Mono-UFMylation promotes misfolding-associated secretion of α-synuclein.

Stressed cells secret misfolded proteins lacking signaling sequence via an unconventional protein secretion (UcPS) pathway, but how misfolded proteins are targeted selectively in UcPS is unclear. Here, we report that misfolded UcPS clients are subject to modification by a ubiquitin-like protein named ubiquitin-fold modifier 1 (UFM1). Using α-synuclein (α-Syn) as a UcPS model, we show that mutating the UFMylation sites in α-Syn or genetic inhibition of the UFMylation system mitigates α-Syn secretion, whereas overexpression of UFBP1, a component of the endoplasmic reticulum-associated UFMylation ligase complex, augments α-Syn secretion in mammalian cells and in model organisms. UFM1 itself is cosecreted with α-Syn, and the serum UFM1 level correlates with that of α-Syn. Because UFM1 can be directly recognized by ubiquitin specific peptidase 19 (USP19), a previously established UcPS stimulator known to associate with several chaperoning activities, UFMylation might facilitate substrate engagement by USP19, allowing stringent and regulated selection of misfolded proteins for secretion and proteotoxic stress alleviation.

Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

Myasthenia Gravis (MG) patients with anti-acetylcholine receptor (AChR) antibodies frequently show hyperplastic thymi with ectopic germinal centers, where autoreactive B cells proliferate with the aid of T cells. In this study, thymus and peripheral blood (PB) samples were collected from ten AChR antibody-positive MG patients. T cell receptor (TCR) repertoires were analyzed using next-generation sequencing (NGS), and compared with that of an age and sex matched control group generated from a public database. Certain V genes and VJ gene recombination pairs were significantly upregulated in the TCR chains of αß-T cells in the PB of MG patients compared to the control group. Furthermore, the TCR chains found in the thymi of MG patients had a weighted distribution to longer CDR3 lengths when compared to the PB of MG patients, and the TCR beta chains (TRB) in the MG group's PB showed increased clonality encoded by one upregulated V gene. When TRB sequences were sub-divided into groups based on their CDR3 lengths, certain groups showed decreased clonality in the MG group's PB compared to the control group's PB. Finally, we demonstrated that stereotypic MG patient-specific TCR clonotypes co-exist in both the PB and thymi at a much higher frequency than that of the clonotypes confined to the PB. These results strongly suggest the existence of a biased T cell-mediated immune response in MG patients, as observed in other autoimmune diseases.

Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.

BACKGROUND: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. METHODS: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. RESULTS: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. CONCLUSION: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.

Magneto-acoustic protein nanostructures for non-invasive imaging of tissue mechanics in vivo.

Measuring cellular and tissue mechanics inside intact living organisms is essential for interrogating the roles of force in physiological and disease processes. Current agents for studying the mechanobiology of intact, living organisms are limited by poor light penetration and material stability. Magnetomotive ultrasound is an emerging modality for real-time in vivo imaging of tissue mechanics. Nonetheless, it has poor sensitivity and spatiotemporal resolution. Here we describe magneto-gas vesicles (MGVs), protein nanostructures based on gas vesicles and magnetic nanoparticles that produce differential ultrasound signals in response to varying mechanical properties of surrounding tissues. These hybrid nanomaterials significantly improve signal strength and detection sensitivity. Furthermore, MGVs enable non-invasive, long-term and quantitative measurements of mechanical properties within three-dimensional tissues and in vivo fibrosis models. Using MGVs as novel contrast agents, we demonstrate their potential for non-invasive imaging of tissue elasticity, offering insights into mechanobiology and its application to disease diagnosis and treatment.

Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma.

BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.

Analysis of Changes in Sleep Quality and Patterns after Hip Fracture Using Real Evidence of Artificial Intelligence Linked (REAL) Hip Cohort Data.

Background and Objectives: Hip fractures are commonly found in elderly patients, and often result in chronic pain and decreased physical function, as well as worsening of overall health. It is known that early surgical intervention during the acute phase and rehabilitation are important for improving clinical outcomes for these patients. However, the importance of management for improving the quality of life of these patients is becoming more emphasized. Studies on changes in sleep patterns after hip fractures are rare overseas. Therefore, the aim of this study is to investigate the prevalence of sleep disturbance in patients with hip fractures and to analyze the changes in sleep disturbance after surgery by comparing the preoperative and postoperative results. Materials and Methods: During the period from August 2022 to January 2023, patients who underwent surgical treatment for hip fractures and were recruited into the REAL Hip Cohort were selected as research subjects. The sleep survey was conducted using the Pittsburgh Sleep Quality Index (PSQI). The PSQI is composed of 18 questions, each divided into areas of sleep quality, sleep latency, duration, efficiency, disturbance, use of medication, and daytime dysfunction. Each area is scored 0-3 points and the total is 0-21. A score greater than five indicates sleep disorder. The PSQI was surveyed during hospitalization and three months after surgery for post-fracture sleep status. To analyze changes before and after the fracture, paired T-tests and chi-square tests were performed. Results: From August 2022 to January 2023, a total of 40 patients who were recruited into the REAL Hip Cohort responded to the PSQI survey. The average age was 77.4 years and 36 were female. Sleep quality worsened from 0.75 ± 1.0 before surgery to 1.4 ± 1.0 three months after surgery (p = 0.019), and sleep efficiency also worsened from 0.4 ± 0.6 to 1.4 ± 1.0 (p < 0.001). The PSQI increased from an average of 5.2 ± 2.8 before surgery to 8.2 ± 4.2 three months after surgery (p = 0.007), and the number of patients who could be diagnosed with sleep disorders also increased from 12 (40%) to 24 (60%) (p = 0.030). Conclusions: A decline in overall sleep status was observed in patients in a survey on sleep patterns three months after hip fracture. Additional management is needed to improve their sleep patterns.

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes.

BACKGROUND: People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments. RESULTS: Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA. CONCLUSIONS: Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.

APOL1-G2 accelerates nephrocyte cell death by inhibiting the autophagy pathway.

People of African ancestry who carry the APOL1 risk alleles G1 or G2 are at high risk of developing kidney diseases through not fully understood mechanisms that impair the function of podocytes. It is also not clear whether the APOL1-G1 and APOL1-G2 risk alleles affect these cells through similar mechanisms. Previously, we have developed transgenic Drosophila melanogaster lines expressing either the human APOL1 reference allele (G0) or APOL1-G1 specifically in nephrocytes, the cells homologous to mammalian podocytes. We have found that nephrocytes that expressed the APOL1-G1 risk allele display accelerated cell death, in a manner similar to that of cultured human podocytes and APOL1 transgenic mouse models. Here, to compare how the APOL1-G1 and APOL1-G2 risk alleles affect the structure and function of nephrocytes in vivo, we generated nephrocyte-specific transgenic flies that either expressed the APOL1-G2 or both G1 and G2 (G1G2) risk alleles on the same allele. We found that APOL1-G2- and APOL1-G1G2-expressing nephrocytes developed more severe changes in autophagic pathways, acidification of organelles and the structure of the slit diaphragm, compared to G1-expressing nephrocytes, leading to their premature death. We conclude that both risk alleles affect similar key cell trafficking pathways, leading to reduced autophagy and suggesting new therapeutic targets to prevent APOL1 kidney diseases.

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

Aspergillus Galactomannan Titer as a Diagnostic Marker of Invasive Pulmonary Aspergillosis in Lung Transplant Recipients: A Single-Center Retrospective Cohort Study.

