PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury.

Stroke is a leading cause of death and long-term disability in industrialized countries. Despite advances in understanding its pathophysiology, little progress has been made in the treatment of stroke. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signaling proteins which could be exploited to design novel therapeutic modalities. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. PPARs regulate gene expression by binding with the retinoid X receptor (RXR) as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/ δ, and γ, have been identified. Recently, they have been found to play an important role for the pathogenesis of various disorders of the central nervous system and accumulating data suggest that PPARs may serve as potential targets for treating ischemic stroke. Activation of all PPAR isoforms, but especially of PPAR γ, was shown to prevent post-ischemic inflammation and neuronal damage in several in vitro and in vivo models, negatively regulating the expression of genes induced by ischemia/ reperfusion (I/R). This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPAR-agonists in the treatment of cerebral I/R injury

The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1β and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation

Effect of Intubation Timing on the Outcome of Patients With Severe Respiratory Distress Secondary to COVID-19 Pneumonia.

Background: The optimal timing of intubation for critically ill patients with severe respiratory illness remains controversial among healthcare providers. The coronavirus disease 2019 (COVID-19) pandemic has raised even more questions about when to implement this life-saving therapy. While one group of providers prefers early intubation for patients with respiratory distress because these patients may deteriorate rapidly without it, other providers believe that intubation should be delayed or avoided because of its associated risks including worse outcomes. Research question: Our objective was to assess whether the timing of intubation in patients with severe COVID-19 pneumonia was associated with differences in mortality or other outcomes. Study design and methods: This was a single-center retrospective observational cohort study. We analyzed outcomes of patients who were intubated secondary to COVID-19 pneumonia between March 13, 2020, and December 12, 2020, at Henry Ford Hospital in Detroit, Michigan. Patients were categorized into two groups: early intubated (intubated within 24 hours of the onset of severe respiratory distress) and late intubated (intubated after 24 hours of the onset of severe respiratory distress). Demographics, comorbidities, respiratory rate oxygenation (ROX) index, sequential organ failure assessment (SOFA) score, and treatment received were compared between groups. The primary outcome was mortality. Secondary outcomes were ventilation time, intensive care unit stay, hospital length of stay, and discharge disposition. Post hoc and Kaplan-Meier survival analyses were performed. Results: A total of 110 patients were included: 55 early intubated and 55 late intubated. We did not observe a significant difference in overall mortality between the early intubated (43%) and the late intubated groups (53%) (p = 0.34). There was no statistically significant difference in patients\u27 baseline characteristics including SOFA scores (the early intubation group had a mean score of 7.5 compared to 6.7 in the late intubation group). Based on the ROX index, the early intubation group had significantly more patients with a reduced risk of intubation (45%) than the late group (27%) (p = 0.029). The early intubation group was treated with a high-flow nasal cannula at a significantly lower rate (47%) than the late intubation group (83%) (p \u3c 0.001). Significant differences in patient baseline characteristics, treatment received, and other outcomes were not observed. Post hoc analysis adjusting for SOFA score between 0 and 9 revealed significantly higher mortality in the late intubation group (49%) than in the early intubation group (26%) (p = 0.03). Patients in the 0 to 9 SOFA group who were intubated later had 2.7 times the odds of dying during hospital admission compared to patients who were intubated early (CI, 1.09-6.67). Interpretation: The timing of intubation for patients with severe COVID-19 pneumonia was not significantly associated with overall mortality or other patient outcomes. However, within the subgroup of patients with SOFA scores of 9 or lower at the time of intubation, patients intubated after 24 hours of the onset of respiratory distress had a higher risk of death than those who were intubated within 24 hours of respiratory distress. Thus, patients with COVID-19 pneumonia who are not at a high level of organ dysfunction may benefit from early mechanical ventilation

The Rapid Outbursting Star GM Cep: An EX-or in Tr 37?

We present optical, IR and millimeter observations of the solar-type star 13-277, also known as GM Cep, in the 4 Myr-old cluster Tr 37. GM Cep experiences rapid magnitude variations of more than 2 mag at optical wavelengths. We explore the causes of the variability, which seem to be dominated by strong increases in the accretion, being similar to EX-or episodes. The star shows high, variable accretion rates (up to ~10$^{-6}$ Msun/yr), signs of powerful winds, and it is a very fast rotator (Vsini~43 km/s). Its strong mid-IR excesses reveal a very flared disk and/or a remnant envelope, most likely out of hydrostatic equilibrium. The 1.3 millimeter fluxes suggest a relatively massive disk (Mdisk~0.1 Msun). Nevertheless, the millimeter mass is not enough to sustain increased accretion episodes over large timescales, unless the mass is underestimated due to significant grain growth. We finally explore the possibility of GM Cep having a binary companion, which could trigger disk instabilities producing the enhanced accretion episodes.Comment: 43 pages, including 10 figures, ApJ in pres

Precision Needle-Punch Tumor Enrichment From Paraffin Blocks Improves the Detection of Clinically Actionable Genomic Alterations and Biomarkers

