Mechanical suppression of premature ventricular complexes during catheter ablation procedures

IntroductionMechanical suppression of premature ventricular complexes (PVCs) is not a well-known observation. We retrospectively reviewed this phenomenon in the Ventricular Arrhythmia (VA) ablation procedures performed at Richard L. Roudebush Veterans Health Administration (VHA) center.MethodsData from 40 consecutive patients who underwent VA ablation at VHA, Indianapolis, IN, with 44 VA was included in the study. Demographic and electrophysiological parameter data was collected.ResultsOverall the mean age of the population was 64 ± 11 years. The phenomenon of mechanical suppression was seen in 11 PVCs. The mean age was 59 ± 15 years in the group in which mechanical suppression was seen. Of the 11 cases, the site of earliest activation was seen in the coronary sinus in 8 and in the pulmonary artery in 3. In one case catheter ablation was not performed because of proximity to the left coronary artery system. However, sustained pressure at the site with earliest electrograms (?35 ms) and 95% pacematch resulted in long-term suppression of PVCs. In the cases in which mechanical suppression was seen, there was a statistically significant reduction in PVC burden compared to pre ablation PVC load (1.1% ± 1.50% (post ablation) versus 24.04% ± 13.07% (pre ablation) versus p < 0.05).In all the 11 cases the site of mechanical suppression was also the site with earliest electrograms.ConclusionThis case series illustrates phenomenon of mechanical suppression of PVCs as an indication for good site for successful ablation in unique veteran patient population.     

Premature ventricular contractions in patients with an implantable cardioverter defibrillator cardiac resynchronization therapy device: Results from the UMBRELLA registry

BackgroundPremature ventricular contractions (PVC) are known to reduce the percentage of biventricular (BiV) pacing in patients with cardiac resynchronization (CRT), decreasing the clinical response. The aim of this study was to evaluate the prevalence of a high PVC burden, as well as therapeutic action (pharmacotherapy, catheter ablation or device programming), in a large CRT implantable-defibrillator (CRT-D) population.MethodsPatients with a CRT-D device from the UMBRELLA multicenter prospective remote monitoring registry were included. The PVC count was collected from each remote monitoring transmission. Patients were divided into two high (≥1 transmission ≥200/≥400 PVC/h, respectively) and one low (all transmissions <200 PVC/h) PVC count groups. The PVC burden following a high PVC count transmission was calculated.ResultsOf 1268 patients, 135 (11%) and 43 (3.4%) presented high PVC count (≥200/≥400 PVC/h, respectively). The majority of patients in the high PVC groups were not treated (61 [79%] and 32 [74%], respectively. Considering the untreated patients in the high PVC groups, median PVC/h was 199 (interquartile range [IQR]: 196) and 271 (IQR: 330), respectively. The PVC burden (proportion of time with PVC/h ≥ 200/≥400) was 40% (IQR 70) and 29% (IQR 59), respectively.ConclusionA significant proportion of CRT-D patients presented a high PVC count, however, few received treatment. In the untreated patients with a high PVC count, the PVC burden during follow-up varied substantially. Several consecutive recordings of a high PVC count should be warranted before considering therapeutic action such as catheter ablation.     

Logit model in prospective coronary heart disease (CHD) risk factors prediction in Saudi population

Analysis through logistic regression explored to investigate the relationship between binary or multivariable ordinal response probability and in one or more explanatory variables. The main objectives of this study to investigate advanced prediction risk factor of Coronary Heart Disease (CHD) using a logit model. Attempts made to reduce risk factors, increase public or professional awareness. Logit model used to evaluate the probability of a person develop CHD, considering any factors such as age, gender, high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, high blood pressure, family history of CHD younger than 45, diabetes, smoking, being post-menopausal for women and being older than 45 for men. Logit concept of brief statistics described with slight modification to estimate the parameters testing for the significance of the coefficients, confidence interval fits the simple, multiple logit models. Besides, interpretation of the fitted logit regression model introduced. Variables showing best results within the scientific context, good explanation data assessed to fit an estimated logit model containing chosen variables, this present experiment used the statistical inference procedure; chi-square distribution, likelihood ratio, Score, or Wald test and goodness-of-fit. Health promotion started with increased public or professional awareness improved for early detection of CHD, to reduce the risk of mortality, aimed to be Saudi vision by 2030.     

