Human neutralizing antibodies elicited by SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global health emergency that is in urgent need of intervention1-3. The entry of SARS-CoV-2 into its target cells depends on binding between the receptor-binding domain (RBD) of the viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2)2,4-6. Here we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells from 8 individuals infected with SARS-CoV-2. We identified antibodies that potently neutralize SARS-CoV-2; this activity correlates with competition with ACE2 for binding to RBD. Unexpectedly, the anti-SARS-CoV-2 antibodies and the infected plasma did not cross-react with the RBDs of SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV), although there was substantial plasma cross-reactivity to their trimeric spike proteins. Analysis of the crystal structure of RBD-bound antibody revealed that steric hindrance inhibits viral engagement with ACE2, thereby blocking viral entry. These findings suggest that anti-RBD antibodies are largely viral-species-specific inhibitors. The antibodies identified here may be candidates for development of clinical interventions against SARS-CoV-2.

Adult age estimation from the sternum using maximum intensity projection images of CT and data mining in a Chinese population.

This study aimed to explore and develop data mining models for adult age estimation based on CT reconstruction images from the sternum. Maximum intensity projection (MIP) images of chest CT were retrospectively collected from a modern Chinese population, and data from 2700 patients (1349 males and 1351 females) aged 20 to 70 years were obtained. A staging technique within four indicators was applied. Several data mining models were established, and mean absolute error (MAE) was the primary comparison parameter. The intraobserver and interobserver agreement levels were good. Within internal validation, the optimal data mining model obtained the lowest MAE of 9.08 in males and 10.41 in females. For the external validation (N = 200), MAEs were 7.09 in males and 7.15 in females. In conclusion, the accuracy of our model for adult age estimation was among similar studies. MIP images of the sternum could be a potential age indicator. However, it should be combined with other indicators since the accuracy level is still unsatisfactory.

Global, regional, and national burden of thalassemia during 1990-2019: A systematic analysis of the Global Burden of Disease Study 2019.

INTRODUCTION: Thalassemia represents a significant public health challenge globally. However, the global burden of thalassemia and the disparities associated with it remain poorly understood. Our study aims to uncover the long-term spatial and temporal trends in thalassemia at global, regional, and national levels, analyze the impacts of age, time periods, and birth cohorts, and pinpoint the global disparities in thalassemia burden. METHODS: We extracted data on the thalassemia burden from the Global Burden of Disease Study (GBD) 2019. We employed a joinpoint regression model to assess temporal trends in thalassemia burden and an age-period-cohort model to evaluate the effects of age, period, and cohort on thalassemia mortality. RESULTS: From 1990 to 2019, the number of thalassemia incident cases, prevalent cases, mortality cases, and disability-adjusted life years (DALYs) decreased by 20.9%, 3.1%, 38.6%, and 43.1%, respectively. Age-standardized rates of incidence, prevalence, mortality, and DALY declined across regions with high, high-middle, middle, and low-middle sociodemographic index (SDI), yet remained the highest in regions with low SDI and low-middle SDI as well as in Southeast Asia, peaking among children under five years of age. The global prevalence rate was higher in males than in females. The global mortality rate showed a consistent decrease with increasing age. CONCLUSION: The global burden of thalassemia has significantly declined, yet notable disparities exist in terms of gender, age groups, periods, birth cohorts, SDI regions, and GBD regions. Systemic interventions that include early screening, genetic counseling, premarital health examinations, and prenatal diagnosis should be prioritized in regions with low, and low-middle SDI, particularly in Southeast Asia. Future population-based studies should focus specifically on thalassemia subtypes and transfusion requirements, and national registries should enhance data capture through newborn screening.

