Role of the Myxoma Virus Soluble CC-Chemokine Inhibitor Glycoprotein, M-T1, during Myxoma Virus Pathogenesis

AbstractMyxoma virus is a poxvirus that causes a virulent systemic disease called myxomatosis in European rabbits. Like many poxviruses, myxoma virus encodes a variety of secreted proteins that subvert the antiviral activities of host cytokines. It was recently demonstrated that the myxoma virus M-T1 glycoprotein is a member of a large poxvirus family of secreted proteins that bind CC-chemokines and inhibit their chemoattractant activities in vitro. To determine the biological role of M-T1 in contributing to myxoma virus virulence, we constructed a recombinant M-T1-deletion mutant virus that was defective in M-T1 expression. Here, we demonstrate that M-T1 is expressed continuously during the course of myxoma virus infection as a highly stable 43-kDa glycoprotein and is dispensable for virus replication in vitro. Deletion of M-T1 had no significant effects on disease progression or in the overall mortality rate of infected European rabbits but heightened the localized cellular inflammation in primary tissue sites during the initial 2 to 3 days of infection. In the absence of M-T1 expression, deep dermal tissues surrounding the primary site of virus inoculation showed a dramatic increase in infiltrating leukocytes, particularly monocytes/macrophages, but these phagocytes remained relatively ineffective at clearing virus infection, likely due to the concerted properties of other secreted myxoma virus proteins. We conclude that M-T1 inhibits the chemotactic signals required for the influx of monocytes/macrophages during the acute-phase response of myxoma virus infection in vivo, as predicted by its ability to bind and inhibit CC-chemokines in vitro

Expression of the Myxoma Virus Tumor Necrosis Factor Receptor Homologue and M11L Genes Is Required to Prevent Virus-Induced Apoptosis in Infected Rabbit T Lymphocytes

AbstractMyxoma virus is a leporipoxvirus that causes a highly lethal virulent disease known as myxomatosis in the European rabbit. An important aspect of myxoma virus pathogenesis is the ability of the virus to productively infect lymphocytes and spread to secondary sites via lymphatic channels. We investigated the infection of the CD4+T lymphoma cell line RL-5 with myxoma virus and Shope fibroma virus, a related but benign leporipoxvirus, and observed that myxoma virus, but not Shope fibroma virus, was able to productively infect RL-5 cells. We also discovered that infection of RL-5 cells with Shope fibroma virus or attenuated myxoma virus mutants containing disruptions in either the T2 or the M11L gene resulted in the rapid induction of DNA fragmentation, followed by morphological changes and loss in cell integrity characteristic of cell death by apoptosis. Purified exogenous T2 protein was unable to prevent apoptosis, suggesting that T2 functions intracellularly. Thus, myxoma virus T2, originally described as a secreted homologue of the tumor necrosis factor receptor, and M11L, a novel transmembrane species with no known cellular homologue, function to extend virus host range for replication in rabbit T lymphocytes through the inhibition of apoptosis in infected T lymphocytes

BRAF activating mutations involving the β3-αC loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma

https://deepblue.lib.umich.edu/bitstream/2027.42/142789/1/40478_2018_Article_525.pd

U.S. public opinion about the safety of gene editing in the agriculture and medical fields and the amount of evidence needed to improve opinions

Introduction: Implementation of gene editing in agriculture and medicine hinges on public acceptance. The objectives of this study were to explore U.S. public opinion about gene editing in agricultural and medical fields and to provide more insight into the relationship between opinions about the safety of gene editing and the potential impact of evidence to improve opinions about safety.Methods: Data were from two samples of U.S. respondents: 1,442 respondents in 2021 and 3,125 respondents in 2022. Survey respondents provided their opinions about the safety of gene editing in the agricultural and medical fields and answered questions about the number of studies or length of time without a negative outcome to improve opinions about the safety of gene editing in the agricultural and medical fields.Results: Results indicated that respondents in both samples were more familiar, more likely to have an opinion about safety, and more positive about the safety of gene editing in the agricultural field than in the medical field. Also, familiarity was more closely associated with opinions about safety than the strength of opinions.Discussion: These findings add to the literature examining perceptions of gene editing in the agricultural or medical fields separately. Opinions about the safety of gene editing were generally more favorable for respondents who were aware of the use of gene editing. These results support a proactive approach for effective communication strategies to inform the public about the use of gene editing in the agricultural and medical fields