Every face tells a story-unravelling a case of bidirectional ventricular tachycardia

Bidirectional ventricular tachycardia is a rare form of tachycardia. We hereby report a case of bidirectional ventricular tachycardia in an 8-year-old boy wherein careful clinical exami-nation led to the diagnosis of Andersen Tawil syndrome. The case also demonstrates the efficacy of flecainide in managing bidirectional ventricular tachycardia in the setting of Andersen Tawil syndrome.     

Unique high sensitivity to heat of axolotl TRPV1 revealed by the heterologous expression system

The thermosensation mechanism plays critical roles in various animals living in different thermal environment. We focused on an axolotl, which is a tailed amphibian originally from Lake Xochimilco area in the Vally of Mexico, and examined its behavior response to heat stimulation. Mild heat at 33 °C induced noxious locomotive activity to axolotls, but the noxious response of another tailed amphibian, Iberian ribbed newt, was not observed at 33 °C. To explore the mechanism for the temperature sensitivity of axolotls, we isolated a cDNA of TRPV1. Using the degenerate primer PCR method, we identified the DNA fragment encoding axolotl TRPV1 (axTRPV1), and then cloned a full-length cDNA. We studied the chemical and thermal sensitivities of axTRPV1 by two-electrode voltage clamp method using Xenopus oocyte expression system. Capsaicin, acid, and 2-aminoethoxydiphenylborane apparently activated axTRPV1 channels in a dose-dependent manner. The analysis of thermal sensitivity showed that axTRPV1 was significantly activated by heat but not by cold. The average temperature threshold for heat-activation was 30.95 ± 0.12 °C. This thermal activation threshold of axTRPV1 is unique and significantly low, when compared with the known thresholds of TRPV1s from various animals. Further, this threshold of axTRPV1 is well consistent with the observation of heat-induced behavior of axolotls at 33 °C, demonstrating that axolotl shows noxious response to mild heat mediated through axTRPV1.     

Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients

Ovarian cancer (OC) is an important cause of gynecologic cancer-related deaths. In Mexico, around 4700 new cases of OC are diagnosed per year and it represents the second cause of gynecological cancer mortality with more than 2700 deaths. Germline mutations in BRCA1/2 genes are present in 13–18% of OC cases. Few studies have evaluated the presence of mutations in BRCA genes in a population of OC Mexican patients and their relationship with clinical response and survival rates.A total of 179 OC patients were studied by molecular testing for BRCA1/2 through next-generation sequencing and multiplex ligation-dependent probe amplification. Recurrence-free survival (RFS) was estimated by the Kaplan–Meier method. BRCA mutation was detected in 33% of patients. A percentage of 66.1% were BRCA1 mutated and 33.9% were BRCA2 mutated. BRCA1 mutation carriers had a worst RFS compared with BRCA2 mutation carriers (37.6 [29–46.2] vs 72.7 [38.4–107.2]; P = 0.030). The most common mutation for BRCA1 was ex9-12del (28.2%) (Mexican founder mutation). The Mexican founder mutation had a better RFS than other BRCA1 mutations (86.1 [37.2–135.1] vs 34.5 [20.7–48.2]; P = 0.033). The presence of BRCA2 mutations in the ovarian cancer cluster region (OCCR) had a significantly better RFS than mutations in breast cancer cluster regions (BCCR) and not-related risk region (NRR) (NR vs 72.8 [39–106.6] vs 25.8 [8.3–43.2]; P = 0.013). These results demonstrate that the prevalence of BRCA1/2 positive patients in OC Mexican patients are the highest reported. Patients with mutations in BRCA2 have a better prognosis than those mutated in BRCA1. The Mexican founder mutation has an important role in clinical outcomes. These results highlight the importance to test all the HGSP (high-grade serous papillary) OC patients with or without cancer family history (CFH) in Mexican population.     

