Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about ...gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects.
Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species.
Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others.
Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies.
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Here, we sought to quantify the effects of experienced fear and worry, engendered by the COVID-19 pandemic, on both cognitive abilities-speed of information processing, task-set shifting, and ...proactive control-as well as economic risk-taking. Leveraging a repeated-measures cross-sectional design, we examined the performance of 1517 participants, collected during the early phase of the pandemic in the US (April-June 2020), finding that self-reported pandemic-related worry predicted deficits in information processing speed and maintenance of goal-related contextual information. In a classic economic risk-taking task, we observed that worried individuals' choices were more sensitive to the described outcome probabilities of risky actions. Overall, these results elucidate the cognitive consequences of a large-scale, unpredictable, and uncontrollable stressor, which may in turn play an important role in individuals' understanding of, and adherence to safety directives both in the current crisis and future public health emergencies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a ...serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.
Background
Despite national guideline recommendations, epidermal growth factor receptor mutated (EGFRm) metastatic non‐small cell lung cancer (mNSCLC) patients may still receive suboptimal treatment ...in the first line (1L). This study evaluated 1L therapy initiation in relation to biomarker testing results and time to next‐treatment or death (TTNTD) in patients receiving EGFR tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) or chemotherapy.
Methods
Stage IV EGFRm mNSCLC adults that initiated 1L EGFR TKI (first, second, or third generation), IO ± chemotherapy (IO users), or chemotherapy alone from 5/2017–12/2019 were identified from the Flatiron database. Logistic regression estimated the likelihood of initiating treatment before receiving testing results for each therapy. Median TTNTD was evaluated via Kaplan–Meier analysis. Adjusted hazards ratios (HRs) and 95% CI examining the association of 1L therapy with TTNTD were reported from multivariable Cox proportional‐hazards models.
Results
Among 758 EGFRm mNSCLC patients, EGFR TKI was used as 1L therapy for 87.3% of patients (n = 662), IO in 8.3% (n = 63), and chemotherapy only in 4.4% (n = 33). The majority of IO (61.9%) and chemotherapy only patients (60.6%) initiated therapy before test results were available, compared to 9.7% of EGFR TKIs. The odds of initiating therapy before receiving test results were higher for IO (OR: 19.6, p < 0.001) and chemotherapy alone (OR: 14.1, p < 0.001) in comparison to EGFR TKIs. Compared to IO and chemotherapy, EGFR TKIs had longer median TTNTD (EGFR TKI: 14.8 months, 95% CI: 13.5–16.3; IO: 3.7 months, 95% CI 2.8–6.2; chemotherapy: 4.4 months, 95% CI 3.1–6.8, p < 0.001). EGFR TKI patients had significantly lower risk of initiating second‐line therapy or death compared to patients on 1L IO (HR: 0.33, p < 0.001) or 1L chemotherapy (HR: 0.34, p < 0.001).
Conclusions
A portion of biomarker testing results were not used to guide 1L therapy. Patients initiating EGFR TKI as 1L therapy had longer TTNTD than IO or chemotherapy.
Ancistrus is a highly diverse neotropical fish genus that exhibits extensive chromosomal variability, encompassing karyotypic morphology, diploid chromosome number (2n = 34–54), and the evolution of ...various types of sex chromosome systems. Robertsonian rearrangements related to unstable chromosomal sites are here described. Here, the karyotypes of two Ancistrus species were comparatively analyzed using classical cytogenetic techniques, in addition to isolation, cloning, sequencing, molecular characterization, and fluorescence in situ hybridization of repetitive sequences (i.e., 18S and 5S rDNA; U1, U2, and U5 snDNA; and telomere sequences). The species analyzed here have different karyotypes: Ancistrus sp. 1 (2n = 38, XX/XY) and Ancistrus cirrhosus (2n = 34, no heteromorphic sex chromosomes). Comparative mapping showed different organizations for the analyzed repetitive sequences: 18S and U1 sequences occurred in a single site in all populations of the analyzed species, while 5S and U2 sequences could occur in single or multiple sites. A sequencing analysis confirmed the identities of the U1, U2, and U5 snDNA sequences. Additionally, a syntenic condition for U2-U5 snDNA was found in Ancistrus. In a comparative analysis, the sequences of rDNA and U snDNA showed inter- and intraspecific chromosomal diversification. The occurrence of Robertsonian rearrangements and other dispersal mechanisms of repetitive sequences are discussed.
Introduction/Aims
The mechanisms that underlie the pathogenesis of statin‐associated muscle symptoms (SAMS) remain unclear. Pregnancy is associated with increased cholesterol levels. Statins may be ...useful during pregnancy, but their safety is uncertain. Hence, we investigated the postpartum effects of exposure to rosuvastatin and simvastatin during pregnancy in Wistar rats, targeting the neuromuscular structures.
Methods
Twenty‐one pregnant Wistar rats were divided into three groups: control (C) treated with vehicle (dimethylsulfoxide + dH20), simvastatin (S) 62.5 mg/kg/day, and rosuvastatin (R) 10 mg/kg/day. Gavage was performed daily from the gestational days 8 to 20. At weaning, the postpartum mother tissues were collected and subjected to morphological and morphometric analysis of the soleus muscle, associated neuromuscular junctions (NMJs), and the sciatic nerve; protein quantification; quantification of the cholesterol and creatine kinase in the serum; and intramuscular collagen analysis.
Results
An increase in morphometric parameters (area, maximum and minimum diameters, Feret diameter, and minimum Feret) was observed in NMJs from the S and R groups in comparison with the C group, and there was also a loss of common NMJ circularity. The number of myofibers with central nuclei was higher in S (17 ± 3.9, P = .0083) and R (18.86 ± 14.42, P = .0498) than in C (6.8 ± 2.6).
Discussion
Gestational exposure to statins induced postpartum NMJ morphology alterations in soleus muscle, which may be caused by the remodeling of clusters of nicotinic acetylcholine receptors. This may be associated with the development and progression of SAMS observed in clinical practice.
Decreased nitric oxide (NO) bioavailability and oxidative stress are hallmarks of endothelial dysfunction and cardiovascular diseases. Although numerous proteins are S‐nitrosated, whether and how ...changes in protein S‐nitrosation influence endothelial function under pathophysiological conditions remains unknown. We report that active endothelial NO synthase (eNOS) interacts with and S‐nitrosates pyruvate kinase M2 (PKM2), which reduces PKM2 activity. PKM2 inhibition increases substrate flux through the pentose phosphate pathway to generate reducing equivalents (NADPH and GSH) and protect against oxidative stress. In mice, the Tyr656 to Phe mutation renders eNOS insensitive to inactivation by oxidative stress and prevents the decrease in PKM2 S‐nitrosation and reducing equivalents, thereby delaying cardiovascular disease development. These findings highlight a novel mechanism linking NO bioavailability to antioxidant responses in endothelial cells through S‐nitrosation and inhibition of PKM2.
Synopsis
Generation of nitric oxide (NO) by endothelial NO synthase (eNOS) is key for a healthy vasculature, but how protein S‐nitrosation affects endothelial cell function is poorly understood. eNOS induces S‐nitrosation and inactivation of pyruvate kinase M2, thereby triggering antioxidant responses in mice through the rewiring of endothelial cell metabolism.
Under homeostatic conditions, PKM2 is part of the endothelial NO synthase (eNOS) signalosome, and is inhibited by S‐nitrosation.
Inhibition of PKM2 shifts glucose catabolism towards the pentose phosphate pathway, which generates NADPH and reduced glutathione.
Knock‐in mice carrying activated eNOS (Y656F‐eNOS) show enhanced endothelium‐dependent NO generation and are protected against angiotensin II‐induced hypertension and endothelial dysfunction.
Endothelial nitric oxide synthase induces S‐nitrosation and inactivation of pyruvate kinase M2, triggering antioxidant responses in mice through the rewiring of endothelial cell metabolism.
This review presents information from several studies that have demonstrated the antiviral activity of extracts (Andrographis paniculata, Artemisia annua, Artemisia afra, Cannabis sativa, Curcuma ...longa, Echinacea purpurea, Olea europaea, Piper nigrum, and Punica granatum) and phytocompounds derived from medicinal plants (artemisinins, glycyrrhizin, and phenolic compounds) against SARS-CoV-2. A brief background of the plant products studied, the methodology used to evaluate the antiviral activity, the main findings from the research, and the possible mechanisms of action are presented. These plant products have been shown to impede the adsorption of SARS-CoV-2 to the host cell, and prevent multiplication of the virus post its entry into the host cell. In addition to antiviral activity, the plant products have also been demonstrated to exert an immunomodulatory effect by controlling the excessive release of cytokines, which is commonly associated with SARS-CoV-2 infections.
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