BACKGROUND: While many molecular assays can detect mutations at low tumor purity and variant allele frequencies, complex biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) require higher tumor purity for accurate measurement. Scalable, quality-controlled, tissue-conserving methods to increase tumor nuclei percentage (TN%) from tumor specimens are needed for complex biomarkers and hence necessary to maximize patient matching to approved therapies or clinical trial enrollment. We evaluated the clinical utility and performance of precision needle-punch enrichment (NPE) compared with traditional razor blade macroenrichment of tumor specimens on molecular testing success. METHODS: Pathologist-directed NPE was performed manually on formalin-fixed, paraffin embedded (FFPE) blocks. Quality control of target capture region and quantity of residual tumor in each tissue block was determined via a post-enrichment histologic slide recut. Resultant tumor purity and biomarker status were determined by the computational analysis pipeline component of the FDA-approved next-generation sequencing (NGS) assay, FoundationOne RESULTS: In real-world clinical samples, enrichment rate via NPE was increased to ~50% over a 2.5-year period, exceeding the prior use of razor blade macro-enrichment ( CONCLUSIONS: Pathologist-directed precision enrichment from tissue blocks (aka NPE) increases tumor purity, and consequently, yields a greater number of successful tests and complex biomarker determinations. Moreover, this process is rapid, safe, inexpensive, scalable, and conserves patient surgical pathology material. NPE may constitute best practice with respect to enriching tumor cells from low-purity specimens for biomarker detection in molecular laboratories

A disk of dust and molecular gas around a high-mass protostar

The processes leading to the birth of low-mass stars such as our Sun have been well studied, but the formation of high-mass (> 8 x Sun's mass) stars has heretofore remained poorly understood. Recent observational studies suggest that high-mass stars may form in essentially the same way as low-mass stars, namely via an accretion process, instead of via merging of several low-mass (< 8 Msun) stars. However, there is as yet no conclusive evidence. Here, we report the discovery of a flattened disk-like structure observed at submillimeter wavelengths, centered on a massive 15 Msun protostar in the Cepheus-A region. The disk, with a radius of about 330 astronomical units (AU) and a mass of 1 to 8 Msun, is detected in dust continuum as well as in molecular line emission. Its perpendicular orientation to, and spatial coincidence with the central embedded powerful bipolar radio jet, provides the best evidence yet that massive stars form via disk accretion in direct analogy to the formation of low-mass stars

Changes in the Optic Nerve Head and Choroid Over 1 Year of Spaceflight

Importance: While 6-month data are available regarding spaceflight-associated neuro-ocular syndrome, manned missions for 1 year and beyond are planned, warranting evaluation for spaceflight-associated neuro-ocular syndrome beyond 6 months. Objective: To determine if the manifestation of spaceflight-associated neuro-ocular syndrome worsens during International Space Station missions exceeding the present 4- to 6-month duration. Design, Setting, and Participants: The One-Year Mission Study used quantitative imaging modalities to investigate changes in ocular structure in 2 crew members who completed a 1-year-long spaceflight mission. This study investigated the ocular structure of crew members before, during, and after their mission on the International Space Station. Two crew members participated in this study from March 2015 to September 2016. Analysis began in March 2015 and ended in May 2020. Exposures: Crew members were tested before, during, and up to 1 year after spaceflight. Main Outcomes and Measures: This study compares ocular changes (peripapillary retinal edema, axial length, anterior chamber depth, and refraction) in two 1-year spaceflight mission crew members with cohort crew members from a 6-month mission (n = 11). Minimum rim width (the shortest distance between Bruch membrane opening and the internal limiting membrane) and peripapillary total retinal thickness were measured using optical coherence tomography. Results: Both crew members were men. Minimum rim width and total retinal thickness increased in both participants throughout the duration of spaceflight exposure to the maximal observed change from preflight (minimum rim width: participant 1, 561 [+149 from preflight] μm at flight day 270; participant 2, 539 [+56 from preflight] μm at flight day 270; total retinal thickness: participant 1, 547 [+135 from preflight] μm at flight day 90; participant 2, 528 [+45 from preflight] μm at flight day 210). Changes in peripapillary choroid engorgement, axial length, and anterior chamber depth appeared similar between the 1-year mission participants and a 6-month mission cohort. Conclusions and Relevance: This report documents the late development of mild optic disc edema in 1 crew member and the progressive development of choroidal folds and optic disc edema in another crew member over the duration of 1 year in low Earth orbit aboard the International Space Station. Previous reports characterized the ocular risk associated with 4 to 6 months of spaceflight. As future spaceflight missions are planned to increase in duration and extend beyond low Earth orbit, further observation of astronaut ocular health on spaceflight missions longer than 6 months in duration may be warranted

'Preconditioning' with Low Dose Lipopolysaccharide Aggravates the Organ Injury/Dysfunction Caused by Hemorrhagic Shock in Rats

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedRS is supported by the Program Science without Borders, CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF, Brazil; NSAP is, in part, supported by the Bart’s and The London Charity (753/1722). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 608765, from the William Harvey Research Foundation and University of Turin (Ricerca Locale ex-60%). This work contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences, supported by the Barts and The London Charity (Award 753/1722

The Greenland Telescope: Construction, Commissioning, and Operations in Pituffik

In 2018, the Greenland Telescope (GLT) started scientific observation in Greenland. Since then, we have completed several significant improvements and added new capabilities to the telescope system. This paper presents a full review of the GLT system, a summary of our observation activities since 2018, the lessons learned from the operations in the Arctic regions, and the prospect of the telescope.Comment: 26 pages, 11 figures, and 8 tables. This is the version of the article before publication editing, as submitted by an author to Publications of the Astronomical Society of the Pacific. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record will be added when it becomes availabl