Transcranial direct current stimulation for upper extremity motor dysfunction in poststroke patients: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of transcranial direct current stimulation in poststroke patients with upper extremity motor dysfunction using a systematic review and meta-analysis. DATA SOURCES: We searched the Web of Science, Cochrane Library, EMBASE, and PubMed for randomized controlled trials investigating the effects of both active and sham stimulation up until January 27, 2024. REVIEW METHODS: Efficacy, including the upper extremity Fugl-Meyer Assessment, Action Research Arm Test, Barthel Index, and safety, were assessed. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool and the Physiotherapy Evidence Database Scale. Meta-analysis was performed using the RevMan 5.4 software. RESULTS: Forty-four studies with 1555 participants were included. Transcranial direct current stimulation proved effective in improving upper extremity motor function (standardized mean difference = 0.22, 95% confidence interval: 0.12-0.32, P < 0.001) and Barthel Index (mean difference = 4.65, 95% confidence interval: 2.82-6.49, P < 0.001). Subgroup analysis revealed the highest transcranial direct current stimulation efficacy in patients with subacute stroke. Both anodal and cathodal stimulation were effective against upper extremity motor dysfunction. C3/C4 was the most effective stimulus target. Optimal stimulation parameters included stimulus current densities <0.057 mA/cm2 for 20-30 min and <30 sessions. Adverse effects and dropouts during follow-up showed that transcranial direct current stimulation is safe and feasible. CONCLUSIONS: Our findings suggest that both anodal and cathodal stimulation were significantly effective in subacute stroke patients, particularly when preceding other treatments and when C3/C4 is targeted.

Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure.

BACKGROUND: The regenerative capacity of the heart after myocardial infarction is limited. Our previous study showed that ectopic introduction of 4 cell cycle factors (4F; CDK1 [cyclin-dependent kinase 1], CDK4 [cyclin-dependent kinase 4], CCNB [cyclin B1], and CCND [cyclin D1]) promotes cardiomyocyte proliferation in 15% to 20% of infected cardiomyocytes in vitro and in vivo and improves cardiac function after myocardial infarction in mice. METHODS: Using temporal single-cell RNA sequencing, we aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. Using rat and pig models of ischemic heart failure, we aimed to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia-induced heart failure. RESULTS: Temporal bulk and single-cell RNA sequencing and further biochemical validations of mature human induced pluripotent stem cell-derived cardiomyocytes treated with either LacZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours after infection with 4F, which was associated mainly with sarcomere disassembly and metabolic reprogramming (n=3/time point/group). Transient overexpression of 4F, specifically in cardiomyocytes, was achieved using a polycistronic nonintegrating lentivirus (NIL) encoding 4F; each is driven by a TNNT2 (cardiac troponin T isoform 2) promoter (TNNT2-4Fpolycistronic-NIL). TNNT2-4Fpolycistronic-NIL or control virus was injected intramyocardially 1 week after myocardial infarction in rats (n=10/group) or pigs (n=6-7/group). Four weeks after injection, TNNT2-4Fpolycistronic-NIL-treated animals showed significant improvement in left ventricular ejection fraction and scar size compared with the control virus-treated animals. At 4 months after treatment, rats that received TNNT2-4Fpolycistronic-NIL still showed a sustained improvement in cardiac function and no obvious development of cardiac arrhythmias or systemic tumorigenesis (n=10/group). CONCLUSIONS: This study provides mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell cycle factors owing to the use of a novel transient and cardiomyocyte-specific viral construct.

Enhanced Cross-Reactive and Polyfunctional Effector-Memory T Cell Responses by ICVAX-a Human PD1-Based Bivalent HIV-1 Gag-p41 Mosaic DNA Vaccine.

Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8+ T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1. IMPORTANCE This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B', CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.

Sustained viremia suppression by SHIVSF162P3CN-recalled effector-memory CD8+ T cells after PD1-based vaccination.

HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in vaccinated macaques following a high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.

Transient gene therapy using cell cycle factors reverses renin-angiotensin-aldosterone system activation in heart failure rat model.

The loss of cardiomyocytes after myocardial infarction (MI) leads to heart failure. Recently, we demonstrated that transient overexpression of 4 cell cycle factors (4F), using a polycistronic non-integrating lentivirus (TNNT2-4F-NIL) resulted in significant improvement in cardiac function in a rat model of MI. Yet, it is crucial to demonstrate the reversal of the heart failure-related pathophysiological manifestations, such as renin-angiotensin-aldosterone system activation (RAAS). To assess that, Fisher 344 rats were randomized to receive TNNT2-4F-NIL or control virus seven days after coronary occlusion for 2 h followed by reperfusion. 4 months after treatment, N-terminal pro-brain natriuretic peptide, plasma renin activity, and aldosterone levels returned to the normal levels in rats treated with TNNT2-4F-NIL but not in vehicle-treated rats. Furthermore, the TNNT2-4F-NIL-treated group showed significantly less liver and kidney congestion than vehicle-treated rats. Thus, we conclude that in rat models of MI, TNNT2-4F-NIL reverses RAAS activation and subsequent systemic congestion.