Sailor Perspectives and Recommendations for Communication About Divisive Events and Inclusion within the Fleet

Recent events, such as the death of George Floyd and the resulting Black Lives Matter (BLM) protests, the post elections attack on the U.S. Capitol, and the COVID-19 pandemic, have brought to light the challenges leaders in both private and public/governmental organizations face when communicating with employees about sensitive events. At both the national and global levels these issues are often tied to deep and long-held societal divisions. The U.S. Navy has frequently taken a progressive stance in supporting diversity and inclusion, and the Navy's recent steps to encourage inclusion and engage in necessary conversations are consistent with these actions. However, recent events and efforts to converse about these events have highlighted the challenges inherent in such communication. This study builds upon previous research focused on the tensions between participation and organizational control in online workplace communities (Aten & Salem, 2020). This research explored Sailors' experiences of sensitive conversations on various topics and of necessary conversations directed by Navy leadership following the attacks on the U.S. Capitol. This current research describes Sailors' perceptions of drivers and outcomes of sensitive conversations. It identifies four needed individual and organizational capacities to support successful conversations about sensitive subjects: metacognition, emotional regulation, cultural curiosity, and communication competence. Participants’ responses and related literature highlight two key conclusions. First, Sailors disagree on how the Navy should manage sensitive conversations: majority and minority groups’ perceptions differ on what topics require conversation, and fail to recognize that the inability to engage effectively in sensitive conversations is a military vulnerability. Second, Navy communication often demonstrates an inadequate capacity for managing these conversations: leaders lack self-awareness, emotional regulation is challenging, cultural curiosity is not developed, and the tensions generated by communication hierarchies limit communication effectiveness. These capability gaps constrain Sailors' positive perceptions of sensitive conversations which contribute to continued divisive conversations, reduced perceptions of inclusion, and increased risk from information warfare

Species and Population Specific Gene Expression in Blood Transcriptomes of Marine Turtles

Background: Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms\u27 responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations.ResultsWe generated high quality blood transcriptome assemblies for hawksbill (Eretmochelys imbricata), loggerhead (Caretta caretta), green (Chelonia mydas), and leatherback (Dermochelys coriacea) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance.ConclusionsObtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles

Species and population specific gene expression in blood transcriptomes of marine turtles

Background: Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms’ responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations. Results: We generated high quality blood transcriptome assemblies for hawksbill (Eretmochelys imbricata), loggerhead (Caretta caretta), green (Chelonia mydas), and leatherback (Dermochelys coriacea) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance. Conclusions: Obtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles

High-fat diet exacerbates SIV pathogenesis and accelerates disease progression

Copyright: © 2019. American Society for Clinical Investigation.Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.This study was funded through NIH/NHLBI/NIAID/NIDDK/ NCRR R01 grants HL117715 (to IP), HL123096 (to IP), AI119346 (to CA), DK113919 (to IP and CA), DK119936 (to CA), RR025781 (to CA and IP), and AI104373 (to RMR). RMR was funded by grant PTDC/ MAT-APL/31602/2017 from the Fundação para a Ciência e Tecnologia (Portugal). DNF and CCW were supported by the University of Colorado GI and Liver Innate Immunity Program. KDR and BBP were partly supported by the NIH Training Grant T32AI065380. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy

Conventional methods for intraoperative histopathologic diagnosis are labor- and time-intensive and may delay decision-making during brain tumor surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain tumor infiltration in fresh, unprocessed human tissues. Previously, the execution of SRS microscopy in a clinical setting has not been possible. We report the first demonstration of SRS microscopy in an operating room using a portable fiber-laser-based microscope in unprocessed specimens from 101 neurosurgical patients. Additionally, we introduce an image-processing method, stimulated Raman histology (SRH), which leverages SRS images to create virtual hematoxylin and eosin- stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, the concordance of SRH and conventional histology for predicting diagnosis was nearly perfect (κ>0.89) and accuracy exceeded 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain tumor subtype with 90% accuracy. This study provides insight into how SRH can now be used to improve the surgical care of brain tumor patients.Chemistry and Chemical Biolog

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie