A vision chip with complementary pathways for open-world sensing.

Image sensors face substantial challenges when dealing with dynamic, diverse and unpredictable scenes in open-world applications. However, the development of image sensors towards high speed, high resolution, large dynamic range and high precision is limited by power and bandwidth. Here we present a complementary sensing paradigm inspired by the human visual system that involves parsing visual information into primitive-based representations and assembling these primitives to form two complementary vision pathways: a cognition-oriented pathway for accurate cognition and an action-oriented pathway for rapid response. To realize this paradigm, a vision chip called Tianmouc is developed, incorporating a hybrid pixel array and a parallel-and-heterogeneous readout architecture. Leveraging the characteristics of the complementary vision pathway, Tianmouc achieves high-speed sensing of up to 10,000 fps, a dynamic range of 130 dB and an advanced figure of merit in terms of spatial resolution, speed and dynamic range. Furthermore, it adaptively reduces bandwidth by 90%. We demonstrate the integration of a Tianmouc chip into an autonomous driving system, showcasing its abilities to enable accurate, fast and robust perception, even in challenging corner cases on open roads. The primitive-based complementary sensing paradigm helps in overcoming fundamental limitations in developing vision systems for diverse open-world applications.

Brown-fat-mediated tumour suppression by cold-altered global metabolism.

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Extracorporeal Versus Conventional Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest: A Propensity Score Matching Cohort Study.

OBJECTIVE: Comparing the effects of extracorporeal cardiopulmonary resuscitation (ECPR) and conventional cardiopulmonary resuscitation (CCPR) on outcomes in patients with in-hospital cardiac arrest (IHCA) in China. The benefits of ECPR over CCPR in patients with IHCA remain controversial. DESIGN: This article analyzed data from the BASeline Investigation of In-hospital Cardiac Arrest (BASIC-IHCA) study, which consecutively enrolled patients with IHCA from July 1, 2019, to December 31, 2020. Patients who received ECPR were selected as the case group and matched with patients who received CCPR as the control group by propensity score at a ratio of 1:4. A parallel questionnaire survey of participating hospitals was conducted, to collect data on ECPR cases from January 1, 2021 to November 30, 2021. The primary outcome was survival to discharge or 30-day survival. SETTING: We included 39 hospitals across 31 provinces in China. PATIENTS: Patients receiving cardiopulmonary resuscitation and without contraindications to ECPR were selected from the BASIC-IHCA database. Patients older than 75 years, not witnessed, or with cardiopulmonary resuscitation duration less than 10 min were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 4853 patients met the inclusion criteria before matching, with 34 undergoing ECPR (median age, 56.5 yr; 67.65% male) and 4819 underwent CCPR (median age, 59 yr; 64.52% male). There were 132 patients receiving CCPR and 33 patients receiving ECPR who were eventually matched. The ECPR group had significantly higher survival rates at discharge or 30-day survival (21.21% vs. 7.58%, p = 0.048). The ECPR group had significantly lower mortality rates (hazard ratio 0.57; 95% CI, 0.38-0.91) than the CCPR group at discharge or 30 days. Besides the BASIC-IHCA study, the volume of ECPR implementations and the survival rate of patients with ECPR (29.4% vs. 10.4%. p = 0.004) in participating hospitals significantly improved. CONCLUSIONS: ECPR may be beneficial compared with CCPR for patient survival after IHCA and should be considered for eligible patients with IHCA.

Alloreactive T cells temporarily increased in peripheral blood of patients before liver allograft rejection.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cells (PBMCs) samples spanning from pre-LTx to one-year post-LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial PBMC samples were collected from 96 non-rejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors and longitudinally compared them to non-rejected patients. Donor-reactive T cell clone was identified and tracked by cross-matching with mappable donor-reactive TCR repertoire of each donor-recipient pair in 9 rejectors and 5 non-rejectors. Before transplantation, the naive T cell percentage and TCR repertoire diversity of rejectors was comparable to healthy control, it was reduced in non-rejectors. After transplantation, the naïve T cell percentages decreased and TCR repertoires were skewed in rejectors, the phenomenon was not observed in non-rejectors. Alloreactive clones increased in proportion in peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T cell decline and memory T cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre- and post-LTx PBMC samples revealed that the pre-transplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases, and may facilitate disease prediction and management.