Invasive pulmonary aspergillosis (IPA) can occur in immunocompromised patients, and an early detection and intensive treatment are crucial. We sought to determine the potential of Aspergillus galactomannan antigen titer (AGT) in serum and bronchoalveolar lavage fluid (BALF) and serum titers of beta-D-glucan (BDG) to predict IPA in lung transplantation recipients, as opposed to pneumonia unrelated to IPA. We retrospectively reviewed the medical records of 192 lung transplant recipients. Overall, 26 recipients had been diagnosed with proven IPA, 40 recipients with probable IPA, and 75 recipients with pneumonia unrelated to IPA. We analyzed AGT levels in IPA and non-IPA pneumonia patients and used ROC curves to determine the diagnostic cutoff value. The Serum AGT cutoff value was 0.560 (index level), with a sensitivity of 50%, specificity of 91%, and AUC of 0.724, and the BALF AGT cutoff value was 0.600, with a sensitivity of 85%, specificity of 85%, and AUC of 0.895. Revised EORTC suggests a diagnostic cutoff value of 1.0 in both serum and BALF AGT when IPA is highly suspicious. In our group, serum AGT of 1.0 showed a sensitivity of 27% and a specificity of 97%, and BALF AGT of 1.0 showed a sensitivity of 60% and a specificity of 95%. The result suggested that a lower cutoff could be beneficial in the lung transplant group. In multivariable analysis, serum and BALF AGT, with a minimal correlation between the two, showed a correlation with a history of diabetes mellitus.

Erratum: Correction of Affiliations in the Article "Outcomes of Patients on the Lung Transplantation Waitlist in Korea: A Korean Network for Organ Sharing Data Analysis".

This corrects the article on p. e294 in vol. 37, PMID: 36281485.

Proposal of a revised International Association for the Study of Lung Cancer grading system in pulmonary non-mucinous adenocarcinoma: The importance of the lepidic proportion.

OBJECTIVES: We aimed to measure the validity of the International Association for the Study of Lung Cancer (IASLC) grading system in Korean patients and propose a modification for an increase of its predictability, especially in grade 2 patients. MATERIALS AND METHODS: From 2012 to 2017, histopathologic characteristics of 1358 patients with invasive pulmonary adenocarcinoma (stage I-III) from two institutions were retrospectively reviewed and re-classified according to the IASLC grading system. Considering the amount of the lepidic proportion, the validity of the revised model (Lepidic-10), derived from the training cohort (hospital A), was measured using the validation cohort (hospital B). Its predictability was compared to that of the IASLC system. RESULTS: Of the 1358 patients, 259 had a recurrence, and 189 died during follow-up. The Harrell's concordance index and area under the curve of the IASLC system were 0.685 and 0.699 for recurrence-free survival (RFS) and 0.669 and 0.679 for death, respectively. From the training cohort, the IASLC grade 2 patients were divided into grades 2a and 2b (Lepidic-10 model) with a 10 % lepidic pattern. This new model further distinguished patients in both institutions that had better performance than the IASLC grading (Hospital A, p < 0.001 for RFS and death; Hospital B, p = 0.0215 for RFS, p = 0.0429 for death). CONCLUSION: The IASLC grading system was easily applicable; its clinical use in predicting the prognosis of Korean patients with pulmonary adenocarcinoma was validated. Furthermore, the introduction of the lepidic proportion as an additional criterion to differentiate grade 2 patients improved its predictability.

The Role of Adjuvant Therapy Following Surgical Resection of Small Cell Lung Cancer: A Multi-Center Study.