Abdominal obesity-related lipid metabolites may mediate the association between obesity and glucose dysregulation.

BACKGROUND: Children with obesity is associated with a higher risk of cardiovascular disease (CV) risk in adulthood. This study is to explore the obesity-related lipid metabolites and identify the associations of lipid metabolites with selected CV risk in children and adolescents. METHODS: A case-control study was designed to include a total of 197 children (aged 9-13 years, male 56.34%, 99 children in the obesity group). The lipidomics profiling was measured by ultra-high-performance liquid tandem chromatography quadrupole time-of-flight mass spectrometry. RESULTS: Four FDR-significant abdominal obesity-related lipid metabolites were identified. Compared to the lean group, decreased phosphatidylcholine O-21:2 level (q = 0.010) and sphingomyelins d21:1 (q = 0.029) were found and two lipid metabolites levels were higher in the obese group, including phosphatidylglycerol 43:6 and one did not match with any candidate compounds in databases. After adjusting for covariates, PC3 (O-21:2) and SM (d21:1) were significantly associated with blood glucose. Mediation analysis showed that all three lipid metabolites may mediate the association between abdominal obesity and glucose regulation. CONCLUSIONS: This study identified several novel central obesity-related lipid metabolites, and we found that PC3 (O-21:2) and SM (d21:1) were significantly associated with blood glucose, and all these lipid metabolites can mediate the association between abdominal obesity and glucose dysregulation. IMPACT: Serum lipidomic profiles in children with abdominal obesity and their associations with selected CV risk factors were examined. Our study identified 4 lipid metabolites associated with abdominal obesity, including PC3 (O-21:2), SM (d21:1), PG (43:6), and one did not match with any candidate compounds in the databases. PC3 (O-21:2) and SM (d21:1) were significantly associated with blood glucose. Mediation analysis showed that all three lipid metabolites [PC3 (O-21:2), SM (d21:1), PG (43:6)] may mediate the association between abdominal obesity and abnormal glucose regulation. This study identified several novel obesity-related lipid metabolites.

Deep learning enables automatic adult age estimation based on CT reconstruction images of the costal cartilage.

OBJECTIVE: Adult age estimation (AAE) is a challenging task. Deep learning (DL) could be a supportive tool. This study aimed to develop DL models for AAE based on CT images and compare their performance to the manual visual scoring method. METHODS: Chest CT were reconstructed using volume rendering (VR) and maximum intensity projection (MIP) separately. Retrospective data of 2500 patients aged 20.00-69.99 years were obtained. The cohort was split into training (80%) and validation (20%) sets. Additional independent data from 200 patients were used as the test set and external validation set. Different modality DL models were developed accordingly. Comparisons were hierarchically performed by VR versus MIP, single-modality versus multi-modality, and DL versus manual method. Mean absolute error (MAE) was the primary parameter of comparison. RESULTS: A total of 2700 patients (mean age = 45.24 years ± 14.03 [SD]) were evaluated. Of single-modality models, MAEs yielded by VR were lower than MIP. Multi-modality models generally yielded lower MAEs than the optimal single-modality model. The best-performing multi-modality model obtained the lowest MAEs of 3.78 in males and 3.40 in females. On the test set, DL achieved MAEs of 3.78 in males and 3.92 in females, which were far better than the MAEs of 8.90 and 6.42 respectively, for the manual method. For the external validation, MAEs were 6.05 in males and 6.68 in females for DL, and 6.93 and 8.28 for the manual method. CONCLUSIONS: DL demonstrated better performance than the manual method in AAE based on CT reconstruction of the costal cartilage. CLINICAL RELEVANCE STATEMENT: Aging leads to diseases, functional performance deterioration, and both physical and physiological damage over time. Accurate AAE may aid in diagnosing the personalization of aging processes. KEY POINTS: • VR-based DL models outperformed MIP-based models with lower MAEs and higher R2 values. • All multi-modality DL models showed better performance than single-modality models in adult age estimation. • DL models achieved a better performance than expert assessments.