In-Depth Characterization of the Clostridioides difficile Phosphoproteome to Identify Ser/Thr Kinase Substrates

Clostridioides difficile is the leading cause of postantibiotic diarrhea in adults. During infection, the bacterium must rapidly adapt to the host environment by using survival strategies. Protein phosphorylation is a reversible post-translational modification employed ubiquitously for signal transduction and cellular regulation. Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases have emerged as important players in bacterial cell signaling and pathogenicity. C. difficile encodes two STKs (PrkC and CD2148) and one phosphatase. We optimized a titanium dioxide phosphopeptide enrichment approach to determine the phosphoproteome of C. difficile. We identified and quantified 2500 proteins representing 63% of the theoretical proteome. To identify STK and serine/threonine phosphatase targets, we then performed comparative large-scale phosphoproteomics of the WT strain and isogenic ΔprkC, CD2148, Δstp, and prkC CD2148 mutants. We detected 635 proteins containing phosphorylated peptides. We showed that PrkC is phosphorylated on multiple sites in vivo and autophosphorylates in vitro. We were unable to detect a phosphorylation for CD2148 in vivo, whereas this kinase was phosphorylated in vitro only in the presence of PrkC. Forty-one phosphoproteins were identified as phosphorylated under the control of CD2148, whereas 114 proteins were phosphorylated under the control of PrkC including 27 phosphoproteins more phosphorylated in the ?stp mutant. We also observed enrichment for phosphothreonine among the phosphopeptides more phosphorylated in the Δstp mutant. Both kinases targeted pathways required for metabolism, translation, and stress response, whereas cell division and peptidoglycan metabolism were more specifically controlled by PrkC-dependent phosphorylation in agreement with the phenotypes of the ΔprkC mutant. Using a combination of approaches, we confirmed that FtsK was phosphorylated in vivo under the control of PrkC and that Spo0A was a substrate of PrkC in vitro. This study provides a detailed mapping of kinase–substrate relationships in C. difficile, paving the way for the identification of new biomarkers and therapeutic targets.     

A Novel Spectral Annotation Strategy Streamlines Reporting of Mono-ADP-ribosylated Peptides Derived from Mouse Liver and Spleen in Response to IFN-γ

Mass-spectrometry-enabled ADP-ribosylation workflows are developing rapidly, providing researchers a variety of ADP-ribosylome enrichment strategies and mass spectrometric acquisition options. Despite the growth spurt in upstream technologies, systematic ADP-ribosyl (ADPr) peptide mass spectral annotation methods are lacking. HCD-dependent ADP-ribosylome studies are common, but the resulting MS2 spectra are complex, owing to a mixture of b/y-ions and the m/p-ion peaks representing one or more dissociation events of the ADPr moiety (m-ion) and peptide (p-ion). In particular, p-ions that dissociate further into one or more fragment ions can dominate HCD spectra but are not recognized by standard spectral annotation workflows. As a result, annotation strategies that are solely reliant upon the b/y-ions result in lower spectral scores that in turn reduce the number of reportable ADPr peptides. To improve the confidence of spectral assignments, we implemented an ADPr peptide annotation and scoring strategy. All MS2 spectra are scored for the ADPr m-ions, but once spectra are assigned as an ADPr peptide, they are further annotated and scored for the p-ions. We implemented this novel workflow to ADPr peptides enriched from the liver and spleen isolated from mice post 4 h exposure to systemic IFN-γ. HCD collision energy experiments were first performed on the Orbitrap Fusion Lumos and the Q Exactive, with notable ADPr peptide dissociation properties verified with CID (Lumos). The m-ion and p-ion series score distributions revealed that ADPr peptide dissociation properties vary markedly between instruments and within instrument collision energy settings, with consequences on ADPr peptide reporting and amino acid localization. Consequentially, we increased the number of reportable ADPr peptides by 25% (liver) and 17% (spleen) by validation and the inclusion of lower confidence ADPr peptide spectra. This systematic annotation strategy will streamline future reporting of ADPr peptides that have been sequenced using any HCD/CID-based method.     

