Search

Abstract Background Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) shares common pathophysiological mechanisms with type 2 diabetes, making them significant risk factors for type 2 diabetes. The present study aimed to assess the epidemiological feature of type 2 diabetes in patients with NAFLD or MAFLD at global levels. Methods Published studies were searched for terms that included type 2 diabetes, and NAFLD or MAFLD using PubMed, EMBASE, MEDLINE, and Web of Science databases from their inception to December 2022. The pooled global and regional prevalence and incidence density of type 2 diabetes in patients with NAFLD or MAFLD were evaluated using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. Results A total of 395 studies (6,878,568 participants with NAFLD; 1,172,637 participants with MAFLD) from 40 countries or areas were included in the meta-analysis. The pooled prevalence of type 2 diabetes among NAFLD or MAFLD patients was 28.3% (95% confidence interval 25.2–31.6%) and 26.2% (23.9–28.6%) globally. The incidence density of type 2 diabetes in NAFLD or MAFLD patients was 24.6 per 1000-person year (20.7 to 29.2) and 26.9 per 1000-person year (7.3 to 44.4), respectively. Conclusions The present study describes the global prevalence and incidence of type 2 diabetes in patients with NAFLD or MAFLD. The study findings serve as a valuable resource to assess the global clinical and economic impact of type 2 diabetes in patients with NAFLD or MAFLD.

As the amount of new energy injected into the power system increases, the system inertia decreases and the spatio-temporal characteristics become apparent. Due to the uneven distribution of inertia in the power system, the dispersion of the frequency response after disturbance is more pronounced, and the inertia estimation error has a random nature when different frequency measurement points are selected. For the above problems, a method is proposed to select the frequency measurement point based on the centre of inertia. Firstly, based on the frequency dynamic response characteristics, the main influencing factors of the frequency distribution characteristics are studied and the spatial and temporal distribution characteristics of the frequency of the new energy power system are analyzed. Secondly, the method of frequency sampling through the centre of inertia is proposed with full consideration of the electrical distance and generator inertia constants. Finally, a 10 machine 39 bus system is simulated as an example. Simulation results show that using the centre of inertia as the frequency sampling point during inertia evaluation can reduce the inertia evaluation error by up to 16.15%. The results verify the correctness of the above theoretical analysis and provide a favourable basis for further improving the accuracy of the power system inertia estimation.

Aiming at the problem that the coherent signal cannot be estimated when the traditional UCA-RB-MUSIC algorithm is used to detect the partial discharge of the transformer, an improved UCA-RB-MUSIC algorithm is suggested to reconstruct the signals captured by the array so that the number of calls sources is equivalent to the rank of the reconstructed signal matrix. The impact of correlated signals is eradicated. The results of simulation analysis and experimental verification show that when the improved UCA-RB-MUSIC algorithm is used to locate a single and double partial discharge source, the improved positioning error is only half of the mistake before improvement, which enhances the accuracy and resolution of uniform circular array positioning and the accuracy of transformer partial discharge detection.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with unknown etiology and treatment options for it were limited. Whether Gastroesophageal reflux disease (GERD) could affect the occurrence of IPF remains unclear. Methods : Using available data from FINNGEN and IEU OpenGWAS, we performed Two-sample mendelian randomization (MR) to explore the causal relationship between GERD and IPF. Results: Using 65 GERD-related SNPs, we found the association between GERD and the risk of IPF was not statistically significant with IVW approach (OR = 1.20, 95% CI = 0.84-1.70, p = .32), MR-Egger regression (OR = 1.65, 95% CI = 0.19-14.43, p = .65) and weighted median approaches (OR = 1.44, 95% CI = 0.94-2.23, p = .09). However, heterogeneity was observed with MR-Egger ( p = .001) and IVW ( p = .001) analysis. Similar results were obtained with MR-PRESSO (global heterogeneity test p value

Small extracellular vesicles (sEVs) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNAs (miRNAs) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cells-derived sEVs (AML-sEVs) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEVs. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEVs impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEVs-delivered miRNAs contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.

Abstract Background Plant-based dietary patterns may affect colorectal cancer (CRC) related outcomes, while risks differ in the quality of plant foods. We aimed to examine the association of plant-based diet quality with risks of CRC incidence and mortality and whether this association was modified by genetic risk. Methods This prospective cohort study included 186,675 participants free of cancer when the last dietary recall was completed. We calculated three plant-based diet indices (PDIs), i.e., the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI) representing adherence to plant-based diets with diverse quality. Genetic risk was characterized using a weighted polygenic risk score (PRS), capturing overall risk variants associated with CRC. Hazard ratios (HR) and 95% confidential intervals (CI) were estimated by the cause-specific Cox proportional hazards model. Results Over a follow-up of 9.5 years, 2163 cases and 466 deaths from CRC were documented. The HR of CRC incidence was 0.88 (95% CI, 0.81–0.96) and 0.91 (95% CI, 0.84–0.99) per 10-score increase in PDI and hPDI, respectively. Compared to the lowest quartile, PDI, hPDI, and uPDI in the highest quartile were associated with a 13% decrease, a 15% decrease, and a 14% increase in risk of incident CRC, respectively. We found a joint association of genetic risk and PDIs with incident CRC, with the highest hazard observed in those carrying higher PRS and adhering to lower-quality PDIs. The inverse association of PDI and hPDI with CRC mortality was pronounced in males. Conclusions Our results suggested that better adherence to overall and healthful plant-based diets was associated with a lower risk of CRC, whereas an unhealthful plant-based diet was associated with a higher CRC risk. Consumption of a higher-quality plant-based diet combined with decreased genetic risk conferred less susceptibility to CRC. Our findings highlighted the importance of food quality when adhering to a plant-based dietary pattern for CRC prevention in the general population.

Abstract Background Diets rich in plant-based foods are associated with lower risks of non-alcoholic fatty liver disease (NAFLD), while the prospective evidence is limited. We aimed to examine longitudinal associations of plant-based diets and genetic susceptibility with NAFLD risk. Methods This longitudinal cohort study included 159,222 participants (58.0 ± 8.0 years old, 55.7% female) free of NAFLD in the UK Biobank. We calculated the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI). New-onset NAFLD was the primary outcome. The weighted polygenic risk score was calculated based on risk variants associated with NAFLD. Hazard ratios (HR) and 95% confidential intervals (CI) were estimated by Cox proportional hazards model. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) measured liver fat content in a subsample of 20,692 participants (57.5 ± 7.4 years old, 52.6% female) was the secondary outcome. The associations between plant-based diet indices and MRI-PDFF were evaluated using generalized linear models. Results During a median follow-up of 9.5 years, 1541 new-onset NAFLD cases were documented. Compared to the lowest quintile, multivariable-adjusted hazard ratios (HRs) of NAFLD in the highest quintile were 0.78 (95% confidential intervals [CI], 0.66–0.93, p-trend =0.02), 0.74 (95% CI, 0.62–0.87, p-trend

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC–matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.

Abstract Melon is an important horticultural crop with a pleasant aromatic flavor and abundance of health-promoting substances. Numerous melon varieties have been cultivated worldwide in recent years, but the high number of varieties and the high similarity between them poses a major challenge for variety evaluation, discrimination, as well as innovation in breeding. Recently, simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs), two robust molecular markers, have been utilized as a rapid and reliable method for variety identification. To elucidate the genetic structure and diversity of melon varieties, we screened out 136 perfect SSRs and 164 perfect SNPs from the resequencing data of 149 accessions, including the most representative lines worldwide. This study established the DNA fingerprint of 259 widely-cultivated melon varieties in China using Target-seq technology. All melon varieties were classified into five subgruops, including ssp. agrestis, ssp. melo, muskmelon and two subgroups of foreign individuals. Compared with ssp. melo, the ssp. agrestis varieties might be exposed to a high risk of genetic erosion due to their extremely narrow genetic background. Increasing the gene exchange between ssp. melo and ssp. agrestis is therefore necessary in the breeding procedure. In addition, analysis of the DNA fingerprints of the 259 melon varieties showed a good linear correlation (R2 = 0.9722) between the SSR genotyping and SNP genotyping methods in variety identification. The pedigree analysis based on the DNA fingerprint of ‘Jingyu’ and ‘Jingmi’ series melon varieties was consistent with their breeding history. Based on the SNP index analysis, ssp. agrestis had low gene exchange with ssp. melo in chromosome 4, 7, 10, 11and 12, two specific SNP loci were verified to distinguish ssp. agrestis and ssp. melon varieties. Finally, 23 SSRs and 40 SNPs were selected as the core sets of markers for application in variety identification, which could be efficiently applied to variety authentication, variety monitoring, as well as the protection of intellectual property rights in melon.

After the high proportion of new energy is connected, the decrease of the proportion of synchronous machine in power system will cause a series of stability hazards, such as the lack of inertia. The distributed asynchronous condenser provides a solution for the above problems because of its high controllability, high inertia and high phase advance ability. In this paper, the performance parameters of the distributed asynchronous condenser are analyzed to further optimize its structure. At the same time, the advantages and disadvantages of different excitation schemes are compared and analyzed, and the best scheme is selected; Secondly, a multi physical domain model is established to analyze the magnetic field distribution in steady-state operation and verify the error between the design value and the simulation value; Finally, the transient characteristics of distributed asynchronous condenser under different fault types and different fault parameters are analyzed. Through the above research, this paper verifies that the distributed asynchronous condenser plays the role of reactive power support and voltage regulation on the stability of new energy system.

Abstract Background Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored. Methods We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. Results Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. Conclusions The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance. Graphic Abstract

Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.

BackgroundAdherence to a healthy lifestyle (no smoking, consuming a healthy diet, engaging in physical activity, and maintaining a healthy weight) is recommended in current guidelines for hypertension prevention. However, evidence regarding the association between sleep behaviors, independently and jointly with traditional lifestyle factors, and the risk of hypertension is limited.MethodsThis prospective study included 165,493 participants who are free of hypertension at baseline from the UK Biobank. Sleep behaviors, including chronotype, sleep duration, insomnia, snoring, and daytime sleepiness were used to construct a healthy sleep score. We also derived a healthy lifestyle score based on smoking status, diet quality, physical activity, and body mass index (BMI). Cox proportional hazards regression models and competing risk analyses were used to estimate the associations of the healthy sleep score and healthy lifestyle score with the risk of hypertension. The population attributable risk percent (PAR%) was estimated for increased cases of hypertension due to poor adherence to a healthy sleep pattern or a healthy lifestyle.ResultsA total of 10,941 incident hypertension cases were documented during a median of 11.8 years of follow-up. The multivariable-adjusted hazard ratio (HR) for hypertension was 0.58 [95% confidence interval (CI): 0.52, 0.65] for participants with a sleep score of 5 compared with 0–1, and 0.48 (95% CI: 0.43, 0.54) for participants with a lifestyle score of 4 compared with those who scored 0. For joint association, those with a poor sleep pattern and a poor lifestyle had the highest risk of hypertension [HR: 2.41 (95% CI: 2.12, 2.74)]. PAR% was 14.7% (95% CI: 12.3%, 17.1%), 20.1% (95% CI: 17.6%, 22.6%), and 31.7% (95% CI: 27.6%, 35.6%) for poor adherence to a healthy sleep pattern, a healthy lifestyle, and the combination of a healthy sleep pattern and a healthy lifestyle.ConclusionBoth a healthy sleep pattern and a healthy lifestyle were associated with a lower risk of hypertension, and the benefits of adhering to a healthy sleep pattern complement the well-established lifestyle for the optimal primary prevention of hypertension. These findings support the current perspective that a healthy sleep pattern is an important part of a healthful and productive lifestyle for hypertension prevention.

BackgroundSeveral cardioprotective mechanisms attributed to n-3 polyunsaturated fatty acids (PUFAs) have been widely documented. Significant interest has recently focused on the role of human gut microbiota in metabolic disorders. However, the role of plant-derived n-3 PUFAs on blood lipid profiles is controversial and the effect on gut microbiota is still unclear.ObjectivesWe aimed to perform a double-blind randomized controlled trial to test the effect of plant-derived n-3 PUFAs on the blood lipids and gut microbiota of patients with marginal hyperlipidemia.MethodsAccording to the inclusion and exclusion criteria, 75 participants with marginal hyperlipidemia were randomly assigned to the intervention group (supplied with n-3 PUFA-enriched plant oil) or control group (supplied with corn oil), respectively, for a 3-month treatment. Participants and assessors were blinded to the allocation. The primary outcomes of the trial were the changes in serum lipid levels. Secondary outcomes were changes in gut microbiota and metabolites. For the primary outcomes, we conducted both an intent-to-treat (ITT) analysis and a per protocol (PP) analysis. For the secondary outcomes, we only conducted the PP analysis among the participants who provided fecal sample.ResultsFifty-one participants completed the trial. Relative to the control group, the n-3 PUFA supplementation resulted in significant reduction in total cholesterol (TC) levels (−0.43 mmol/L, 95% CI−0.84 to−0.01 mmol/L, P < 0.05). The n-3 PUFA supplementation was also associated with significantly increased relative abundance of Bacteroidetes in phylum level (P < 0.01; false discovery rate (FDR) corrected p = 0.11), and decreased the ratio between Firmicutes and Bacteroidetes (P < 0.05; FDR corrected p = 0.16). At genus level, the intervention of plant derived n-3 PUFAs resulted in a significant decrease in relative abundance of Phascolarctobacterium (P < 0.01; FDR corrected p = 0.18) and Veillonella (P < 0.01; FDR corrected p = 0.18) after the intervention.ConclusionsOur results demonstrated that plant-derived n-3 PUFAs beneficially affected the serum levels of TC and decreased the ratio between Firmicutes and Bacteroidetes during the 12-week intervention period, which might confer advantageous consequences for lipid metabolism and intestinal health.

Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.

The doubly fed induction generator with super capacitor is helpful to enhance the system inertia. At the same time, its structural characteristics are more suitable for the power grid topology without communication lines. However, the change of its topology also brings some problems. In this article, when SCESS-DFIG is participating in frequency regulation, DC bus voltage fluctuation caused by power imbalance of multiple converters is studied. The dynamic power response of super capacitor with DC-DC converter is a step load for grid side converter. The load of DC bus is nonlinear and random, so the balance and stability of the original system will change accordingly. Because of the complex topology and system composition of the doubly fed induction generator with super capacitor, the conventional feed-forward compensation control strategy can not be used to improve its dynamic response speed. Therefore, this article designs a control strategy which is applied for DC bus voltage fluctuation of the doubly fed induction generator with super capacitor. The theory proposed in this article is verified by simulation model and experiment.

In a doubly-fed induction generator (DFIG)-based wind energy conversion system (WECS), when the grid voltage sags severely, the rotor side converter (RSC) suffers from overvoltage and overcurrent owing to the large electromotive force (EMF). To ensure that the converter operates within a safe range when grid faults occur, this paper proposes a double impedance-substitution control (DISC) strategy to improve the system’s low-voltage ride through (LVRT) capability. When the grid voltage sag is detected, the grid side converter (GSC) and RSC are connected in parallel to the rotor circuit by changing the topology of the system. In the new topology, GSC and RSC are equivalent to inductive impedance by controlling, which can not only suppress the overvoltage and overcurrent at the rotor side, but also effectively reduce the torque ripple. Additionally, the DISC strategy can provide reactive power support to the grid during LVRT. Finally, the simulation results show that the DISC strategy can maintain the current flowing through the RSC within ±1 p.u., and compared with the existing control strategy, the effectiveness of the proposed method was further demonstrated.

The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1–0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Most cases of hepatocellular carcinoma (HCC) are already advanced at the time of diagnosis, which limits treatment options. Challenges in early‐stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated. Here, we employed STAR‐Fusion and identified 43 recurrent fusion events in our own and four public RNA‐seq datasets. We identified 2354 different gene fusions in two hepatitis B virus (HBV)‐HCC patients. Validation analysis against the four RNA‐seq datasets revealed that only 1.8% (43/2354) were recurrent fusions. Comparison with the four fusion databases demonstrated that 19 recurrent fusions were not previously annotated to diseases and three were annotated as disease‐related fusion events. Finally, we validated six of the novel fusion events, including RP11‐476K15.1‐CTD‐2015H3.2, by RT‐PCR and Sanger sequencing of 14 pairs of HBV‐related HCC samples. In summary, our study provides new insights into gene fusions in HCC and may contribute to the development of anti‐HCC therapy.

Background: The emerging coronavirus disease 2019 (COVID-19) has become a serious public health concern with a high number of fatalities. It is unclear whether corticosteroids could be a candidate for an early intervention strategy for patients with COVID-19.Methods: In this retrospective cohort study, we analyzed data from 28 corticosteroid-treated patients with non-severe but advanced COVID-19, in which short-course and low-dose corticosteroids were administered because of unremitting or worsening clinical conditions during hospitalization. To compare the effect of corticosteroids on viral clearance, 44 corticosteroid-untreated patients were included as controls.Results: At the time of admission, corticosteroid-treated patients (n = 28) had a more advanced baseline illness compared with corticosteroid-untreated patients (n = 44), as reflected by poorer blood laboratory parameters (lymphocytes, C-reactive protein, and lactate dehydrogenase) and more extensive chest computed tomography (CT) abnormalities. Corticosteroids were given because of radiological evidence of pneumonia progression (26/28) and/or unremitting fever (22/28) after admission. The median time from illness onset to corticosteroid treatment was 9 days (IQR, 7–10). The median duration and accumulated dose of corticosteroid treatment were 4.5 days [interquartile range (IQR), 3–5] and 140 mg of methylprednisolone (IQR, 120–200). Intravenous immunoglobulin (20 g per day for 3–5 days) was co-administered with corticosteroids. With the corticosteroid treatment, all patients achieved an abatement of fever within 1 day, and 78.6% (22/28) of the patients achieved radiological remission when evaluated about 3 days later. Only one (3.6%) patient progressed to severe COVID-19, and all patients recovered and were discharged without any sequela. The median time from illness onset to viral clearance was similar, as compared with 44 corticosteroid-untreated patients with relatively milder disease [18 (IQR 14.3–23.5) days vs. 17 (IQR, 12–20) days, p = 0.252]. When adjusted for age, sex, underlying comorbidities, baseline blood laboratory parameters, viral load, and chest radiological findings, the causal hazard ratio of corticosteroid treatment for the viral clearance was 0.79 (95%CI, 0.48–1.30, p = 0.34).Conclusion: Short-course and low-dose applications of corticosteroids, when co-administered with intravenous immunoglobulin, in non-severe COVID-19 patients during the stage of clinical deterioration may possibly prevent disease progression, while having a negligible impact on the viral clearance.

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38–/– mice and CD38–/– neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.

Endothelial cells play a critical role in the process of angiogenesis during skin wound healing. The migration and proliferation of endothelial cells are processes that are initiated by the hypoxic microenvironment in a wound, but the underlying mechanisms remain largely unknown. Here, we identified a novel role for microtubule-associated protein 4 (MAP4) in angiogenesis. We firstly demonstrated that MAP4 phosphorylation was induced in hypoxic endothelial cells; the increase in MAP4 phosphorylation enhanced the migration and proliferation of endothelial cells. We also found that hypoxia (2% O2) activated p38/mitogen-activated protein kinase (MAPK) signaling, and we identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in endothelial cells. Moreover, we showed that the promigration and proproliferation effects of MAP4 phosphorylation were attributed to its role in microtubule dynamics. These results indicated that MAP4 phosphorylation induced by p38/MAPK signaling promotes angiogenesis by inducing the proliferation and migration of endothelial cells cultured under hypoxic conditions via microtubule dynamics regulation. These findings provide new insights into the potential mechanisms underlying the initiation of the migration and proliferation of endothelial cells.