Distribution and prognostic value of high-sensitivity cardiac troponin T and I across glycemic status: a population-based study.

BACKGROUND: Whether distributions and prognostic values of high-sensitivity cardiac troponin (hs-cTn) T and I are different across normoglycemic, prediabetic, and diabetic populations is unknown. METHODS: 10127 adult participants from the National Health and Nutrition Examination Survey 1999-2004 with determined glycemic status and measurement of at least one of hs-cTn assays were included, from whom healthy participants and presumably healthy diabetic and prediabetic participants were selected to investigate pure impacts of glycemic status on distributions of hs-cTn. The nonparametric method and bootstrapping were used to derive the 99th upper reference limits of hs-cTn and 95% CI. Participants with available follow-up and hs-cTn concentrations of all 4 assays were included in prognostic analyses. Associations of hs-cTn with all-cause and cardiac-specific mortality were modeled by Cox proportional hazard regression under the complex survey design. The incremental value of hs-cTn to an established risk score in predicting cardiac-specific mortality was assessed by the 10-year area under time-dependent receiver operating characteristic curve (AUC) using the Fine-Grey competing risk model. RESULTS: Among 9714 participants included in prognostic analyses, 5946 (61.2%) were normoglycemic, 2172 (22.4%) prediabetic, and 1596 (16.4%) diabetic. Hyperglycemic populations were older than the normoglycemic population but sex and race/ethnicity were similar. During the median follow-up of 16.8 years, hs-cTnT and hs-cTnI were independently associated with all-cause and cardiac-specific mortality across glycemic status. In the diabetic population, adjusted hazard ratios per 1-standard deviation increase of log-transformed hs-cTnT and hs-cTnI (Abbott) concentrations were 1.77 (95% CI 1.48-2.12; P < .001) and 1.83 (95% CI 1.33-2.53; P < .001), respectively, regarding cardiac-specific mortality. In the diabetic but not the normoglycemic population, adding either hs-cTnT (difference in AUC: 0.062; 95% CI 0.038-0.086; P < 0.001) or hs-cTnI (Abbott) (difference in AUC: 0.071; 95% CI 0.046-0.097; P < 0.001) would significantly increase the discriminative ability of the risk score; AUC of the score combined with hs-cTnT would be further improved by incorporating hs-cTnI (0.018; 95%CI 0.006-0.029; P = 0.002). The 99th percentile of hs-cTnT of the presumably healthy diabetic population was higher than the healthy population and had no overlap in 95% CIs, however, for hs-cTnI 99th percentiles of the two populations were very close and 95% CIs extensively overlapped. CONCLUSIONS: Hs-cTnT and hs-cTnI demonstrated consistent prognostic associations across glycemic status but incremental predictive values in hyperglycemic populations only. The susceptibility of hs-cTnT 99th percentiles to diabetes plus the additive value of hs-cTnI to hs-cTnT in diabetic cardiovascular risk stratification suggested hs-cTnI and hs-cTnT may be differentially associated with glycemic status, but further research is needed to illustrate the interaction between hyperglycemia and hs-cTn.

Contribution of Tinnitus and Hearing Loss to Depression: NHANES Population Study.