Human HSPB1 mutation recapitulates features of distal hereditary motor neuropathy (dHMN) in Drosophila

Distal hereditary motor neuropathies (dHMN) are a group of inherited peripheral nerve disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy. Missense mutations in the gene encoding small heat shock protein HSPB1 (HSP27) have been associated with hereditary neuropathies including dHMN. HSPB1 is a member of the small heat shock protein (sHSP) family characterized by a highly conserved α-crystallin domain that is critical to their chaperone activity. In this study, we modeled HSPB1 mutant-induced neuropathies in Drosophila using a human HSPB1^S135F mutant that has a missense mutation in its α-crystallin domain. Overexpression of the HSPB1 mutant produced no significant defect in the Drosophila development, however, a partial reduction in the life span was observed. Further, the HSPB1 mutant gene induced an obvious loss of motor activity when expressed in Drosophila neurons. Moreover, suppression of histone deacetylase 6 (HDAC6) expression, which has critical roles in HSPB1 mutant-induced axonal defects, successfully rescued the motor defects in the HSPB1 mutant Drosophila model.     

High Sensitivity and Wide Linearity LC-MS/MS Method for Oxylipin Quantification in Multiple Biological Samples

Oxylipins are important biological regulators that have received extensive research attention. Due to the extremely low concentrations, large concentration variations, and high structural similarity of many oxylipins, the quantitative analysis of oxylipins in biological samples is always a great challenge. Here, we developed a liquid chromatography-tandem mass spectrometry-based method with high sensitivity, wide linearity, and acceptable resolution for quantitative profiling of oxylipins in multiple biological samples. A total of 104 oxylipins, some with a high risk of detection crosstalk, were well separated on a 150 mm column over 20 min. The method showed high sensitivity with lower limits of quantitation for 87 oxylipins, reaching 0.05–0.5 pg. Unexpectedly, we found that the linear range for 16, 18, and 17 oxylipins reached 10,000, 20,000, and 40,000 folds, respectively. Due to the high sensitivity, while reducing sample consumption to below half the volume of previous methods, 74, 78, and 59 low-abundance oxylipins, among which some were difficult to detect like lipoxins and resolvins, were well quantified in the tested mouse plasma, mouse liver, and human plasma samples, respectively. Additionally, we determined that analytes with multifarious concentrations of over a 1,000-fold difference could be well quantified simultaneously due to the wide linearity. In conclusion, most likely due to the instrumental advancement, this method effectively improves the quantitative sensitivity and linear range over existing methods, which will facilitate and advance the study of the physiological and pathophysiological functions of oxylipins.     

Delta-6 desaturase (Fads2) deficiency alters triacylglycerol/fatty acid cycling in murine white adipose tissue

The Δ-6 desaturase (D6D) enzyme is not only critical for the synthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from α-linolenic acid (ALA), but recent evidence suggests that it also plays a role in adipocyte lipid metabolism and body weight; however, the mechanisms remain largely unexplored. The goal of this study was to investigate if a D6D deficiency would inhibit triacylglycerol storage and alter lipolytic and lipogenic pathways in mouse white adipose tissue (WAT) depots due to a disruption in EPA and DHA production. Male C57BL/6J D6D knockout (KO) and wild-type (WT) mice were fed either a 7% w/w lard or flax (ALA rich) diet for 21 weeks. Energy expenditure, physical activity, and substrate utilization were measured with metabolic caging. Inguinal and epididymal WAT depots were analyzed for changes in tissue weight, fatty acid composition, adipocyte size, and markers of lipogenesis, lipolysis, and insulin signaling. KO mice had lower body weight, higher serum nonesterified fatty acids, smaller WAT depots, and reduced adipocyte size compared to WT mice without altered food intake, energy expenditure, or physical activity, regardless of the diet. Markers of lipogenesis and lipolysis were more highly expressed in KO mice compared to WT mice in both depots, regardless of the diet. These changes were concomitant with lower basal insulin signaling in WAT. Collectively, a D6D deficiency alters triacylglycerol/fatty acid cycling in WAT by promoting lipolysis and reducing fatty acid re-esterification, which may be partially attributed to a reduction in WAT insulin signaling.     

