A non-proteolytic release mechanism for HMCES-DNA-protein crosslinks.

The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non-proteolytic release mechanism for HMCES-DNA-protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA-dsDNA junctions, HMCES-DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re-crosslinks or dissociates. Our study reveals that the protective role of HMCES-DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.

Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates.

N-degron pathways are proteolytic systems that target proteins bearing N-terminal (Nt) degradation signals (degrons) called N-degrons. Nt-Arg of a protein is among Nt-residues that can be recognized as destabilizing ones by the Arg/N-degron pathway. A proteolytic cleavage of a protein can generate Arg at the N terminus of a resulting C-terminal (Ct) fragment either directly or after Nt-arginylation of that Ct-fragment by the Ate1 arginyl-tRNA-protein transferase (R-transferase), which uses Arg-tRNAArg as a cosubstrate. Ate1 can Nt-arginylate Nt-Asp, Nt-Glu, and oxidized Nt-Cys* (Cys-sulfinate or Cys-sulfonate) of proteins or short peptides. Ate1 genes of fungi, animals, and plants have been cloned decades ago, but a three-dimensional structure of Ate1 remained unknown. A detailed mechanism of arginylation is unknown as well. We describe here the crystal structure of the Ate1 R-transferase from the budding yeast Kluyveromyces lactis. The 58-kDa R-transferase comprises two domains that recognize, together, an acidic Nt-residue of an acceptor substrate, the Arg residue of Arg-tRNAArg, and a 3'-proximal segment of the tRNAArg moiety. The enzyme's active site is located, at least in part, between the two domains. In vitro and in vivo arginylation assays with site-directed Ate1 mutants that were suggested by structural results yielded inferences about specific binding sites of Ate1. We also analyzed the inhibition of Nt-arginylation activity of Ate1 by hemin (Fe3+-heme), and found that hemin induced the previously undescribed disulfide-mediated oligomerization of Ate1. Together, these results advance the understanding of R-transferase and the Arg/N-degron pathway.

Engineering CAR-T cells to activate small-molecule drugs in situ.

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.

N-Terminally arginylated ubiquitin is attached to histone H2A by RING1B E3 ligase in human cells.

Ubiquitin (Ub) is highly conserved in all eukaryotic organisms and begins at the N-terminus with Met and Gln. Our recent research demonstrates that N-terminally (Nt-) arginylated Ub can be produced in the yeast Saccharomyces cerevisiae. However, the existence of Nt-arginylated Ub in multicellular organisms remains unknown. Here we explore the mechanism for creating Nt-arginylated Ub using human embryonic kidney HEK293 cells that express various Nt-modified Ubs. We found that Gln-starting Q-Ub was converted into Glu-starting E-Ub by NTAQ1 Nt-deamidase and subsequently Nt-arginylated by ATE1 arginyltransferase in HEK293 cells. We also found that the resulting Arg-Glu-starting RE-Ub was mainly deposited on the Lys119 residue of histone H2A. Furthermore, RING1B E3 Ub ligase mediated the attachment of RE-Ub to H2A. These findings reveal a previously unknown type of histone ubiquitylation which greatly increases the combinatorial complexity of histone and ubiquitin codes.

N-terminal methionine excision of proteins creates tertiary destabilizing N-degrons of the Arg/N-end rule pathway.

All organisms begin protein synthesis with methionine (Met). The resulting initiator Met of nascent proteins is irreversibly processed by Met aminopeptidases (MetAPs). N-terminal (Nt) Met excision (NME) is an evolutionarily conserved and essential process operating on up to two-thirds of proteins. However, the universal function of NME remains largely unknown. MetAPs have a well-known processing preference for Nt-Met with Ala, Ser, Gly, Thr, Cys, Pro, or Val at position 2, but using CHX-chase assays to assess protein degradation in yeast cells, as well as protein-binding and RT-qPCR assays, we demonstrate here that NME also occurs on nascent proteins bearing Met-Asn or Met-Gln at their N termini. We found that the NME at these termini exposes the tertiary destabilizing Nt residues (Asn or Gln) of the Arg/N-end rule pathway, which degrades proteins according to the composition of their Nt residues. We also identified a yeast DNA repair protein, MQ-Rad16, bearing a Met-Gln N terminus, as well as a human tropomyosin-receptor kinase-fused gene (TFG) protein, MN-TFG, bearing a Met-Asn N terminus as physiological, MetAP-processed Arg/N-end rule substrates. Furthermore, we show that the loss of the components of the Arg/N-end rule pathway substantially suppresses the growth defects of naa20Δ yeast cells lacking the catalytic subunit of NatB Nt acetylase at 37 °C. Collectively, the results of our study reveal that NME is a key upstream step for the creation of the Arg/N-end rule substrates bearing tertiary destabilizing residues in vivo.

N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2.

Perilipin 2 (PLIN2) is a major lipid droplet (LD)-associated protein that regulates intracellular lipid homeostasis and LD formation. Under lipid-deprived conditions, the LD-unbound (free) form of PLIN2 is eliminated in the cytosol by an as yet unknown ubiquitin (Ub)-proteasome pathway that is associated with the N-terminal or near N-terminal residues of the protein. Here, using HeLa, HEK293T, and HepG2 human cell lines, cycloheximide chase, in vivo ubiquitylation, split-Ub yeast two-hybrid, and chemical cross-linking-based reciprocal co-immunoprecipitation assays, we found that TEB4 (MARCH6), an E3 Ub ligase and recognition component of the Ac/N-end rule pathway, directly targets the N-terminal acetyl moiety of Nα-terminally acetylated PLIN2 for its polyubiquitylation and degradation by the 26S proteasome. We also show that the TEB4-mediated Ac/N-end rule pathway reduces intracellular LD accumulation by degrading PLIN2. Collectively, these findings identify PLIN2 as a substrate of the Ac/N-end rule pathway and indicate a previously unappreciated role of the Ac/N-end rule pathway in LD metabolism.

Prevalence of genetically diagnosed familial hypercholesterolemia in Vietnamese patients with premature acute myocardial infarction.

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated low-density lipoprotein cholesterol (LDL-C) levels, which manifest early in the first decades of life. It is a major cause of premature coronary artery disease worldwide, leading to significant public health challenges. The prevalence of genetically determined FH in patients with premature coronary artery disease remains underestimated, particularly in developing countries. This study aimed to assess the prevalence of genetically defined FH in Vietnamese patients with premature acute myocardial infarction (AMI) in the Vietnamese population. This cross-sectional study enrolled 218 consecutive patients diagnosed with premature AMI who underwent coronary angiography. The low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 genes were analyzed by next-generation sequencing. FH was diagnosed according to Dutch Lipid Clinic Network criteria. Among the patients with premature AMI who underwent coronary angiography, the mean age was 46.9 ±â€…6.1 years, with a predominance of males (83.9%). The prevalence of potential FH diagnosed using Dutch Lipid Clinic Network criteria was 14.7% (definite FH, 6.0%; probable FH, 8.7%). Pathogenic or likely pathogenic variants in LDLR, apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 were found in 9 of 218 patients (4.1%), all of which were causative mutations in LDLR. Patients with premature AMI and FH had significantly greater LDL-C levels (217.6 vs 125.7 mg/dL) and more severe coronary artery lesions, as assessed by the Gensini score (100.3 vs 60.5), than did those in the No FH group. The prevalence of genetically determined FH among Vietnamese patients with premature AMI is relatively high. Screening and diagnosis of hereditary conditions in patients with premature AMI are essential to improve early detection and management and reduce the burden of coronary artery disease in this population.

Has the role of veno-arterial extracorporeal membrane oxygenation in patients with cardiogenic shock following acute myocardial infarction been fully determined? A case report.

Background: The persistent challenge of high mortality rates in acute myocardial infarction-induced cardiogenic shock endures notwithstanding advancements in the diagnosis and treatment of this disease over the past two decades. While recent studies present conflicting evidence on the efficacy of veno-arterial extracorporeal membrane oxygenation (VA ECMO), observational research supports the benefits of early VA ECMO initiation. However, the current lack of robust support from randomized clinical trials for VA ECMO use in this context highlights the ongoing uncertainty surrounding its effectiveness. Case summary: A 52-year-old male with sudden, intense chest pain was diagnosed with cardiogenic shock due to non-ST-elevation acute myocardial infarction at a local hospital. Initial treatment included aspirin, clopidogrel, and noradrenaline. Upon transfer to our hospital, the patient's condition deteriorated, leading to acute respiratory distress and severe hypotension. Prior to emergent percutaneous coronary intervention, peripheral VA ECMO was initiated. Coronary angiography revealed left main coronary artery occlusion, and a successful intervention was performed. Post-intervention, the patient's haemodynamic parameters significantly improved, and after 7 days, ECMO was successfully discontinued. The patient was discharged in stable condition after 25 days, with favourable outcomes persisting at the 30-day mark. Continuous monitoring is planned during outpatient follow-up. Discussion: The clinical case illustrates a successful treatment outcome achieved through teamwork by the heart team, supporting the efficacy of the VA ECMO pre-percutaneous coronary intervention approach. The careful selection of appropriate candidates and strategic initiation of VA ECMO may play a role in enhancing outcomes for individuals experiencing acute myocardial infarction complicated by challenging cardiogenic shock.

Complex Coronary Artery Lesions in a Young Woman With an Acute Myocardial Infarction and Genetically Confirmed Familial Hypercholesterolemia: A Case Report and Literature Review From a Developing Country.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) in the blood from an incredibly early age. This condition leads to the early development of atherosclerotic arterial diseases, which can manifest even in the first few decades of life. Mutations in genes related to the LDL receptor (LDL-R), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) are the main molecular mechanisms causing familial hypercholesterolemia. This case involves a 44-year-old Vietnamese female who presented at the emergency department with chest pain and was diagnosed with acute myocardial infarction (AMI) complicated by cardiogenic shock. Clinical signs and an elevated LDL-C level pointed to prolonged exposure to high cholesterol. A Dutch Lipid Clinic Network (DLCN) score of 10 further supported the diagnosis of FH. The reverse T-stenting and small protrusion (TAP) technique was selected and successfully employed to stent the LMCA, left anterior descending artery (LAD) and left circumflex artery (LCx). This technique was chosen due to its simplicity and rapid execution, making it particularly suitable in situations of cardiogenic shock where time-consuming procedures should be avoided. Genetic testing confirmed a heterozygous pathogenic mutation in the LDL-R gene, corroborating the clinical diagnosis of FH. The patient's condition has gradually stabilized, and they have been discharged from the hospital. The patient is currently being monitored as an outpatient at the cardiology clinic. This case emphasizes the importance of considering FH in patients with premature cardiovascular events by applying the clinical diagnostic criteria and confirming by genetic analysis. It also highlights advanced interventional techniques for managing complex coronary lesions, such as reverse TAP.

Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state.

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

Assessment of Health-Related Quality of Life in Patients with Chronic Heart Failure: A Cross-Sectional Study in Vietnam.

Introduction Heart failure is currently a global health issue, imposing a burden on disease prevalence and mortality rates for patients, while simultaneously impacting the quality of life for affected individuals. Data on assessing the health-related quality of life (HRQoL) of patients with chronic heart failure in developing countries, including Vietnam, is still limited. This study was conducted with the aim of describing the quality of life of patients with chronic heart failure in Vietnam. Methods This cross-sectional investigation enrolled 140 chronic heart failure outpatients, utilizing a convenience sample at Hai Duong Province Hospital, Vietnam, spanning from December 2021 to April 2022. Essential patient variables encompassing age, gender, and heart failure duration were gathered. Surveying of patients took place at the outpatient clinic during chronic heart failure follow-up visits using the 36-Item Short Form Health Survey (SF-36) questionnaire. The SF-36 comprises eight dimensions: (1) Physical functioning, (2) Role limitations due to physical health, (3) Bodily pain, (4) General health perceptions, (5) Vitality, (6) Social role functioning, (7) Role limitations due to emotional health, and (8) Mental health. Component analysis of the SF-36 revealed two distinct concepts: a physical component summary (PCS) reflecting the physical aspect and a mental component summary (MCS) reflecting the mental aspect. Results The research involved 140 participants diagnosed with chronic heart failure, having a median age of 59 years (interquartile range (IQR): 52-63). Among them, 61.4% were male, and 50% exhibited reduced left ventricular ejection fraction (LVEF) (≤ 40%). The role limitations due to the physical health domain indicated the lowest score, registering a median value of 0 (IQR 0-25). Domains with median scores below the 25-point threshold encompassed role limitations due to physical health (0 points). Those with scores ranging from 25 to 49 points constituted general health perceptions (25 points), role limitations due to emotional health (33.3 points), vitality (45 points), and mental health (48 points). Bodily pain and social role functioning achieved median scores at a moderate level (50-74 points), scoring 62 and 62.5 points, respectively. The overall HRQoL score on the SF-36 scale was 45.2 (IQR: 32.1-58.7) points. Median scores for the PCS and MCS were 44.3 (IQR: 30.5-52) and 47.0 (IQR: 32.6-65.4), respectively. No statistically significant differences in PCS and MCS scores were observed when subgroup analysis was performed based on variables like age, gender, or LVEF. However, in the vitality domain, female patients exhibited a significantly lower median score than male patients (p-value = 0.046). In the physical functioning domain, individuals aged ≥ 60 had lower median scores than those aged < 60 years (p = 0.022). Additionally, the group with LVEF ≤ 40% had lower median scores compared to the group with LVEF > 40% (p = 0.038) in role limitations due to emotional health domain. Conclusion In Vietnam, the HRQoL in the outpatient population with chronic heart failure was notably low when assessed using the SF-36 questionnaire. Large-scale, multicenter studies are needed to provide stronger, more conclusive evidence.

Prevalence and impact of metabolic syndrome on in-hospital outcomes in patients with acute myocardial infarction: A perspective from a developing country.

Acute myocardial infarction (AMI) often suffers from a high prevalence of metabolic syndrome (MetS). However, few studies in developing countries have focused on the effect of MetS on in-hospital outcomes in patients with AMI. We analyzed 199 patients with AMI who underwent primary percutaneous coronary intervention. This study aimed to determine the impact of MetS and factors related to in-hospital outcomes in patients with AMI. The study included 199 patients who met the criteria, with a mean age of 64.5 ±â€…11.3 years. Out Of the total number of patients, 136 (68.3%) were found to have MetS. Patients with MetS were more likely to be female, have a higher body mass index, larger waist circumference, and a higher prevalence of hypertension and diabetes than those without MetS. The rates of major complications, such as cardiogenic shock, heart failure, mechanical complications, and arrhythmias, were not significantly different between the 2 groups. MetS was not associated with in-hospital mortality with OR, 4.92 (95% CI 0.62-39.31, P = .13). In this study, increased waist circumference was associated with an increased all-cause mortality rate. However, the MetS group had a significantly higher rate of cardiovascular mortality than the group without MetS (P = .03). Among patients with AMI, the prevalence of metabolic syndrome was high. Patients with MetS did not exhibit an increased all-cause in-hospital mortality rate. Increased waist circumference is associated with increased all-cause mortality.

Prediction of obstructive coronary artery disease in patients undergoing heart valve surgery: A cross-sectional study in a tertiary care hospital.

