Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD.

TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however, activation of cell stress pathways may contribute to pathogenesis. We, therefore, sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS and FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical integrated stress response (ISR) effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic cleaved caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

Repurposing sodium stibogluconate as an uracil DNA glycosylase inhibitor against prostate cancer using a time-resolved oligonucleotide-based drug screening platform.

Repurposing drugs can significantly reduce the time and costs associated with drug discovery and development. However, many drug compounds possess intrinsic fluorescence, resulting in aberrations such as auto-fluorescence, scattering and quenching, in fluorescent high-throughput screening assays. To overcome these drawbacks, time-resolved technologies have received increasing attention. In this study, we have developed a rapid and efficient screening platform based on time-resolved emission spectroscopy in order to screen for inhibitors of the DNA repair enzyme, uracil-DNA glycosylase (UDG). From a database of 1456 FDA/EMA-approved drugs, sodium stibogluconate was discovered as a potent UDG inhibitor. This compound showed synergistic cytotoxicity against 5-fluorouracil-resistant cancer cells. This work provides a promising future for time-resolved technologies for high-throughput screening (HTS), allowing for the swift identification of bioactive compounds from previously overlooked scaffolds due to their inherent fluorescence properties.

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

Risk factors and in-hospital mortality of postoperative hyperlactatemia in patients after acute type A aortic dissection surgery.

BACKGROUND: Hyperlactatemia may be caused by increased production due to tissue hypoxia or non-hypoxia. The aim of this study was first to identify risk factors for postoperative hyperlactatemia (POHL) after Stanford type A acute aortic dissection surgery (AADS) and construct a predictive model, and second to evaluate the impact of POHL on prognosis. METHODS: This retrospective study involved patients undergoing AADS from January 2016 to December 2019 in Wuhan Union Hospital. Multivariate logistic regression analysis was performed to identify independent risk factors for POHL. A nomogram predicting POHL was established based on these factors and was validated in the original dataset. The receiver operating characteristic curve was drawn to assess the ability of postoperative lactate levels to predict the in-hospital mortality. RESULTS: A total of 188 patients developed POHL after AADS (38.6%). Male gender, surgery history, red blood cell transfusion and cardiopulmonary bypass time were identified as independent predictors. The C-index of the prediction model for POHL was 0.72, indicating reasonable discrimination. The model was well calibrated by visual inspection and goodness-of-fit test (Hosmer-Lemeshow χ2 = 10.25, P = 0.25). Decision and clinical impact curves of the model showed good clinical utility. The overall in-hospital mortality rate was 10.1%. Postoperative lactate levels showed a moderate predictive power for postoperative in-hospital mortality (C-index: 0.72). CONCLUSION: We developed and validated a prediction model for POHL in patients undergoing AADS, which may have clinical utility in personal risk evaluation and preventive interventions. The POHL could be a good predictor for in-hospital mortality.

Neurons in the Intermediate Reticular Nucleus Coordinate Postinspiratory Activity, Swallowing, and Respiratory-Sympathetic Coupling in the Rat.

Breathing results from sequential recruitment of muscles in the expiratory, inspiratory, and postinspiratory (post-I) phases of the respiratory cycle. Here we investigate whether neurons in the medullary intermediate reticular nucleus (IRt) are components of a central pattern generator (CPG) that generates post-I activity in laryngeal adductors and vasomotor sympathetic nerves and interacts with other members of the central respiratory network to terminate inspiration. We first identified the region of the (male) rat IRt that contains the highest density of lightly cholinergic neurons, many of which are glutamatergic, which aligns well with the putative postinspiratory complex in the mouse (Anderson et al., 2016). Acute bilateral inhibition of this region reduced the amplitudes of post-I vagal and sympathetic nerve activities. However, although associated with reduced expiratory duration and increased respiratory frequency, IRt inhibition did not affect inspiratory duration or abolish the recruitment of post-I activity during acute hypoxemia as predicted. Rather than representing an independent CPG for post-I activity, we hypothesized that IRt neurons may instead function as a relay that distributes post-I activity generated elsewhere, and wondered whether they could be a site of integration for para-respiratory CPGs that drive the same outputs. Consistent with this idea, IRt inhibition blocked rhythmic motor and autonomic components of fictive swallow but not swallow-related apnea. Our data support a role for IRt neurons in the transmission of post-I and swallowing activity to motor and sympathetic outputs, but suggest that other mechanisms also contribute to the generation of post-I activity.SIGNIFICANCE STATEMENT Interactions between multiple coupled oscillators underlie a three-part respiratory cycle composed from inspiratory, postinspiratory (post-I), and late-expiratory phases. Central post-I activity terminates inspiration and activates laryngeal motoneurons. We investigate whether neurons in the intermediate reticular nucleus (IRt) form the central pattern generator (CPG) responsible for post-I activity. We confirm that IRt activity contributes to post-I motor and autonomic outputs, and find that IRt neurons are necessary for activation of the same outputs during swallow, but that they are not required for termination of inspiration or recruitment of post-I activity during hypoxemia. We conclude that this population may not represent a distinct CPG, but instead may function as a premotor relay that integrates activity generated by diverse respiratory and nonrespiratory CPGs.