Structural features and oligomeric nature of human podocin domain

Podocytes are crucial cells of the glomerular filtration unit and plays a vital role at the interface of the blood-urine barrier. Podocyte slit-diaphragm is a modified tight junction that facilitates size and charge-dependent permselectivity. Several proteins including podocin, nephrin, CD2AP, and TRPC6 form a macromolecular assembly and constitute the slit-diaphragm. Podocin is an integral membrane protein attached to the inner membrane of the podocyte via a short transmembrane region (101–125). The cytosolic N- and C-terminus help podocin to attain a hook-like structure. Podocin shares 44% homology with stomatin family proteins and similar to the stomatin proteins, podocin was shown to associate into higher-order oligomers at the site of slit-diaphragm. However, the stoichiometry of the homo-oligomers and how it partakes in the macromolecular assemblies with other slit-diaphragm proteins remains elusive. Here we investigated the oligomeric propensity of a truncated podocin construct (residues:126–350). We show that the podocin domain majorly homo-oligomerizes into a 16-mer. Circular dichroism and fluorescence spectroscopy suggest that the 16-mer oligomer has considerable secondary structure and moderate tertiary packing.     

Structural Studies Reveal Unique Non-canonical Regulators of G Protein Signaling Homology (RH) Domains in Sorting Nexins

As a subgroup of sorting nexins (SNXs) that contain regulator of G protein signaling homology (RH) domain, SNX-RH proteins, including SNX13, SNX14 and SNX25, were proposed to play bifunctional roles in protein sorting and GPCR signaling regulation. However, mechanistic details of SNX-RH proteins functioning via RH domain remain to be illustrated. Here, we delineate crystal structures of the RH domains of SNX13 and SNX25, revealing a homodimer of SNX13 RH domain mediated by unique extended α4 and α5 helices, and a thiol modulated homodimer of SNX25-RH triggered by a unique cysteine on α6 helix. Further studies showed that RH domains of SNX-RH do not possess binding capacity toward Gα subunits, owing to the lack of critical residues for interaction. Thus, this study identifies a group of novel non-canonical RH domains that can act as a dimerization module in sorting nexins, which provides structural basis for mechanism studies on SNX-RH protein functions.     

LINC01140 regulates osteosarcoma proliferation and invasion by targeting the miR-139-5p/HOXA9 axis

Osteosarcoma is one of the commonest metastatic tumor in children and teenagers, and has a hopeless, prognosis. Long non-coding RNA (lncRNA) acts momentous roles as a regulator on the proliferation and migration of cancer. Here, we performed GEO database analysis and qPCR to identify differentially expressed lncRNAs in osteosarcoma cells. Knockdown of lncRNA LINC01140 was used to detect the effect of LINC01140 on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. Bioinformatics analysis and qPCR identified the LINC01140/miR-139-5p/Homeobox A9 (HOXA9) regulatory axis. RNA immunoprecipitation assay, Dual-luciferase assay, and rescue experiments confirmed the interaction of LINC01140/miR-139-5p/HOXA9 in osteosarcoma. LINC01140 was overexpressed in osteosarcoma and knocking down LINC01140 restrained the proliferation and invasion of osteosarcoma cells and EMT. In Saos2 and MG63 cells, LINC01140 sponged miR-139-5p, and a miR-139-5p inhibitor overturned the suppression of LINC01140 knockdown on the proliferation and migration of osteosarcoma cells. Moreover, miR-139-5p depressed the invasion, proliferation, and EMT of osteosarcoma cells via targeting HOXA9. Our results indicate that LINC01140 downregulation inhibits the invasion, proliferation, and EMT in osteosarcoma cells through targeting the miR-139-5p/HOXA9 axis. Therefore, LINC01140 is a potential therapeutic target for osteosarcoma.     