OBJECTIVES: Hearing loss affects the emotional well-being of adults and is sometimes associated with clinical depression. Chronic tinnitus is highly comorbid with hearing loss and separately linked with depression. In this article, the authors investigated the combined effects of hearing loss and tinnitus on depression in the presence of other moderating influences such as demographic, lifestyle, and health factors. DESIGN: The authors used the National Health and Nutrition Examination Survey data (2011-2012 and 2015-2016) to determine the effects of hearing loss and tinnitus on depression in a population of US adults (20 to 69 years). The dataset included the Patient Health Questionnaire-9 for depression screening, hearing testing using pure-tone audiometry, and information related to multiple demographic, lifestyle, and health factors (n = 5845). RESULTS: The statistical analysis showed moderate to high associations between depression and hearing loss, tinnitus, and demographic, lifestyle, and health factors, separately. Results of logistic regression analysis revealed that depression was significantly influenced by hearing loss (adjusted odds ratios [OR] = 3.0), the functional impact of tinnitus (adjusted OR = 2.4), and their interaction, both in the absence or presence of the moderating influences. The effect of bothersome tinnitus on depression was amplified in the presence of hearing loss (adjusted OR = 2.4 in the absence of hearing loss to adjusted OR = 14.9 in the presence of hearing loss). Conversely, the effect of hearing loss on depression decreased when bothersome tinnitus was present (adjusted OR = 3.0 when no tinnitus problem was present to adjusted OR = 0.7 in the presence of bothersome tinnitus). CONCLUSIONS: Together, hearing loss and bothersome tinnitus had a significant effect on self-reported depression symptoms, but their relative effect when comorbid differed. Tinnitus remained more salient than hearing loss and the latter's contribution to depression was reduced in the presence of tinnitus, but the presence of hearing loss significantly increased the effects of tinnitus on depression, even when the effects of the relevant demographic, lifestyle, or health factors were controlled. Treatment strategies that target depression should screen for hearing loss and bothersome tinnitus and provide management options for the conditions.

Long-term PM2.5 exposure associated with severity of angina pectoris and related health status in patients admitted with acute coronary syndrome: Modification effect of genetic susceptibility and disease history.

Long-term particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) exposure has been associated with the occurrence of acute coronary syndrome (ACS). However, the impact of PM2.5 exposure and its components on the severity of angina pectoris and disease-related health status in patients hospitalized for ACS is understudied. To assess the association between long-term exposure to PM2.5 components and the angina pectoris severity in ACS patients, as well as the modification effects of genetic factors and disease history in north China. During 2017-2019, 6729 ACS patients were collected in Shandong Province and Beijing, with their angina pectoris severity evaluated using Seattle Angina Questionnaire (SAQ). The 0-3 years' average concentrations of PM2.5 and its five major components were assigned to each patient's residential address. Linear mixed-effects model, weighted quantile regression, and quantile g-computation were used to estimate the effects of both single and joint associations between PM2.5 components and SAQ scores. The interactive effect was estimated by polygenic risk scores and disease history. For each interquartile range increase in PM2.5, the overall SAQ score changed by -3.71% (95%CI: -4.54% to -2.88%), with score of angina stability more affected than angina frequency and other dimensions of angina pectoris severity. Sulfate and ammonium were major contributors to the effect of PM2.5 exposure. Significant modification effect was only observed for disease history, especially for the dimension of physical limitation. Among a series of pre-existing diseases, patients with a family history of coronary artery disease, previous percutaneous coronary intervention or coronary artery bypass grafting, and stroke were more susceptible to PM2.5 exposure than others. Greater exposure to PM2.5 is associated with more serious angina pectoris and worse disease-related health status in ACS patients. Public health and clinical priority should be given to cutting down key effective components and protecting highly vulnerable individuals.

Characterization of Fusarium solani associated with tobacco (Nicotiana tabacum L.) root rot in Henan, China.

The aim of this study was to characterize the Fusarium solani species complex (FSSC) population obtained from tobacco roots with root rot symptoms using morphological characteristics, molecular tests, and assessment of pathogenicity. Cultures isolated from roots were white to cream with sparse mycelium on PDA with colony growth of 21.5 ± 0.5 to 29.5 ± 0.5 mm after 3 days. Sporodochia were cream on carnation leaf agar (CLA) and spezieller nährstoffarmer agar (SNA), and macroconidia formed in sporodochia were 3- to 6-septate, straight to slightly curved, with wide central cells, a slightly short blunt apical cell, and a straight to almost cylindrical basal cell with a distinct foot shape, ranging in size from 20.92 to 64.37 µm × 3.91 to 6.57 µm. Microconidia formed on CLA were reniform and fusiform with 0 or 1 to occasionally 2 septa, that formed on long monophialidic conidiogenous cells, with a size range of 5.99 to 32.32 µm × 1.76 to 5.84 µm. Globose to oval chlamydospores were smooth to rough-walled, 6.5 to 13.3 ± 0.37 µm in diameter, terminal or intercalary, single or in pairs, occasionally in short chains on SNA. Molecular tests consisted of sequencing and phylogenetic analysis of the translation elongation factor-1 alpha (EF-1α), RNA polymerase II largest subunit (RPB1), and second largest subunit (RPB2) regions. All the obtained sequences revealed 98.14%~100% identity to Fusarium solani in both Fusarium ID and Fusarium MLST databases. Phylogenetic trees of the EF-1α gene and concatenated three-loci data showed that isolates from tobacco in Henan grouped in the proposed group 5, which is nested within FSSC clade 3 (FSSC 5). Twenty-seven of the 28 isolates caused a root rot of artificially inoculated tobacco seedlings, with a disease index ranging from 15.00 ± 1.67 to 91.11 ± 2.22. Cross pathogenicity tests showed that three representative isolates were virulent to six species of Solanaceae and two of Poaceae, with disease indexes ranging from 6.12 ± 0.56 to 84.44 ± 0.00, indicating that these isolates have a wide host range. The results may inform control of tobacco root rot through improved crop rotations.

A national survey on current state and development needs of clinical and academic emergency medicine in China.

BACKGROUND: To characterize the current state of emergency medicine (EM) and the requirements for advancing EM clinical practice, education and research in China. METHODS: An anonymous electronic survey was conducted by Chinese Society of Emergency Medicine during September to October 2021. The survey contained 30 questions divided into 2 sections: the current state of EM development and the requirements for EM growth. RESULTS: 722 hospitals were included, of 487 were Level III and 235 were Level II hospitals. We found that after 40 years of development, EM had established a mature disciplinary system and refined sub-specialties including critical care, cardiopulmonary resuscitation, toxicology, disaster and emergency rescue. In Level III hospitals, 70.8% of EDs were standardized training centers for EM residents, but master's degree program, Doctor Degree program and post-doctoral degree program was approved in only 37.8%, 8.4% and 2.9% of EDs respectively and postgraduate curriculum was available in 1/4 of EDs. Only 8% have national or provincial key laboratories. In addition to advance clinical practice, there was also a high demand to improve teaching and research capacities, mainly focusing on literature review, research design and delivery, paper writing, residency training. CONCLUSIONS: EM has built a mature discipline system and refined sub-specialties in China. Teaching and research developed parallel with clinical practice. However, there was still a lack of EM master's and doctoral programs and research capacities need to be improved. More outstanding clinical and academic training should be provided to promote the rapid growth of EM in China.

[Effect of Intensive Insulin Therapy on Prognosis in Patients With Acute Myocardial Infarction].