Suppressive Monocytes Impair MAIT Cells Response via IL-10 in Patients with Severe COVID-19.

Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe COVID-19, the number of HLA-DRlow/- monocytes was significantly increased, but that of mucosal-associated invariant T (MAIT) cells was greatly reduced. MAIT cells were highly activated but functionally impaired in response to Escherichia coli and IL-12/IL-18 stimulation in patients with severe COVID-19, especially those with microbial coinfection. Single-cell transcriptome analysis revealed that IFN-stimulated genes were significantly upregulated in peripheral MAIT cells and monocytes from patients with severe COVID-19. IFN-α pretreatment suppressed MAIT cells' response to E. coli by triggering high levels of IL-10 production by HLA-DRlow/--suppressive monocytes. Blocking IFN-α or IL-10 receptors rescued MAIT cell function in patients with severe COVID-19. Moreover, plasma from patients with severe COVID-19 inhibited HLA-DR expression by monocytes through IL-10. These data indicate a unique pattern of immune dysregulation in severe COVID-19, which is characterized by enrichment of suppressive HLA-DRlow/- monocytes associated with functional impairment of MAIT cells through the IFN/IL-10 pathway.

First Report of Anthracnose on Tetrapanax papyriferus Caused by Colletotrichum fructicola in China.

Tetrapanax papyriferus is an evergreen shrub native to China and traditionally used as a herbal medicine (Li et al., 2021). In September 2021, a serious leaf spot disease with symptoms similar to anthracnose was extensively observed on T. papyriferus in Shibing county (E 127°12'0", N 25°11'60"), Qiandongnan Miao and Dong Autonomous Prefecture, Guizhou province, China. Field surveys were conducted in about 1000 T. papyriferus plants in Shibing in September 2021. The incidence of the leaf spot on leaves was 45% to 60%, significantly reducing the quality of medicinal materials. The symptoms began as small yellow spots, developing a brown center and dark brown to black margin, and eventually the diseased leaves were wiltered and rotted. Symptomatic leaves were collected from 20 trees. Symptomatic tissue from diseased leaves was surface desinfected (0.5 min in 75% ethanol and 1 min in 3% NaOCl, washed three times with sterilized distilled water), small pieces of symptomatic leaf tissue (0.2 × 0.2 cm) were plated on potato dextrose agar (PDA) and incubated at 25°C for about 7 days (Fang. 2007). Three single-spore isolates were obtained (GUTC37, GUTC310 and GUTC311) and deposited in the collection of the Plant Pathology Deparment, College of Agriculture, Guizhou University, China (GUCC) (with the accession numbers, GUCC220241, GUCC220242, GUCC220243 respectively). These isolates were identical in morphology and in the sequences of internal transcribed spacer region [ITS], glyceraldehy-3-phosphate dehydrogenase [GAPDH], chitin synthase [CHS-1], actin [ACT], and calmodulin [CAL] genes (White et al. 1990; Carbone and Kohn 1999; Templeton et al. 1992). Therefore, the representative isolate GUTC37 was used for further analysis. The pathogenicity of GUTC37 was tested through a pot assay. Plants were inoculated by spraying a spore suspension (106 spores·ml-1) of isolated strains onto leaves until runoff, and the control leaves sprayed with sterile water. The inoculated plants were incubated in a growth chamber at 28 ℃ and 95% relative humidity for 10 days. Pathogenicity tests were repeated three times (Fang. 2007). The symptoms developed on the inoculated leaves, while control remained asymptomatic. The lesions were first visible 72 h after inoculation, and typical lesions like those observed on field plants appeared after 10 days. The same fungus was reisolated and identified based on the morphological characterization and molecular analyses from the infected leaves but not from the non-inoculated leaves. Results of pathogenicity experiments of isolated fungi fulfilled Koch's postulates. Fungal colonies on PDA were villiform, creamy-white or greyish, aerial mycelium pale grey, dense, surface partly covered with orange conidial masses. The conidia were abundant, oval-ellipsoid, aseptate, and 13.89 (11.62 to 15.21) × 5.21 (4.39 to 5.65) µm (n=50). Appressorium were greyish green, nearly ovoid to cylindrical, 9.64 (6.62 to 14.61) × 6.33 (5.45-7.72) µm (n=50). The morphological features were consistent with the descriptions of Colletotrichum fructicola Prihast., L. Cai & K.D. Hyde (Prihastuti et al. 2009). The pathogen was identified to be C. fructicola by amplification and sequencing of the five genes. The sequences of the PCR products were deposited in GenBank with accession numbers OP143657 (ITS), OP177868 (GAPDH), OP177865 (CHS-1), OP278677 (ACT) and OP177862 (CAL). BLAST searches of the obtained sequences revealed 100% (509/509 nucleotides), 99.63% (269/270 nucleotides), 99.31% (287/289 nucleotides), 99.29% (280/282 nucleotides), and 99.86% (728/729 nucleotides) homology with those of C. fructicola in GenBank (JX010165, JX010033, JX009866, FJ907426, and JX009676, respectively). Phylogenetic analysis (MEGA 7.0) using the maximum likelihood method placed the isolate GUTC37 in a well-supported cluster with C. fructicola. To our knowledge, this is the first report of anthracnose on T. papyriferus caused by C. fructicola in Guizhou, China. This study provides valuable information for the identification and control of the anthracnose on T. papyriferus.