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes

ObjectiveThyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4).MethodsWe conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes.ResultsOne hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19–11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17–0.71; P = .004).ConclusionThyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.     

Targeting histone acetylation/deacetylation in parasites: an update (2017–2020)

Histone modifying enzymes have vital roles in the growth and survival of both parasites and humans. Targeting the epigenome can be a new strategy for the treatment of parasitic diseases. Compounds modulating histone acetylation/deacetylation have recently been reported hampering Plasmodium, Schistosoma, Leishmania, and Trypanosoma infections. Beside new histone deacetylase inhibitors, PfGCN5 and bromodomain inhibitors have been recently described to inhibit Plasmodium proliferation. Sm histone deacetylase 8 and SmSIRT2, as well as Leishmania and Trypanosoma sirtuins (SIR2rps), seem to be the most reliable targets to effectively fight the related protozoan infections. The selectivity toward parasite over mammalian cells is still an open question, and significant optimization efforts of epidrugs are still required to improve potency/selectivity and decrease toxicity. Recent reports on the alteration of cellular signaling pathways provoked by parasite infection through changes in the host acetylation/deacetylation status at gene promoters may suggest novel therapeutic strategies to treat these diseases.     

Probability of lung cancer in a population excluded from screening due to low PLCOM2012 risk

BackgroundSeveral randomized trials demonstrated have reduced lung cancer mortality with screening using computed tomography. However, there remains debate about the optimal approach for determining screening eligibility, and no evidence yet exists reporting lung cancer rates in those excluded from screening due to too low of a personalized risk.MethodsThis study was based on the Alberta Lung Cancer Screening Study, which received 1737 applicants and enrolled 850 based on the NLST criteria or a PLCO_M2012 risk ≥ 1.5%. We excluded 887 applicants who were interested in screening but deemed ineligible. We report lung cancer rates in the screened and unscreened cohorts.ResultsWe observed 30 and 8 lung cancers in the screened and unscreened groups, respectively. Only 1 of 8 lung cancers were among those considered too low risk (0.14%), while the remaining 7 were among those excluded for other reasons, including symptoms requiring more immediate workup. No NLST eligible but PLCO risk < 1.5% screened individual had a lung cancer detected as part of the study, so that of all applicants contacting the program with risk estimates less than 1.5%, only 1/857 (0.12%) developed lung cancer.ConclusionOur findings indicate that a risk-based approach for screening eligibility is unlikely to miss many lung cancers.     

New Insights on Effects of Glucocorticoids in Patients With SARS-CoV-2 Infection

ObjectiveSince January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients.MethodsTo review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury.ResultsIn our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs.ConclusionFor clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.     

In Saccharomyces cerevisiae,withdrawal of the carbon source results in detachment of glycolytic enzymes from the cytoskeleton and in actin reorganization

Metabolons are dynamic associations of enzymes catalyzing consecutive reactions within a given pathway. Association results in enzyme stabilization and increased metabolic efficiency. Metabolons may use cytoskeletal elements, membranes and membrane proteins as scaffolds. The effects of glucose withdrawal on a putative glycolytic metabolon/F-actin system were evaluated in three Saccharomyces cerevisiae strains: a WT and two different obligate fermentative (OxPhos-deficient) strains, which obtained most ATP from glycolysis. Carbon source withdrawal led to inhibition of fermentation, decrease in ATP concentration and dissociation of glycolytic enzymes from F-actin. Depending on the strain, inactivation/reactivation transitions of fermentation took place in seconds. In addition, when ATP was very low, green fluorescent protein-labeled F-actin reorganized from highly dynamic patches to large, non-motile actin bodies containing proteins and enzymes. Glucose addition restored fermentation and cytoskeleton dynamics, suggesting that in addition to ATP concentration, at least in one of the tested strains, metabolon assembly/disassembly is a factor in the control of the rate of fermentation.