Network-based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA.

Dual-Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta-Activated Kinase 1 Suppression.

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low-grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual-specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver-specific Dusp26-knockout (KO) mice but ameliorated in liver-specific Dusp26-transgenic mice induced by a high-fat diet. In addition, the degree of liver fibrosis was aggravated in high-fat high-cholesterol diet-induced Dusp26-KO mice. We further found that the binding of Dusp26 to transforming growth factor beta-activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1-p38/c-Jun NH2-terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1-dependent therapeutic target for NAFLD.

Therapeutic effects of Chinese herbal medicine against neuroendocrinological diseases especially related to hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axis.

This is a systemic review of plants used traditionally for neuroendocrinological diseases related to hypothalamus-pitutary-adrenal (HPA) and hypothalamus-pitutary-gland (HPG) axis. By searching from PubMed literature search system (1950-2013), Medline (1950-2013) and CNKI (China Journals of Full-text database; 1989-2013), 105 papers met the inclusion criteria were displayed in this review. 96 herbal drugs were classified into two parts which include hormones mainly related to HPA and HPG axis. The full scientific name of each herbal medicine, dose ranges and routes, models or diseases, affect on hormones and pertinent references are presented via synoptic tables. Herbal remedies that have demonstrable the activities of hormones have provided a potential to various diseases related to neunoendocrine and deserve increased attention in future studies. This review provides a basis for herbs use in neuroendocrinological diseases. The data collected here will benefit to further research associated to herbal medicines and hormones.

Single-cell RNA sequencing identifies interferon-inducible monocytes/macrophages as a cellular target for mitigating the progression of abdominal aortic aneurysm and rupture risk.

AIMS: Abdominal aortic aneurysm (AAA) represents a life-threatening condition characterized by medial layer degeneration of the abdominal aorta. Nevertheless, knowledge regarding changes in regulators associated with aortic status remains incomplete. A thorough understanding of cell types and signalling pathways involved in the development and progression of AAAs is essential for the development of medical therapy. METHODS AND RESULTS: We harvested specimens of the abdominal aorta with different pathological features in Angiotensin II (AngII)-infused ApoE-/- mice, conducted scRNA-seq, and identified a unique population of interferon-inducible monocytes/macrophages (IFNICs), which were amply found in the AAAs. Gene set variation analysis revealed that activation of the cytosolic DNA sensing cGAS-STING and JAK-STAT pathways promoted the secretion of type I interferons in monocytes/macrophages and differentiated them into IFNICs. We generated myeloid cell-specific deletion of Sting1 (Lyz2-Cre+/-; Sting1flox/flox) mice and performed bone marrow transplantation and found that myeloid cell-specific deletion of Sting1 or Ifnar1 significantly reduced the incidence of AAA, aortic rupture rate, and diameter of the abdominal aorta. Mechanistically, the activated pyroptosis- and inflammation-related signalling pathways, regulated by IRF7 in IFNICs, play critical roles in the developing AAAs. CONCLUSION: IFNICs are a unique monocyte/macrophage subset implicated in the development of AAAs and aortic rupture.

Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway.