Objective To evaluate the clinical efficacy and safety of intensive insulin therapy in the patients with acute myocardial infarction and provide guidance for improving the prognosis. Methods The articles involving the randomized controlled trials(RCT)focusing on the effects of intensive versus conventional insulin therapy on the clinical outcomes of the patients with acute myocardial infarction were retrieved from Cochrane,Embase,PubMed,CNKI,Wanfang Data,VIP,and CBM with the time interval from inception to October 2022.The data of each RCT were extracted and used for meta-analysis in RevMan5.4. Results A total of 8 articles were included in this study,involving 726 patients(372 in the intensive insulin group and 354 in the normal insulin group).The meta-analysis results showed that the intensive insulin group had lower incidence of major cardiovascular adverse events (RR=0.53, 95%CI=0.44-0.64, P<0.001), lower all-cause mortality (RR=0.51, 95%CI=0.33-0.78, P=0.002),lower high-sensitivity C-reactive protein level on day 7(WMD=-2.00,95%CI=-2.17- -1.83,P<0.001),higher left ventricular ejection fraction on day 30 (WMD=3.94, 95%CI=2.45-5.43,P<0.001), and higher incidence of hypoglycemia events (RR=2.96, 95%CI=1.12-7.83,P=0.030) than the normal insulin group.There was no significant difference between the two groups in terms of no-reflow event after percutaneous coronary intervention(RR=0.39,95%CI=0.14-1.13,P=0.080). Conclusion Intensive insulin therapy might be associated with more clinical benefits in the patients with acute myocardial infarction,while the conclusion remains to be confirmed by more studies.

Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant.

Natural killer (NK) cells contribute to liver transplant (LTx) rejection. However, the blood-circulating NK-cell dynamics of patients who experience acute rejection (AR) are unclear. Herein, we longitudinally profiled the total NK cells and their subsets, along with the expression of activating and inhibitory receptors in sequential peripheral blood mononuclear cell samples, spanning from before LTx to the first year after LTx of 32 patients with AR and 30 patients under a steady immune status. Before transplantation, patients with AR (rejectors) contained a significantly higher proportion of the immature CD56 bright CD16 - subset and a lower cytolytic CD56 dim CD16 + in the total blood-circulating NK cells than patients with steady immunity. Both subsets contained a high NKp30-positive population, and CD56 dim CD16 + additionally exhibited a high NKp46-positive ratio. The NKp30-positive ratio in CD56 dim CD16 + subset showed the most prominent AR predictive ability before LTx and was an independent risk factor of LTx AR. After transplantation, the blood-circulating NK cells in rejectors maintained a higher CD56 bright CD16 - and lower CD56 dim CD16 + composition than the controls throughout the first year after LTx. Moreover, both subsets maintained a high NKp30-positive ratio, and CD56 dim CD16 + retained a high NKp46-positive ratio. The blood-circulating NK cell subset composition was consistent during AR, while the expressions of NKp30 and NKp46 were augmented. Collectively, a more immature CD56 bright CD16 - subset composition and an activated phenotype of high NKp30 expression were the general properties of blood-circulating NK cells in rejected LTx recipients, and the NKp30-positive ratio in CD56 dim CD16 + NK subset before LTx possessed AR predictive potential.

Drug-coated balloon for the treatment of small vessel disease: 9 months of angiographic results and 12 months of clinical outcomes of the PEPCAD China SVD study.

BACKGROUND: Whether the drug-coated balloons (DCBs)-alone strategy was superior to plain old balloon angioplasty (POBA) in treating SVD remains unknown. AIMS: We aimed to evaluate the efficacy and safety of DCBs for the treatment of coronary de novo small vessel disease (SVD) and provide further evidence for extending the clinical indications of DCBs. (ChiCTR1800014966). METHODS: Eligible patients were randomized at a 2:1 ratio to receive DCB treatment or POBA in this prospective, multicenter clinical trial. The reference vessel diameter of lesions was visually assessed to be 2.0 to 2.75 mm. The primary endpoint of the study was angiographic in-segment late luminal loss (LLL) at the 9-month follow-up to demonstrate the superiority of DCB treatment to POBA in SVD. The composite clinical endpoints included clinically driven target lesion revascularization (CD-TLR), target lesion failure (TLF), major adverse cardiac events (MACEs), and thrombosis at the 12-month follow-up. RESULTS: A total of 270 patients were enrolled (181 for DCB, 89 for POBA) at 18 centers in China. The primary endpoint of 9-month in-segment LLL in the intention-to-treat population was 0.10 ± 0.33 mm with DCB and 0.25 ± 0.38 mm with POBA (p = 0.0027). This difference indicated significant superiority of DCB treatment (95% CI: -0.22, -0.04, psuperiority = 0.0068). The rates of the clinical endpoints-CD-TLR, TLF, and MACEs-were comparable between groups. No thrombosis events were reported. CONCLUSIONS: DCB treatment of de novo SVD was superior to POBA with lower 9-month in-segment LLL. The rates of clinical events were comparable between the two devices.