PURPOSE: This multi-center, retrospective study was conducted to evaluate the long-term survival in patients who underwent surgical resection for small cell lung cancer (SCLC) and to identify the benefit of adjuvant therapy following surgery. MATERIALS AND METHODS: The data of 213 patients who underwent surgical resection for SCLC at four institutions were retrospectively reviewed. Patients who received neoadjuvant therapy or an incomplete resection were excluded. RESULTS: The mean patient age was 65.29±8.93 years, and 184 patients (86.4%) were male. Lobectomies and pneumonectomies were performed in 173 patients (81.2%), and 198 (93%) underwent systematic mediastinal lymph node dissections. Overall, 170 patients (79.8%) underwent adjuvant chemotherapy, 42 (19.7%) underwent radiotherapy to the mediastinum, and 23 (10.8%) underwent prophylactic cranial irradiation. The median follow-up period was 31.08 months (interquartile range, 13.79 to 64.52 months). The 5-year overall survival (OS) and disease-free survival were 53.4% and 46.9%, respectively. The 5-year OS significantly improved after adjuvant chemotherapy in all patients (57.4% vs. 40.3%, p=0.007), and the survival benefit of adjuvant chemotherapy was significant in patients with negative node pathology (70.8% vs. 39.7%, p=0.004). Adjuvant radiotherapy did not affect the 5-year OS (54.6% vs. 48.5%, p=0.458). Age (hazard ratio [HR], 1.032; p=0.017), node metastasis (HR, 2.190; p < 0.001), and adjuvant chemotherapy (HR, 0.558; p=0.019) were associated with OS. CONCLUSION: Adjuvant chemotherapy after surgical resection in patients with SCLC improved the OS, though adjuvant radiotherapy to the mediastinum did not improve the survival or decrease the locoregional recurrence rate.

Risk factors for neuromuscular complications in lower limbs after lung transplantation.

Objective: This study aimed to analyze the prevalence and risk factors of neuromuscular complications after lung transplantation (LT), as well as the association between neuromuscular complications and extracorporeal membrane oxygenation (ECMO) support. Methods: We retrospectively included 201 patients who underwent LT between 2013 and 2020. Patients were classified into three groups based on the presence and the pattern of postoperative leg weakness: no weakness group, asymmetric weakness group, and symmetric weakness group. Comorbidities, duration of ECMO therapy, and postoperative complications were compared between the three groups. Results: Of the 201 recipients, 16 (8.0%) and 29 (14.4%) patients developed asymmetric and symmetric leg weakness, respectively. Foot drop was the main complaint in patients with asymmetric weakness. The presumed site of nerve injury in the asymmetric weakness group was the lumbosacral plexus in 8 (50%), peroneal nerve in 4 (25%), sciatic nerve in 2 (12.5%), and femoral nerve in 2 (12.5%) patients. In multivariate analysis, the use of preoperative ECMO was found to be independently associated with asymmetric weakness (OR, 3.590; 95% CI [1.227-10.502]). Symmetric leg weakness was associated with age at LT (1.062 [1.002-1.125]), diabetes mellitus (2.873 [1.037-7.965]), myositis (13.250 [2.179-80.584]), postoperative continuous renal replacement therapy (4.858 [1.538-15.350]), and duration of stay in the intensive care unit (1.052 [1.015-1.090]). Conclusion: More than 20% of patients developed leg weakness after LT. Early suspicion for peripheral neuropathy is required in patients after LT who used ECMO preoperatively, and who suffered from medical complications after LT.

Effect of Propofol versus Sevoflurane Anesthesia on Acute Kidney Injury after Lung Transplantation Surgery: A Prospective Randomized Controlled Trial.

This prospective randomized controlled trial aimed to compare the effects of sevoflurane and propofol anesthesia on the occurrence of acute kidney injury (AKI) following lung transplantation (LTx) surgery. Sixty adult patients undergoing bilateral LTx were randomized to receive either inhalation of sevoflurane or continuous infusion of propofol for general anesthesia. The primary outcomes were AKI incidence according to the Acute Kidney Injury Network (AKIN) criteria and blood biomarker of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C levels within 48 h of surgery. Serum interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and superoxide dismutase were measured before and after surgery. The post-operative 30-day morbidity and long-term mortality were also assessed. Significantly fewer patients in the propofol group developed AKI compared with the sevoflurane group (13% vs. 38%, p = 0.030). NGAL levels were significantly lower in the propofol group at immediately after, 24 h, and 48 h post-operation. IL-6 levels were significantly lower in the propofol group immediately after surgery. AKI occurrence was significantly associated with a lower 5-year survival rate. Total intravenous anesthesia with propofol reduced the AKI incidence in LTx compared with sevoflurane, which is understood to be mediated by the attenuation of inflammatory responses.