Introduction: Estimating the probability of obstructive coronary artery disease in patients undergoing noncoronary cardiac surgery should be considered compulsory. Our study sought to evaluate the prevalence of obstructive coronary artery disease in patients undergoing valvular heart surgery and to utilize predictive methodology of concomitant obstructive coronary artery disease in these patients. Methods: The retrospective study cohort was derived from a tertiary care hospital registry of patients undergoing coronary angiogram prior to valvular heart operations. Decision tree, logistic regression, and support vector machine models were built to predict the probability of the appearance of obstructive coronary artery disease. A total of 367 patients from 2016 to 2019 were analyzed. Results: The mean age of the study population was 57.3±9.3 years, 45.2% of the patients were male. Of 367 patients, 76 (21%) patients had obstructive coronary artery disease. The decision tree, logistics regression, and support vector machine models had an area under the curve of 72% (95% CI: 62% - 81%), 67% (95% CI: 56% - 77%), and 78% (95% CI: 68% - 87%), respectively. Multivariate analysis indicated that hypertension (OR 1.98; P=0.032), diabetes (OR 2.32; P=0.040), age (OR 1.05; P=0.006), and typical angina (OR 5.46; P<0.001) had significant role in predicting the presence of obstructive coronary artery disease. Conclusion: Our study revealed that approximately one-fifth of patients who underwent valvular heart surgery had concomitant obstructive coronary artery disease. The support vector machine model showed the highest accuracy compared to the other model.

Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.

N-Terminal Modifications of Ubiquitin via Methionine Excision, Deamination, and Arginylation Expand the Ubiquitin Code.

Ubiquitin (Ub) is post-translationally modified by Ub itself or Ub-like proteins, phosphorylation, and acetylation, among others, which elicits a variety of Ub topologies and cellular functions. However, N-terminal (Nt) modifications of Ub remain unknown, except the linear head-to-tail ubiquitylation via Nt-Met. Here, using the yeast Saccharomyces cerevisiae and an Nt-arginylated Ub-specific antibody, we found that the detectable level of Ub undergoes Nt-Met excision, Nt-deamination, and Nt-arginylation. The resulting Nt-arginylated Ub and its conjugated proteins are upregulated in the stationary-growth phase or by oxidative stress. We further proved the existence of Nt-arginylated Ub in vivo and identified Nt-arginylated Ub-protein conjugates using stable isotope labeling by amino acids in cell culture (SILAC)-based tandem mass spectrometry. In silico structural modeling of Nt-arginylated Ub predicted that Nt-Arg flexibly protrudes from the surface of the Ub, thereby most likely providing a docking site for the factors that recognize it. Collectively, these results reveal unprecedented Nt-arginylated Ub and the pathway by which it is produced, which greatly expands the known complexity of the Ub code.

Chest X-ray Severity Score as a Putative Predictor of Clinical Outcome in Hospitalized Patients: An Experience From a Vietnamese COVID-19 Field Hospital.