Review: Acetylation mechanisms and targeted therapies in cardiac fibrosis.

Cardiac fibrosis is a common pathophysiological remodeling process that occurs in a variety of cardiovascular diseases and greatly influences heart structure and function, progressively leading to the development of heart failure. However, to date, few effective therapies for cardiac fibrosis exist. Abnormal proliferation, differentiation, and migration of cardiac fibroblasts are responsible for the excessive deposition of extracellular matrix in the myocardium. Acetylation, a widespread and reversible protein post-translational modification, plays an important role in the development of cardiac fibrosis by adding acetyl groups to lysine residues. Many acetyltransferases and deacetylases regulate the dynamic alterations of acetylation in cardiac fibrosis, regulating a range of pathogenic conditions including oxidative stress, mitochondrial dysfunction, and energy metabolism disturbance. In this review, we demonstrate the critical roles that acetylation modifications caused by different types of pathological injury play in cardiac fibrosis. Furthermore, we propose therapeutic acetylation-targeting strategies for the prevention and treatment of patients with cardiac fibrosis.

Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development.

BACKGROUND: Clinical studies show that the most common single-point mutation in humans, ALDH2 (aldehyde dehydrogenase 2) rs671 mutation, is a risk factor for the development and poor prognosis of atherosclerotic cardiovascular diseases, but the underlying mechanism remains unclear. Apoptotic cells are phagocytosed and eliminated by macrophage efferocytosis during atherosclerosis, and enhancement of arterial macrophage efferocytosis reduces atherosclerosis development. METHODS: Plaque areas, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated in APOE-/- mice with bone marrow transplanted from APOE-/-ALDH2-/- and APOE-/- mice. RNA-seq, proteomics, and immunoprecipitation experiments were used to screen and validate signaling pathways affected by ALDH2. Efferocytosis and protein levels were verified in human macrophages from wild-type and rs671 mutation populations. RESULTS: We found that transplanting bone marrow from APOE-/-ALDH2-/- to APOE-/- mice significantly increased atherosclerosis plaques compared with transplanting bone marrow from APOE-/- to APOE-/- mice. In addition to defective efferocytosis in plaques of APOE-/- mice bone marrow transplanted from APOE-/-ALDH2-/- mice in vivo, macrophages from ALDH2-/- mice also showed significantly impaired efferocytotic activity in vitro. Subsequent RNA-seq, proteomics, and immunoprecipitation experiments showed that wild-type ALDH2 directly interacted with Rac2 and attenuated its degradation due to decreasing the K48-linked polyubiquitination of lysine 123 in Rac2, whereas the rs671 mutant markedly destabilized Rac2. Furthermore, Rac2 played a more crucial role than other Rho GTPases in the internalization process in which Rac2 was up-regulated, activated, and clustered into dots. Overexpression of wild-type ALDH2 in ALDH2-/- macrophages, rather than the rs671 mutant, rescued Rac2 degradation and defective efferocytosis. More importantly, ALDH2 rs671 in human macrophages dampened the apoptotic cells induced upregulation of Rac2 and subsequent efferocytosis. CONCLUSIONS: Our study has uncovered a pivotal role of the ALDH2-Rac2 axis in mediating efferocytosis during atherosclerosis, highlighting a potential therapeutic strategy in cardiovascular diseases, especially for ALDH2 rs671 mutation carriers.

Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo.

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.

First report of Fusarium tricinctum Species complex causing root rot of tobacco in China.