Prognosis of resected invasive mucinous adenocarcinoma compared with the IASLC histologic grading system for invasive nonmucinous adenocarcinoma: Surgical database study in the TKIs era in Korea.

BACKGROUND: The prognosis of invasive mucinous adenocarcinoma (IMA) remains controversial and should be clarified by comparison with the International Association for the Study of Lung Cancer (IASLC) histologic grading system for invasive nonmucinous adenocarcinoma (INMA). METHODS: This study included patients with IMA who underwent curative resection. Their clinicopathological outcomes were compared with those of patients with INMA. Propensity score matching was performed to compare the prognosis of IMA with IASLC grade 2 or 3. Kaplan-Meier survival curves and log-rank tests were used to analyze recurrence-free survival (RFS) and overall survival (OS). RESULTS: The prognoses of IMA and IASLC grade 2 were similar in terms of RFS and OS. Although patients with IMA had better RFS than patients with IASLC grade 3, the OS was not significantly different. After propensity score matching, IMA demonstrated similar RFS to IASLC grade 2 but superior to IASLC grade 3; there was no difference in the OS compared with grades 2/3. Multivariate analysis revealed that tumor size (hazard ratio [HR] = 1.20, p = 0.028), lymphovascular invasion (HR = 127.5, p = 0.003), and maximum standardized uptake value (HR = 1.24, p = 0.005) were poor prognostic predictors for RFS. Patients with IMA demonstrated RFS similar to and significantly better than that of patients with IASLC grades 2 and 3, respectively. For OS, IMA prognosis was between that of IASLC grades 2 and 3. CONCLUSIONS: Since the prognosis of IMA among lung adenocarcinomas appears to be relatively worse, further clinical studies investigating IMA-specific treatment and follow-up plans are necessary to draw more inferences.

Outcomes of Patients on the Lung Transplantation Waitlist in Korea: A Korean Network for Organ Sharing Data Analysis.

BACKGROUND: The demand for lung transplants continues to increase in Korea, and donor shortages and waitlist mortality are critical issues. This study aimed to evaluate the factors that affect waitlist outcomes from the time of registration for lung transplantation in Korea. METHODS: Data were obtained from the Korean Network for Organ Sharing for lung-only registrations between September 7, 2009, and December 31, 2020. Post-registration outcomes were evaluated according to the lung disease category, blood group, and age. RESULTS: Among the 1,671 registered patients, 49.1% had idiopathic pulmonary fibrosis (group C), 37.0% had acute respiratory distress syndrome and other interstitial lung diseases (group D), 7.2% had chronic obstructive pulmonary disease (group A), and 6.6% had primary pulmonary hypertension (group B). Approximately half of the patients (46.1%) were transplanted within 1 year of registration, while 31.8% died without receiving a lung transplant within 1 year of registration. Data from 1,611 patients were used to analyze 1-year post-registration outcomes, which were classified as transplanted (46.1%, n = 743), still awaiting (21.1%, n = 340), removed (0.9%, n = 15), and death on waitlist (31.8%, n = 513). No significant difference was found in the transplantation rate according to the year of registration. However, significant differences occurred between the waitlist mortality rates (P = 0.008) and the still awaiting rates (P = 0.009). The chance of transplantation after listing varies depending on the disease category, blood type, age, and urgency status. Waitlist mortality within 1 year was significantly associated with non-group A disease (hazard ratio [HR], 2.76, P < 0.001), age ≥ 65 years (HR, 1.48, P < 0.001), and status 0 at registration (HR, 2.10, P < 0.001). CONCLUSION: Waitlist mortality is still higher in Korea than in other countries. Future revisions to the lung allocation system should take into consideration the high waitlist mortality and donor shortages.

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis.

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis-with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.