants of the 3R duplication) can, in most instances be related to at least 4 whole or partial chromosomal arms in the salmonid species. Multiple arm assignments in the two salmonid species do not clearly support a 13 proto-linkage group model, and suggest that a 12 proto-linkage group arrangement (i.e., a separate single chromosome duplication and ancestral fusion/fissions/recombination within the putative G/H/I groupings) may have occurred in the more basal soft-rayed fishes. We also found evidence supporting the model that ancestral linkage group M underwent a single chromosome duplication following the 3R duplication. In the salmonids, the M ancestral linkage groups are localized to 5 whole arm, and 3 partial arm regions (i.e., 6 whole arm regions expected). Thus, 3 distinct ancestral linkage groups are postulated to have existed in the G/H and M lineage chromosomes in the ancestor of the salmonids

A Quality Assessment of a Collaborative Model of a Pediatric Antimicrobial Stewardship Program

BACKGROUND: Infectious Diseases Society of America guidelines recommend that key antimicrobial stewardship program (ASP) personnel include an infectious disease (ID) physician leader and dedicated ID-trained clinical pharmacist. Limited resources prompted development of an alternative model by using ID physicians and service-based clinical pharmacists at a pediatric hospital. The aim of this study was to analyze the effectiveness and impact of this alternative ASP model. METHODS: The collaborative ASP model incorporated key strategies of education, antimicrobial restriction, day 3 audits, and practice guidelines. High-use and/or high-cost antimicrobial agents were chosen with audits targeting vancomycin, caspofungin, and meropenem. The electronic medical record was used to identify patients requiring day 3 audits and to communicate ASP recommendations. Segmented regression analyses were used to analyze quarterly antimicrobial agent prescription data for the institution and selected services over time. RESULTS: Initiation of ASP and day 3 auditing was associated with blunting of a preexisting increasing trend for caspofungin drug starts and use and a significant downward trend for vancomycin drug starts (relative change -12%) and use (-25%), with the largest reduction in critical care areas. Although meropenem use was already low due to preexisting requirements for preauthorization, a decline in drug use (-31%, P = .021) and a nonsignificant decline in drug starts (-21%, P = .067) were noted. A 3-month review of acceptance of ASP recommendations found rates of 90%, 93%, and 100% for vancomycin, caspofungin, and meropenem, respectively. CONCLUSIONS: This nontraditional ASP model significantly reduced targeted drug usage demonstrating acceptance of integration of service-based clinical pharmacists and ID consultants

Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology

The Fading Optical Counterpart of GRB~970228, Six Months and One Year Later

We report on observations of the fading optical counterpart of the gamma-ray burst GRB 970228, made with the Hubble Space Telescope STIS CCD approximately six months after outburst and with the HST/NICMOS and Keck/NIRC approximately one year after outburst. The unresolved counterpart is detected by STIS at V=28.0 +/- 0.25, consistent with a continued power-law decline with exponent -1.14 +/- 0.05. The counterpart is located within, but near the edge of, a faint extended source with diameter ~0."8 and integrated magnitude V=25.8 +/- 0.25. A reanalysis of HST and NTT observations performed shortly after the burst shows no evidence of proper motion of the point source or fading of the extended emission. Only the extended source is visible in the NICMOS images with a magnitude of H=23.3 +/- 0.1. The Keck observations find K = 22.8 +/- 0.3. Several distinct and independent means of deriving the foreground extinction in the direction of GRB 970228 all agree with A_V = 0.75 +/- 0.2. After adjusting for Galactic extinction, we find that the size of the observed extended emission is consistent with that of galaxies of comparable magnitude found in the Hubble Deep Field (HDF) and other deep HST images. Only 2% of the sky is covered by galaxies of similar or greater surface brightness; therefore the extended source is almost certainly the host galaxy. Additionally, we find that the extinction-corrected V - H and V - K colors of the host are as blue as any galaxy of comparable or brighter magnitude in the HDF. Taken in concert with recent observations of GRB 970508, GRB 971214, and GRB 980703 our work suggests that all four GRBs with spectroscopic identification or deep multicolor broad-band imaging of the host lie in rapidly star-forming galaxies.Comment: 24 pages, Latex, 4 PostScript figures, to appear in the May 10 issue of The Astrophysical Journal (Note: displayed abstract is abridged

Evaluation Research and Institutional Pressures: Challenges in Public-Nonprofit Contracting

This article examines the connection between program evaluation research and decision-making by public managers. Drawing on neo-institutional theory, a framework is presented for diagnosing the pressures and conditions that lead alternatively toward or away the rational use of evaluation research. Three cases of public-nonprofit contracting for the delivery of major programs are presented to clarify the way coercive, mimetic, and normative pressures interfere with a sound connection being made between research and implementation. The article concludes by considering how public managers can respond to the isomorphic pressures in their environment that make it hard to act on data relating to program performance.This publication is Hauser Center Working Paper No. 23. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers