Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that ...repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.
We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up.
Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score.
GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.
ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.
We employ robust weak gravitational lensing measurements to improve cosmological constraints from measurements of the galaxy cluster mass function and its evolution, using X-ray selected clusters ...detected in the ROSAT All-Sky Survey. Our lensing analysis constrains the absolute mass scale of such clusters at the 8 per cent level, including both statistical and systematic uncertainties. Combining it with the survey data and X-ray follow-up observations, we find a tight constraint on a combination of the mean matter density and late-time normalization of the matter power spectrum, ..., with marginalized, one-dimensional constraints of ... and ... For these two parameters, this represents a factor of 2 improvement in precision with respect to previous work, primarily due to the reduced systematic uncertainty in the absolute mass calibration provided by the lensing analysis. Our new results are in good agreement with constraints from cosmic microwave background (CMB) data, both Wilkinson Microwave Anisotropy Probe (WMAP) and Planck (plus WMAP polarization), under the assumption of a flat ...CDM cosmology with minimal neutrino mass. Consequently, we find no evidence for non-minimal neutrino mass from the combination of cluster data with CMB, supernova and baryon acoustic oscillation measurements, regardless of which all-sky CMB data set is used (and independent of the recent claimed detection of B modes on degree scales). We also present improved constraints on models of dark energy (both constant and evolving), modifications of gravity, and primordial non-Gaussianity. Assuming flatness, the constraints for a constant dark energy equation of state from the cluster data alone are at the 15 per cent level, improving to ~6 per cent when the cluster data are combined with other leading probes. (ProQuest: ... denotes formulae/symbols omitted.)
Despite their widespread adoption, concerns remain that virtual work arrangements can harm employee job performance and citizenship behavior. Does telecommuting really hamper these critical ...dimensions of employee effectiveness? To answer this question, we develop a theoretical framework linking telecommuting to task and contextual performance via a dual set of mechanisms—reflecting proposed effects of i‐deals and job resources. Further, we propose that the meaning of and outcomes from these paths depend on the social context surrounding telecommuting. We test the framework with field data from 323 employees and 143 matched supervisors across a variety of organizations. As predicted, we find that telecommuting is positively associated with task and contextual performance, directly and indirectly via perceived autonomy. These beneficial effects are contingent upon two aspects of the social context: leader‐member exchange and signals of its normative appropriateness among coworkers and one's supervisor.
The majority of the brain's vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using ...two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain.
The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of ...immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.
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•scRNA-seq defines the infiltrating immune populations in ccRCC across disease stages•Terminally exhausted CD8+ T cells and M2-like TAMs are enriched in advanced ccRCC•Exhausted CD8+ T cells and TAMs interact to form an immune dysfunction circuit•Signature of terminal exhaustion/TAM interaction is associated with worse prognosis
The immune cell changes that occur with advancing disease stage in renal cell carcinoma are incompletely characterized. Braun et al. show that terminally exhausted CD8+ T cells and M2-like tumor-associated macrophages are enriched in advanced disease and interact to form an immune dysfunction circuit that is associated with poorer prognosis.
Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene ...positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes ⅓ to ⅔ of a gene’s normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation.
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•Tissue-specific NETs direct repositioning of critical muscle genes during myogenesis•Expression changes for NET-repositioned genes depend on cell differentiation state•Isolating position from differentiation reveals its contribution to gene expression•Three NETs together affect 37% of all genes normally changing in myogenesis
Muscle-specific nuclear envelope transmembrane proteins (NETs) optimize myogenic gene expression by physically recruiting genes to the periphery and enhancing their repression. Specifically manipulating the position of endogenous genes in myoblasts and myotubes indicates that peripheral localization enhances repression, but only in context of other changes in differentiation.
The Sociocultural Attitudes Towards Appearance Questionnaire-3 (SATAQ-3) and its earlier versions are measures designed to assess societal and interpersonal aspects of appearance ideals. ...Correlational, structural equation modeling, and prospective studies of the SATAQ-3 have shown consistent and significant associations with measures of body image disturbance and eating pathology. In the current investigation, the SATAQ-3 was revised to improve upon some conceptual limitations and was evaluated in 4 U.S. and 3 international female samples, as well as a U.S. male sample. In Study 1, exploratory and confirmatory factor analyses for a sample of women from the Southeastern United States (N = 859) indicated a 22-item scale with 5 factors: Internalization: Thin/Low Body Fat, Internalization: Muscular/Athletic, Pressures: Family, Pressures: Media, Pressures: Peers. This scale structure was confirmed in 3 independent and geographically diverse samples of women from the United States (East Coast N = 440, West Coast N = 304, and North/Midwest N = 349). SATAQ-4 scale scores demonstrated excellent reliability and good convergent validity with measures of body image, eating disturbance, and self-esteem. Study 2 replicated the factorial validity, reliability, and convergent validity of the SATAQ-4 in an international sample of women drawn from Italy, England, and Australia (N = 362). Study 3 examined a sample of college males from the United States (N = 271); the 5-factor solution was largely replicated, yet there was some evidence of an underlying structure unique to men. Future research avenues include additional item testing and modification of the scale for men, as well as adaptation of the measure for children and adolescents.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
Diabetes mellitus predisposes the host to bacterial infections. Moreover, hyperglycemia has been shown to be an independent risk factor for respiratory infections. The luminal surface of airway ...epithelia is covered by a thin layer of airway surface liquid (ASL) and is normally sterile despite constant exposure to bacteria. The balance between bacterial growth and killing in the airway determines the outcome of exposure to inhaled or aspirated bacteria: infection or sterility. We hypothesized that restriction of carbon sources--including glucose--in the ASL is required for sterility of the lungs. We found that airway epithelia deplete glucose from the ASL via a novel mechanism involving polarized expression of GLUT-1 and GLUT-10, intracellular glucose phosphorylation, and low relative paracellular glucose permeability in well-differentiated cultures of human airway epithelia and in segments of airway epithelia excised from human tracheas. Moreover, we found that increased glucose concentration in the ASL augments growth of P. aeruginosa in vitro and in the lungs of hyperglycemic ob/ob and db/db mice in vivo. In contrast, hyperglycemia had no effect on intrapulmonary bacterial growth of a P. aeruginosa mutant that is unable to utilize glucose as a carbon source. Our data suggest that depletion of glucose in the airway epithelial surface is a novel mechanism for innate immunity. This mechanism is important for sterility of the airways and has implications in hyperglycemia and conditions that result in disruption of the epithelial barrier in the lung.
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