Self-reported critical gaps in the essential knowledge and capacity of spatial epidemiology between the current university education and competency-oriented professional demands in preparing for a future pandemic among public health postgraduates in China: a nationwide cross-sectional survey.

BACKGROUND: Spatial epidemiology plays an important role in public health. Yet, it is unclear whether the current university education in spatial epidemiology in China could meet the competency-oriented professional demands. This study aimed to understand the current situation of education and training, practical application, and potential demands in spatial epidemiology among public health postgraduates in China, and to assess the critical gaps in a future emerging infectious diseases (EID) pandemic preparedness and response. METHODS: This study was divided into three parts. The first part was a comparative study on spatial epidemiology education in international public health postgraduate training. The second part was a cross-sectional survey conducted among public health professionals. The third part was a nationwide cross-sectional survey conducted among public health postgraduates at Chinese universities from October 2020 to February 2021. Data was collected by the WeChat-based questionnaire star survey system and analyzed using the SPSS software. RESULTS: International education institutions had required public health postgraduates to master the essential knowledge and capacity of spatial epidemiology. A total of 198 public health professionals were surveyed, and they had a median of 4.00 (IQR 3.13-4.53) in demand degree of spatial epidemiology. A total of 1354 public health postgraduates were surveyed from 51 universities. Only 29.41% (15/51) of universities offered spatial epidemiology course. Around 8.05% (109/1354) of postgraduates had learned spatial epidemiology, and had a median of 1.05 (IQR 1.00-1.29) in learning degree and a median of 1.91 (IQR 1.05-2.78) in practical application degree of spatial epidemiology. To enhance professional capacity, 65.95% (893/1354) of postgraduates hoped that universities would deliver a credit-course of spatial epidemiology. CONCLUSIONS: A huge unmet education and training demand in spatial epidemiology existed in the current education system of public health postgraduates in China. To enhance the competency-oriented professional capacity in preparedness and response to a future pandemic, it is urgent to incorporate the teaching and training of spatial epidemiology into the compulsory curriculum system of public health postgraduates in China.