AIMS: Aortic aneurysm and dissection (AAD) is caused by the progressive loss of aortic smooth muscle cells (SMCs) and is associated with a high mortality rate. Identifying the mechanisms underlying SMC apoptosis is crucial for preventing AAD. Neutrophil cytoplasmic factor 1 (Ncf1) is essential in reactive oxygen species production and SMC apoptosis; Ncf1 absence leads to autoimmune diseases and chronic inflammation. Here, the role of Ncf1 in angiotensin II (Ang II)-induced AAD was investigated. METHODS AND RESULTS: Ncf1 expression increased in injured SMCs. Bioinformatic analysis identified Ncf1 as a mediator of AAD-associated SMC damage. Ncf1 expression is positively correlated with DNA replication and repair in SMCs of AAD aortas. AAD incidence increased in Ang II-challenged Sm22CreNcf1fl mice. Transcriptomics showed that Ncf1 knockout activated the stimulator of interferon genes (STING) and cell death pathways. The effects of Ncf1 on SMC death and the STING pathway in vitro were examined. Ncf1 regulated the hydrogen peroxide-mediated activation of the STING pathway and inhibited SMC apoptosis. Mechanistically, Ncf1 knockout promoted the ubiquitination of nuclear factor erythroid 2-related factor 2 (NRF2), thereby inhibiting the negative regulatory effect of NRF2 on the stability of STING mRNA and ultimately promoting STING expression. Additionally, the pharmacological inhibition of STING activation prevented AAD progression. CONCLUSION: Ncf1 deficiency in SMCs exacerbated Ang II-induced AAD by promoting NRF2 ubiquitination and degradation and activating the STING pathway. These data suggest that Ncf1 may be a potential therapeutic target for AAD treatment.

Comparative investigation of neoadjuvant immunotherapy versus adjuvant immunotherapy in perioperative patients with cancer: a global-scale, cross-sectional, and large-sample informatics study.

BACKGROUND: Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis. METHODS: This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding nonpeer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis. RESULTS: This analysis included 1373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18 vs. 6.52% and global collaboration (International Co-authorships) of 19.93 vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) [Average Publication Year (APY): 2021.70±0.70 vs. 2017.54±4.59] are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R 2 =0.7500, P =0.0025) and biomarkers (R 2 =0.6505, P =0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R 2 =0.5571, P =0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that 'neoadjuvant immunotherapy, nonsmall cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma' and 'adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells' (Relevance Percentage: 100 vs. 100%, Development Percentage: 37.5 vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation. CONCLUSION: This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources.

Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus.

BACKGROUND: Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic avian influenza H5N6 virus and its high fatality rate posed a potential threat, necessitating the search for a more effective treatment. METHODS: Longitudinal clinical data and specimens were collected from five H5N6 patients after admission. All patients received antiviral treatment of either sequential monotherapy of oseltamivir and baloxavir or the two drugs in combination. Severity of illness; viral load in sputum, urine, and blood; and cytokine levels in serum and sputum were serially analyzed. FINDINGS: All patients developed acute respiratory distress syndrome (ARDS) and viral sepsis within 1 week after disease onset. When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. In addition, levels of IL-18, M-CSF, IL-6, and HGF in sputum and Mig and IL-18 in serum that reflected ARDS and sepsis deterioration, respectively, were also reduced with baloxavir usage. However, three patients eventually died from exacerbation of underlying disease and secondary bacterial infection. Nonsurvivors had more severe extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response. CONCLUSIONS: For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness. FUNDING: This work was funded by the National Natural Science Foundation of China (81761128014).

Covalent inhibition of epidermal growth factor receptor using a long-lived iridium(III)-afatinib probe.

The overexpression and overactivation of epidermal growth factor receptor (EGFR) are frequently observed in human cancers, including squamous cell carcinoma and adenocarcinoma. In this study, a covalent EGFR probe was developed by conjugating afatinib to an iridium(III) scaffold. Complex 1 showed enhanced luminescence in living epidermoid squamous carcinoma A431 cells compared to other cell lines, via engaging EGFR as confirmed via CETSA and knockdown experiments. Moreover, complex 1 inhibited downstream targets of EGFR in cellulo with repression persisting after removal of the complex, indicating an irreversible mode of inhibition. Finally, complex 1 showed potent antiproliferative activity against A431 cells with comparable potency to afatinib alone. To our knowledge, complex 1 is the first EGFR covalent inhibitor based on an iridium scaffold reported in the literature, with the potential to be further explored as a theranostic agent in the future.