Tobacco (Nicotiana tabacum L.) is an economically important crop in China. In June 2021, a root rot disease was observed on tobacco (cv. Yunyan99) in Lushi, Mianchi, and Luoning counties of western Henan, China. Diseased tobacco plants exhibited wilting with leaf chlorosis and root rot accompanied by purplish to brown vascular discoloration. The symptoms were observed in four surveyed fields, 57 ha in total, and disease incidence ranged from 21 to 56%. Five symptomatic plants with leaf chlorosis and root rot were randomly collected from each field for pathogen isolation. Tissue pieces from diseased roots were surface sterilized in 75% ethanol for 30 s then rinsed with sterile distilled water three times, air dried, and placed onto potato dextrose agar (PDA) medium. Five isolates, SL1, SL2, SL3, LN and KC, were purified by single-spore culturing. On PDA, colonies grew at a rate of 2-5 mm/day and produced abundant cottony, white to pink aerial mycelia and rose pigment on the reverse side of the culture plate. From 7-day-old cultures grown on carnation leaf agar (CLA), macroconidia were straight to subarcuate, with blunt and slightly hooked apical and basal cells, had three to four septa, measured 23.4 to 44.6×3.5 to 4.2 µm (n=30). Cylindrical, napiform or oval microconidia were one to two-celled, measuring 6.3 to 22.9×2.2 to 4.9 µm (n=30). Spherical chlamydospores were intercalary or terminal, in chains. Such characteristics resembled those of the Fusarium tricinctum species comples (FTSC; Batra and Lichtwardt 1962; Leslie and Summerell 2006). To confirm the morphological diagnosis, the genomic DNA of the isolates were extracted, the translation elongation factor 1-alpha (EF-1α), RNA polymerase I largest subunit (RPB1) and second largest subunit (RPB2) genes were amplified with primers EF1/EF2, F5/G2R and 5f2/7cr respectively (O'Donnell et al. 2010), and sequenced. Maximum likelihood analysis was carried out using MEGA 7. Sequences were 97.55% to 100% identical to corresponding DNA sequences of FTSC based on GenBank and Fusarium MLST BLASTn analysis, and deposited in GenBank (ON637268.1-ON637272.1, ON637275.1-ON637279.1, ON637282.1-ON637286.1). Based on the morphological characteristics and phylogenetic analysis, the isolates were identified as F. acuminatum (SL1, SL2, SL3 and LN; Senatore et al. 2021) and F. reticulatum (KC; Moreira et al. 2019). Koch's postulates were conducted to verify the pathogenicity of individual isolates. The four-leaf stage healthy tobacco seedlings (Yunyan99, n=30) were inoculated by pouring 20 mL conidial suspension (1×107 conidia/mL) around the rhizosphere. Control seedlings were inoculated with sterilized water (n=30). All the treatments were maintained under greenhouse conditions with a 12-h light/dark photoperiod at 25±0.5℃ and 70% relative humidity for 30 days. The assay was conducted three times. Foliage chlorosis and root rot were observed on the inoculated tobacco seedlings, whereas the control seedlings remained asymptomatic after 30 days. The pathogens were reisolated from the necrotic tissue from all inoculated seedlings and were identified by sequencing partial EF-1α and RPB2 genes. Fusarium tricinctum species complex are known as an important causal of cereals Fusarium Head Blight (FHB; Laraba, et al. 2022). In China, F. acuminatum can also infect herb plants and fruits, such as Angelica sinensis, Schisandra chinensis (Ma et al. 2022; Shen et al. 2021). To our knowledge, this is the first report of root rot on tobacco caused by FTSC members in China as well as the world. This finding expands the host range known for FTSC and will be helpful for developing effective control strategies of tobacco root rot.

Conversion therapy in liver transplantation for hepatocellular carcinoma: What's new in the era of molecular and immune therapy?