CENPF/CDK1 signaling pathway enhances the progression of adrenocortical carcinoma by regulating the G2/M-phase cell cycle.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor and is prone to local invasion and metastasis. And, overexpressed Centromere Protein F (CENPF) is closely related to the oncogenesis of various neoplasms, including ACC. However, the prognosis and exact biological function of CENPF in ACC remains largely unclear. METHODS: In the present essay, the expression patterns and prognostic value of CENPF in ACC were investigated in clinical specimens and public cancer databases, including GEO and TCGA. The potential signaling mechanism of CENPF in ACC was studied based on gene-set enrichment analysis (GSEA). Furthermore, a small RNA interference experiment was conducted to probe the underlying biological function of CENPF in the human ACC cell line, SW13 cells. Lastly, two available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. RESULTS: The expression of CENPF in human ACC samples, GEO, and TCGA databases depicted that CENPF was overtly hyper-expressed in ACC patients and positively correlated with tumor stage. The aberrant expression of CENPF was significantly correlated with unfavorable overall survival (OS) in ACC patients. Then, the GSEA analysis declared that CENPF was mainly involved in the G2/M-phase mediated cell cycle and p53 signaling pathway. Further, the in vitro experiment demonstrated that the interaction between CENPF and CDK1 augmented the G2/M-phase transition of mitosis, cell proliferation and might induce p53 mediated anti-tumor effect in human ACC cell line, SW13 cells. Lastly, immune infiltration analysis highlighted that ACC patients with high CENPF expression harbored significantly different immune cell populations, and high TMB/MSI score. The gene-drug interaction network stated that CENPF inhibitors, such as Cisplatin, Sunitinib, and Etoposide, might serve as potential drugs for the therapy of ACC. CONCLUSION: The result points out that CENPF is significantly overexpressed in ACC patients. The overexpressed CENPF predicts a poor prognosis of ACC and might augment the progress of ACC. Thus, CENPF and related genes might serve as a novel prognostic biomarker or latent therapeutic target for ACC patients.

Bohm Criterion of Plasma Sheaths away from Asymptotic Limits.

The plasma exit flow speed at the sheath entrance is constrained by the Bohm criterion. The so-called Bohm speed regulates the plasma particle and power exhaust fluxes to the wall, and it is commonly deployed as a boundary condition to exclude the sheath region in quasineutral plasma modeling. Here the Bohm criterion analysis is performed in the intermediate plasma regime away from the previously known limiting cases of adiabatic laws and the asymptotic limit of infinitesimal Debye length in a finite-size system, using the transport equations of an anisotropic plasma. The resulting Bohm speed has explicit dependence on local plasma heat flux, temperature isotropization, and thermal force. Comparison with kinetic simulations demonstrates its accuracy over the plasma-sheath transition region in which quasineutrality is weakly perturbed and the Bohm criterion applies.

Clinical trials of cell therapy for heart failure: recent results warrant continued research.

PURPOSE OF REVIEW: Clinical trials of adult cell therapy for chronic heart failure are often misrepresented in an unfairly negative light. Results are claimed to be 'negative', 'incremental', or 'modest'. This common misconception is detrimental to medical progress and needs to be dispelled. RECENT FINDINGS: Contrary to the false narrative of scientific and lay media, the outcome of recent trials of cell therapy for heart failure has been encouraging and even exciting. Specifically, with the exception of ALLSTAR, in the past 2 years several Phase II-III double-blind, randomized trials have yielded impressive results, demonstrating not just safety but also salubrious effects on cardiac function (MSC-HF) or clinical events (MSC-HF, CONCERT-HF, and DREAM-HF) for at least 1 year after a single administration of cells. Such outcomes were neither incremental nor minor, nor achievable with one dose of any other nondevice therapy for heart failure. SUMMARY: The oft-repeated assertion that cell therapy does not benefit patients with chronic heart failure is based on a misrepresentation of the literature and is contrary to the available scientific evidence. Although the mechanism of action of cell therapy is unclear, research on its use in heart failure should continue, as only rigorous, well designed, Phase III trials can definitely confirm or refute its efficacy.

A Δ42PD1 fusion-expressing DNA vaccine elicits enhanced adaptive immune response to HIV-1: the key role of TLR4.

Since its discovery in the 1990s, the DNA vaccine has been of great interest because of its ability to elicit both humoral and cellular immune responses while showing relative advantages regarding producibility, stability and storage. However, when applied to human subjects, inadequate immunogenicity remains as the greatest challenge for the practical use of DNA vaccines. In this study, we generated a DNA vaccine Δ42PD1-P24 encoding a fusion protein comprised of the HIV-1 Gag p24 antigen and the extracellular domain of murine Δ42PD1, a novel endogenous Toll-like receptor 4 (TLR4) agonist. Using a mouse model, we found that Δ42PD1-P24 DNA vaccine elicited a higher antibody response and an increased number of IFN-γ-producing CD4 and CD8 T cells. Moreover, mice with Δ42PD1-P24 DNA vaccination were protected from a subcutaneous challenge with murine mesothelioma cells expressing the HIV-1 p24 antigen. Importantly, the Δ42PD1-mediated enhancement of immune responses was not observed in TLR4 knockout mice. Collectively, these data demonstrate that the immunogenicity and efficacy of DNA vaccines could be improved by the fusion of the extracellular domain of Δ42PD1 to target the immunogen to dendritic cells.

