Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier ...mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.
Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) ...pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles. These abundant, reactive microglia selectively cleared neuronal hTDP-43. Finally, when microgliosis was blocked during the early recovery phase using PLX3397, a CSF1R and c-kit inhibitor, rNLS8 mice failed to regain full motor function, revealing an important neuroprotective role for microglia. Therefore, reactive microglia exert neuroprotective functions in this amyotrophic lateral sclerosis model, and definition of the underlying mechanism could point toward novel therapeutic strategies.
Aerosol generation with modes of oxygen therapy such as high-flow nasal cannula and noninvasive positive-pressure ventilation is a concern for healthcare workers during the severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) pandemic. The amount of aerosol generation from the respiratory tract with these various oxygen modalities is unknown.
To measure the size and number concentration of particles and droplets generated from the respiratory tract of humans exposed to various oxygen delivery modalities.
Ten healthy participants with no active pulmonary disease were enrolled. Oxygen modalities tested included nonhumidified nasal cannula, face mask, heated and humidified high-flow nasal cannula, and noninvasive positive-pressure ventilation. Aerosol generation was measured with each oxygen mode while participants performed maneuvers of normal breathing, talking, deep breathing, and coughing. Testing was conducted in a negative-pressure room. Particles with a diameter between 0.37 and 20 μm were measured using an aerodynamic particle spectrometer.
Median particle concentration ranged from 0.041 to 0.168 particles/cm
. Median diameter ranged from 1.01 to 1.53 μm. Cough significantly increased the number of particles measured. Measured aerosol concentration did not significantly increase with the use of either humidified high-flow nasal cannula or noninvasive positive-pressure ventilation. This was the case during normal breathing, talking, deep breathing, and coughing.
Oxygen delivery modalities of humidified high-flow nasal cannula and noninvasive positive-pressure ventilation do not increase aerosol generation from the respiratory tract in healthy human participants with no active pulmonary disease measured in a negative-pressure room.
The COVID-19 pandemic and its associated vaccine have highlighted vaccine hesitancy among healthcare workers (HCWs). Vaccine hesitancy among this group existed prior to the pandemic and particularly ...centered around influenza vaccination. Being a physician, having more advanced education, and previous vaccination habits are frequently associated with vaccine acceptance. The relationship between age and caring for patients on COVID-19 vaccination is unclear, with studies providing opposing results. Reasons for hesitancy include concerns about safety and efficacy, mistrust of government and institutions, waiting for more data, and feeling that personal rights are being infringed upon. Many of these reasons reflect previous attitudes about influenza vaccination as well as political beliefs and views of personal autonomy. Finally, several interventions to encourage vaccination have been studied, including education programs and non-monetary incentives with the most effective studies using a combination of methods.
Limonene is a valuable monoterpene used in the production of several commodity chemicals and medicinal compounds. Among them, perillyl alcohol (POH) is a promising anti-cancer agent that can be ...produced by hydroxylation of limonene. We engineered E. coli with a heterologous mevalonate pathway and limonene synthase for production of limonene followed by coupling with a cytochrome P450, which specifically hydroxylates limonene to produce POH. A strain containing all mevalonate pathway genes in a single plasmid produced limonene at titers over 400mg/L from glucose, substantially higher than has been achieved in the past. Incorporation of a cytochrome P450 to hydroxylate limonene yielded approximately 100mg/L of POH. Further metabolic engineering of the pathway and in situ product recovery using anion exchange resins would make this engineered E. coli a potential production platform for any valuable limonene derivative.
•We report limonene production in E. coli using a heterologous mevalonate pathway.•Perillyl alcohol was produced in E. coli from endogenously generated limonene.•Limonene and perillyl alcohol titers were highly improved by metabolic engineering.•An anion exchange resin was used to improve specific recovery of perillyl alcohol.
Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (N
= 270/N
...= 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (P
= 2.19 × 10
, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10
at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 95% CI: 1.09-3.02) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10
, HR = 0.91 95% CI :0.89-0.93, for MI) and Million Veteran Program (P = 9.33 × 10
, OR = 0.95 95% CI: 0.94-0.96, for CAD; P = 3.35 × 10
, OR = 0.96 95% CI: 0.95-0.98 for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.
Genome reduction has been observed in many bacterial lineages that have adapted to specialized environments. The extreme genome degradation seen for obligate pathogens and symbionts appears to be ...dominated by genetic drift. In contrast, for free-living organisms with reduced genomes, the dominant force is proposed to be direct selection for smaller, streamlined genomes. Most variation in gene content for these free-living species is of "accessory" genes, which are commonly gained as large chromosomal islands that are adaptive for specialized traits such as pathogenicity. It is generally unclear, however, whether the process of accessory gene loss is largely driven by drift or selection. Here we demonstrate that selection for gene loss, and not a shortened genome, per se, drove massive, rapid reduction of accessory genes. In just 1,500 generations of experimental evolution, 80% of populations of Methylobacterium extorquens AM1 experienced nearly parallel deletions removing up to 10% of the genome from a megaplasmid present in this strain. The absence of these deletion events in a mutation accumulation experiment suggested that selection, rather than drift, has dominated the process. Reconstructing these deletions confirmed that they were beneficial in their selective regimes, but led to decreased performance in alternative environments. These results indicate that selection can be crucial in eliminating unnecessary genes during the early stages of adaptation to a specialized environment.
Axisymmetric Radiative Transfer Models of Kilonovae Korobkin, Oleg; Wollaeger, Ryan T.; Fryer, Christopher L. ...
Astrophysical journal/The Astrophysical journal,
04/2021, Letnik:
910, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
The detailed observations of GW170817 proved for the first time directly that neutron star mergers are a major production site of heavy elements. The observations could be fit by a number of ...simulations that qualitatively agree, but can quantitatively differ (e.g., in total r-process mass) by an order of magnitude. We categorize kilonova ejecta into several typical morphologies motivated by numerical simulations, and apply a radiative transfer Monte Carlo code to study how the geometric distribution of the ejecta shapes the emitted radiation. We find major impacts on both spectra and light curves. The peak bolometric luminosity can vary by two orders of magnitude and the timing of its peak by a factor of five. These findings provide the crucial implication that the ejecta masses inferred from observations around the peak brightness are uncertain by at least an order of magnitude. Mixed two-component models with lanthanide-rich ejecta are particularly sensitive to geometric distribution. A subset of mixed models shows very strong viewing angle dependence due to lanthanide “curtaining,” which persists even if the relative mass of lanthanide-rich component is small. The angular dependence is weak in the rest of our models, but different geometric combinations of the two components lead to a highly diverse set of light curves. We identify geometry-dependent P Cygni features in late spectra that directly map out strong lines in the simulated opacity of neodymium, which can help to constrain the ejecta geometry and to directly probe the r-process abundances.
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