Aortic Dissection Research in China: Analysis of Studies Funded by the National Natural Science Foundation of China.

OBJECTIVE: The National Natural Science Foundation of China (NSFC) has made great progress in promoting the development of aortic dissection research in recent years. This study aimed to examine the development and research status of aortic dissection research in China so as to provide references for future research. METHODS: The NSFC projects data from 2008 to 2019 were collected from the Internet-based Science Information System and other websites utilized as search engines. The publications and citations were retrieved by Google Scholar, and the impact factors were checked by the InCite Journal Citation Reports database. The investigator's degree and department were identified from the institutional faculty profiles. RESULTS: A total of 250 grant funds totaling 124.3 million Yuan and resulting in 747 publications were analyzed. The funds in economically developed and densely populated areas were more than those in underdeveloped and sparsely populated areas. There was no significant difference in the amount of funding per grant between different departments' investigators. However, the funding output ratios of the grants for cardiologists were higher than those for basic science investigators. The amount of funding for clinical researchers and basic scientific researchers in aortic dissection was also similar. Clinical researchers were better in terms of the funding output ratio. CONCLUSION: These results suggest that the medical and scientific research level of aortic dissection in China has been greatly improved. However, there are still some problems that urgently need to be solved, such as the unreasonable regional allocation of medical and scientific research resources, and the slow transition from basic science to clinical practice.

MicroRNA let-7a mediates posttranscriptional inhibition of Nr4A1 and exacerbates cardiac allograft rejection.

BACKGROUND: Acute allograft rejection remains a major obstacle after heart transplantation, and CD4+ T cells play a crucial role in allograft rejection. Upregulation of Nr4A1 could regulate CD4+ T-cell function and alleviate allograft rejection. However, the regulatory mechanism of Nr4A1 in allograft rejection remains elusive. METHODS: BALB/c mouse hearts were transplanted into WT C57BL/6 mice, and dynamic detection of the changes in Nr4A1 expression revealed that Nr4A1 was regulated posttranscriptionally after heart transplantation. Potential upstream miRNAs of Nr4A1 were screened, and the transfection of cells with these miRNA mimics/inhibitors and dual-luciferase reporter experiments were performed to clarify the regulatory mechanism of miRNAs on Nr4A1 expression. The miRNA agomiR/antagomiR was applied in vivo to validate the role of the corresponding miRNA in heart transplantation. Finally, Nr4A1 knockout mice and an adoptive T-cell cotransfer model were used to confirm the specific effects of miRNA. RESULTS: The expression of Nr4A1 protein (rather than mRNA) exhibited a trend of initially increasing and then decreasing rapidly, and this phenomenon could not be reversed by lysosomal or proteasomal inhibitors. The miRNA let-7a directly binds to the Nr4A1 3'UTR and posttranscriptionally regulates Nr4A1 expression. The let-7a antagomiR prolonged allograft survival and regulated CD4+ T-cell function by upregulating Nr4A1 protein expression in CD4+ T cells. CONCLUSIONS: This study confirmed that let-7a is a potential target for interfering with Nr4A1 expression in CD4+ T cells and preventing the pathological progression of cardiac allograft rejection.

Violating the isolated pentagon rule (IPR): endohedral non-IPR C98 cages of Gd2@C98.