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with limited therapies and unsatisfactory prognosis once in the advanced stages. With promising advances in locoregional and systematic treatments, fast development of targeted drugs, the success of immunotherapy, as well as the emergence of the therapeutic alliance, conversion therapy has recently become more well developed and an effective therapeutic strategy. This article aimed to review recent developments in conversion therapy in liver transplantation (LT) for HCC. DATA SOURCES: We searched for relevant publications on PubMed before September 2022, using the terms "HCC", "liver transplantation", "downstaging", "bridging treatment" and "conversion therapy." RESULTS: Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT. Although combining various local and systematic treatments in conversion therapy is still controversial, growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time, which ultimately increases the opportunities for LT. Moreover, the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors. CONCLUSIONS: In the era of targeted therapy and immunotherapy, applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients. With the expansion of conversion therapy concepts, further investigation and research is required to realize the full potential of conversion treatment strategies, including accurately selecting candidates, determining the timing of surgery, improving the conversion rate, and guaranteeing the safety and long-term efficacy of treatment.

Prognostic of red blood cell transfusion during extracorporeal membrane oxygenation therapy on mortality: A meta-analysis.

BACKGROUND: This meta-analysis aimed to explore the impact of red blood cell (RBC) transfusion on mortality during extracorporeal membrane oxygenation (ECMO). Previous studies investigated the prognostic impact of RBC transfusion during ECMO on the risk of mortality, but no meta-analysis has been published before. METHODS: The PubMed, Embase, and the Cochrane library were systematically searched for papers published up to 13 December 2021, using the MeSH terms "ECMO", "'Erythrocytes", and "Mortality" to identify meta-analyses. Total or daily RBC transfusion during ECMO and mortality were examined. RESULTS: The random-effect model was used. Eight studies (794 patients, including 354 dead) were included. The total volume of RBC was associated with higher mortality standardized weighted difference (SWD = -0.62, 95% CI: -1.06,-0.18, p = .006; I2 = 79.7%, Pheterogeneity = 0.001). The daily volume of RBC was associated with higher mortality (SWD = -0.77, 95% CI: -1.11,-0.42, p < .001; I2 = 65.7%, Pheterogeneity = 0.020). The total volume of RBC was associated with mortality for venovenous (VV) (SWD = -0.72, 95% CI: -1.23, -0.20, p = .006) but not venoarterial ECMO (p = .126) or when reported together (p = .089). The daily volume of RBC was associated with mortality for VV (SWD = -0.72, 95% CI: -1.18, -0.26, p = 0.002; I2 = 0.0%, Pheterogeneity = 0.642) and venoarterial (SWD = -0.95, 95% CI: -1.32, -0.57, p < .001) ECMO, but not when reported together (p = .067). The sensitivity analysis suggested the robustness of the results. CONCLUSION: When considering the total and daily volumes of RBC transfusion during ECMO, the patients who survived received smaller total and daily volumes of RBC transfusion. This meta-analysis suggests that RBC transfusion might be associated with a higher risk of mortality during ECMO.

Expansion kinetics of graft-versus-host T cell clones in patients with post-liver transplant graft-versus-host disease.

Graft-versus-host disease (GVHD) following liver transplantation is induced by the graft-versus-host (GVH) T cell that is transferred with the liver graft, but the dynamics remain poorly investigated in clinical liver transplantation GVHD. Here, we report that in two liver transplantation recipients who developed GVHD, both of whom showed donor T cell macrochimerism in the blood before clinical GVHD onset. Longitudinal tracking of GVH T cell clones in one of these recipients revealed that GVH T cell clonal expansion occurred before disease onset, and the dominant GVH T cells might also derive from non-hepatic tissue-resident memory T cells in the liver-graft. Additionally, a comparison of the inflammatory cytokine levels and TCR repertoire diversities in recipient pre-liver transplantation blood between 4 patients with GVHD and 12 non-GVHD patients showed that the levels of TNF-α and IL-8, and the overall TCR repertoire skewness in pre-transplant recipient blood samples may serve as potential independent risk factors for the disease.