Effect of intravenous cell therapy in rats with old myocardial infarction.

Mounting evidence shows that cell therapy provides therapeutic benefits in experimental and clinical settings of chronic heart failure. However, direct cardiac delivery of cells via transendocardial injection is logistically complex, expensive, entails risks, and is not amenable to multiple dosing. Intravenous administration would be a more convenient and clinically applicable route for cell therapy. Thus, we determined whether intravenous infusion of three widely used cell types improves left ventricular (LV) function and structure and compared their efficacy. Rats with a 30-day-old myocardial infarction (MI) received intravenous infusion of vehicle (PBS) or 1 of 3 types of cells: bone marrow mesenchymal stromal cells (MSCs), cardiac mesenchymal cells (CMCs), and c-kit-positive cardiac cells (CPCs), at a dose of 12 × 106 cells. Rats were followed for 35 days after treatment to determine LV functional status by serial echocardiography and hemodynamic studies. Blood samples were collected for Hemavet analysis to determine inflammatory cell profile. LV ejection fraction (EF) dropped ≥ 20 points in all hearts at 30 days after MI and deteriorated further at 35-day follow-up in the vehicle-treated group. In contrast, deterioration of EF was halted in rats that received MSCs and attenuated in those that received CMCs or CPCs. None of the 3 types of cells significantly altered scar size, myocardial content of collagen or CD45-positive cells, or Hemavet profile. This study demonstrates that a single intravenous administration of 3 types of cells in rats with chronic ischemic cardiomyopathy is effective in attenuating the progressive deterioration in LV function. The extent of LV functional improvement was greatest with CPCs, intermediate with CMCs, and least with MSCs.

Effect of screen time intervention on obesity among children and adolescent: A meta-analysis of randomized controlled studies.

Several studies have investigated the effect of screen time interventions on obesity in children and adolescents, but the existing results were controversial. This study aimed to analyze the effect of screen time intervention on obesity in children and adolescents. PubMed, Cochrane, Web of Science, Embase databases were searched through December 2020 to identify publications meeting a priori inclusion criteria and references in the published articles were also reviewed. Finally, 14 randomized controlled trials and 1894 subjects were included in this meta-analysis. The results showed that interventions targeting screen time are effective in reducing total screen time (MD: -6.90 h/week, 95% CI: [-9.19 to -4.60], p < 0.001) and television time (MD: -6.17 h/week, 95% CI: [-10.70 to -1.65], p < 0.001) in children and adolescents. However, there was no significant difference between the intervention and control groups in body mass index and body mass index-z score. In conclusion, there is no evidence that screen time interventions alone can decrease obesity risk in children and adolescents, though they can effectively reduce screen time.

Coupled Aerobic Methane Oxidation and Arsenate Reduction Contributes to Soil-Arsenic Mobilization in Agricultural Fields.

Microbial oxidation of organic compounds can promote arsenic release by reducing soil-associated arsenate to the more mobile form arsenite. While anaerobic oxidation of methane has been demonstrated to reduce arsenate, it remains elusive whether and to what extent aerobic methane oxidation (aeMO) can contribute to reductive arsenic mobilization. To fill this knowledge gap, we performed incubations of both microbial laboratory cultures and soil samples from arsenic-contaminated agricultural fields in China. Incubations with laboratory cultures showed that aeMO could couple to arsenate reduction, wherein the former bioprocess was carried out by aerobic methanotrophs and the latter by a non-methanotrophic bacterium belonging to a novel and uncultivated representative of Burkholderiaceae. Metagenomic analyses combined with metabolite measurements suggested that formate served as the interspecies electron carrier linking aeMO to arsenate reduction. Such coupled bioprocesses also take place in the real world, supported by a similar stoichiometry and gene activity in the incubations with natural paddy soils, and contribute up to 76.2% of soil-arsenic mobilization into pore waters in the top layer of the soils where oxygen was present. Overall, this study reveals a previously overlooked yet significant contribution of aeMO to reductive arsenic mobilization.