Background Through the coronavirus disease 2019 (COVID-19) pandemic, portable radiography was particularly useful for assessing and monitoring the COVID-19 disease in Vietnamese field hospitals. It provides a convenient and precise picture of the progression of the disease. The purpose of this study was to evaluate the predictive value of chest radiograph reporting systems (Brixia and total severity score (TSS)) and the National Early Warning Score (NEWS) clinical score in a group of hospitalized patients with COVID-19. Methods This retrospective cohort study used routinely collected clinical data from polymerase chain reaction (PCR)-positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients admitted to Field Hospital District 8, Ho Chi Minh City, Vietnam, from August 2021 to September 2021. The initial chest radiographs were scored based on the TSS and Brixia scoring systems to quantify the extent of lung involvement. After the chest radiograph score was reported, two residents calculated the rate of all-cause in-hospital mortality with the consultation of expert radiologists. In this study, NEWS2 scores on hospital admission were calculated. The gradient boosting machines (GBMs) and Shapley additive exPlanations (SHAP) were applied to access the important variable and improve the accuracy of mortality prediction. The adjusted odds ratio for predictor was presented by univariate analysis and multivariate analysis. Results The chest X-rays (CXRs) at the admission of 273 patients (mean age 59 years +/-16, 42.1% were male) were scored. In the univariate analysis, age, vaccination status, previous disease, NEWS2, a saturation of peripheral oxygen (Sp02), the Brixia and TSS scores were significant predictors of mortality (p-value < 0.05). In multivariate analysis, there were statistically significant differences in mortality between age, Sp02, Brixia score, and patients with previous diseases were independent predictors of mortality and hospitalization. A gradient boosting machine was performed in the train data set, which showed that the best hyperparameters for predicting the mortality of patients are the Brixia score (exclude TSS score). In the top five predictors, an increase in Brixia, age, and BMI increased the logarithmic number of probability clarifying as death status. Although the TSS and Brixia scores evaluated chest imaging, the TSS score was not essential as the Brixia score (rank 6/11). It was clear that the BMI and NEWS2 score was positively correlated with the Brixia score, and age did not affect this correlation. Meanwhile, we did not find any trend between the TSS score versus BMI and NEWS2. Conclusion When integrated with the BMI and NEWS2 clinical classification systems, the severity score of COVID-19 chest radiographs, particularly the Brixia score, was an excellent predictor of all-cause in-hospital mortality.

The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis.

Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6-/- mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis.

The effects of the COVID-19 lockdown on patients with chronic cardiovascular disease in Vietnam.

INTRODUCTION: We evaluated the impact of the lockdown policy during the COVID-19 pandemic on cardiovascular outpatients of a cardiology clinic in Vietnam from April to June 2020. We estimated the occurrence of different cardiovascular problems in general and the stability of blood pressure. METHODOLOGY: During the Covid-19 outbreak in Vietnam, we conducted a cross-sectional study to evaluate its impact on blood pressure stability of hypertensive patients treated as outpatients at the clinic of the University Medical Center (UMC), Ho Chi Minh City. RESULTS: The mean age of the recruited 493 patients was 62.2 ± 10.2 years. The stable blood pressure group consisted of 87% patients, while the unstable blood pressure group consisted of 13% patients. We found that 68% of the study population attended their follow-up appointments as scheduled: 87% with stable blood pressure versus only 13% with unstable blood pressure. Significant differences were noticed in body weight changes and cardiovascular problems between the two groups: body weight increase (22.6% vs. 10.2%), body weight decrease (3.2% vs. 6.7%), worsening of cardiovascular problems (35.5% vs. 17.9%) in the unstable and stable blood pressure groups, respectively. Multivariable regression analysis reflected the impact of the increase in body weight and occurrence of cardiovascular problems on the patients with unstable blood pressure. CONCLUSIONS: Our study provided concrete proof of the impact of the lockdown on chronic patients, which should warrant further surveys, and evaluation of the lockdown policy.

Long-Term Outcome of Thrombolytic Therapy for Massive Pulmonary Embolism in Pregnancy.

A 25-year-old pregnant woman presented at 12 weeks of gestation with syncope and shortness of breath caused by massive pulmonary embolism. Due to persistent shock, fibrinolytic therapy with rtPA was administered. After fibrinolysis, clinical and hemodynamic response was excellent. No bleeding and fetal complications were recorded.

Control of protein degradation by N-terminal acetylation and the N-end rule pathway.

Nα-terminal acetylation (Nt-acetylation) occurs very frequently and is found in most proteins in eukaryotes. Despite the pervasiveness and universality of Nt-acetylation, its general functions in terms of physiological outcomes remain largely elusive. However, several recent studies have revealed that Nt-acetylation has a significant impact on protein stability, activity, folding patterns, cellular localization, etc. In addition, Nt-acetylation marks specific proteins for degradation by a branch of the N-end rule pathway, a subset of the ubiquitin-mediated proteolytic system. The N-end rule associates a protein's in vivo half-life with its N-terminal residue or modifications on its N-terminus. This review provides a current understanding of intracellular proteolysis control by Nt-acetylation and the N-end rule pathway.