The geometric, electronic structure, and thermodynamic stability of large gadolinium-containing endohedral metallofullerenes, Gd(2)@C(98), have been systematically investigated by comprehensive density functional theory calculations combined with statistical mechanics treatments. The Gd(2)@C(2)(230924)-C(98) structure, which satisfies the isolated-pentagon rule (IPR), is determined to possess the lowest energy followed with some stable non-IPR isomers. In order to clarify the relative stabilities at elevated temperatures, entropy contributions are taken into account on the basis of the Gibbs energy at the B3LYP level for the first time. Interestingly, a novel non-IPR Gd(2)@C(1)(168785)-C(98) isomer which has one pair of pentagon adjacency is more thermodynamically stable than the lowest energy IPR species within a wide temperature interval related to fullerene formation. Therefore, the Gd(2)@C(1)(168785)-C(98) is predicted to be the most proper isomer obtained experimentally, which is the largest non-IPR carbon cage found so far. Our findings demonstrate that interaction between metals and carbon cages could stabilize the fused pentagons effectively, and thus, the non-IPR isomers should not be ignored in some cases of endohedral metallofullerenes. The IR features of Gd(2)@C(98) are simulated to assist its future experimental characterization.

Development and validation of a nomogram model for pneumonia after redo cardiac surgery.

AIMS: Postoperative pneumonia (POP) after redo cardiac surgery is prevalent, associated with poor outcome. The aim of this study was to identify independent risk factors for POP after redo cardiac surgery and to develop and validate a prediction model. METHODS: Adults undergoing redo cardiac surgery from 2016 to 2019 were identified in a single-institution database. Using a 2: 1 ratio, the patients were randomly divided into training and validation sets. Univariate and multivariate analyses were applied to identify independent predictors for POP in the training set. A nomogram model was constructed for clinical utility and was validated in the validation set. RESULTS: POP developed in 72 of the 376 patients (19.1%). Four independent risk factors were identified, including age, chronic obstructive pulmonary disease, serum creatinine level and intraoperative blood transfusion volume. A nomogram based on the four predictors was constructed, with good discrimination in both the training (c-index: 0.86) and validation sets (c-index: 0.78). The model was well calibrated, with a Hosmer-Lemeshow χ 2 -value of 7.31 ( P   =  0.50) in the training set and 7.41 ( P   =  0.49) in the validation set. The calibration was also good by visual inspection. The decision and clinical impact curves of the nomogram indicated good clinical utility. Three risk intervals were identified based on the nomogram for better risk stratification. CONCLUSION: We developed and validated a nomogram model for POP after redo cardiac surgery. The model may have good clinical utility in risk evaluation and individualized treatment to reduce adverse events. Graphical abstract Incidence, risk factor, and outcomes of postoperative pneumonia after redo cardiac surgery: http://links.lww.com/JCM/A445 .

Development and validation of a risk prediction model for postoperative pneumonia in adult patients undergoing Stanford type A acute aortic dissection surgery: a case control study.

BACKGROUND: Pneumonia is a common complication after Stanford type A acute aortic dissection surgery (AADS) and contributes significantly to morbidity, mortality, and length of stay. The purpose of this study was to identify independent risk factors associated with pneumonia after AADS and to develop and validate a risk prediction model. METHODS: Adults undergoing AADS between 2016 and 2019 were identified in a single-institution database. Patients were randomly divided into training and validation sets at a ratio of 2:1. Preoperative and intraoperative variables were included for analysis. A multivariate logistic regression model was constructed using significant variables from univariate analysis in the training set. A nomogram was constructed for clinical utility and the model was validated in an independent dataset. RESULTS: Postoperative pneumonia developed in 170 of 492 patients (34.6%). In the training set, multivariate analysis identified seven independent predictors for pneumonia after AADS including age, smoking history, chronic obstructive pulmonary disease, renal insufficiency, leucocytosis, low platelet count, and intraoperative transfusion of red blood cells. The model demonstrated good calibration (Hosmer-Lemeshow χ2 = 3.31, P = 0.91) and discrimination (C-index = 0.77) in the training set. The model was also well calibrated (Hosmer-Lemeshow χ2 = 5.73, P = 0.68) and showed reliable discriminatory ability (C-index = 0.78) in the validation set. By visual inspection, the calibrations were good in both the training and validation sets. CONCLUSION: We developed and validated a risk prediction model for pneumonia after AADS. The model may have clinical utility in individualized risk evaluation and perioperative management.

Cytosporone B (Csn-B), an NR4A1 agonist, attenuates acute cardiac allograft rejection by inducing differential apoptosis of CD4+T cells.

CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.

Erratum: Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation: Erratum.

[This corrects the article DOI: 10.7150/thno.43507.].