Water stress has a major influence on plant growth, development, and productivity. However, the cross-talk networks involved in drought tolerance are not well understood. Arabidopsis PCaP2 is a plasma membrane-associated Ca2+-binding protein. In this study, we employ qRT-PCR and β-glucuronidase (GUS) histochemical staining to demonstrate that PCaP2 expression was strongly induced in roots, cotyledons, true leaves, lateral roots, and whole plants under water deficit conditions. Compared with the wild type (WT) plants, PCaP2-overexpressing (PCaP2-OE) plants displayed enhanced water deficit tolerance in terms of seed germination, seedling growth, and plant survival status. On the contrary, PCaP2 mutation and reduction via PCaP2-RNAi rendered plants more sensitive to water deficit. Furthermore, PCaP2-RNAi and pcap2 seedlings showed shorter root hairs and lower relative water content compared to WT under normal conditions and these phenotypes were exacerbated under water deficit. Additionally, the expression of PCaP2 was strongly induced by exogenous abscisic acid (ABA) and salicylic acid (SA) treatments. PCaP2-OE plants showed insensitive to exogenous ABA and SA treatments, in contrast to the susceptible phenotypes of pcap2 and PCaP2-RNAi. It is well-known that SNF1-related kinase 2s (SnRK2s) and pathogenesis-related (PRs) are major factors that influence plant drought tolerance by ABA- and SA-mediated pathways, respectively. Interestingly, PCaP2 positively regulated the expression of drought-inducible genes (RD29A, KIN1, and KIN2), ABA-mediated drought responsive genes (SnRK2.2, -2.3, -2.6, ABF1, -2, -3, -4), and SA-mediated drought responsive genes (PR1, -2, -5) under water deficit, ABA, or SA treatments. Taken together, our results showed that PCaP2 plays an important and positive role in Arabidopsis water deficit tolerance by involving in response to both ABA and SA signals and regulating root hair growth. This study provides novel insights into the underlying cross-talk mechanisms of plants in response to water deficit stress.

This paper proposes a two-dimensional finite element mathematical model taking the mf-15 simulation generator in the dynamic model laboratory as the research object. The electromagnetic performance of the motor under no-load and rated load was analyzed to verify the correctness of the model. By using the method of field-circuit coupling combined with simulation analysis, the limit value of the generator's phase-in depth is determined, and the variation law of the electric and magnetic field distribution with the depth of the generator's established Leading phase operation is analyzed, as well as the influence of the phase-in operation on the system's operation stability. The results obtained provide a reference for the phase-in operation analysis of large generators.

As a new type of generator, an asynchronized high-voltage generator has the characteristics of an asynchronous generator and high voltage generator. The effect of the loss of an excitation fault for an asynchronized high-voltage generator and its fault diagnosis technique are still in the research stage. Firstly, a finite element model of the asynchronized high-voltage generator considering the field-circuit-movement coupling is established. Secondly, the three phase short-circuit loss of excitation fault, three phase open-circuit loss of excitation fault, and three phase short-circuit fault on the stator side are analyzed by the simulation method that is applied abroad at present. The fault phenomenon under the stator three phase short-circuit fault is similar to that under the three phase short-circuit loss of excitation. Then, a symmetrical loss of the excitation fault diagnosis system based on wavelet packet analysis and the Back Propagation neural network (BP neural network) is established. At last, we confirm that this system can eliminate the interference of the stator three phase short-circuit fault, accurately diagnose the symmetrical loss of the excitation fault, and judge the type of symmetrical loss of the excitation fault. It saves time to find the fault cause and improves the stability of system operation.

Background and objective AKT2 is a critical actor in the PI3K signal transduction pathway. Activation of AKT2 can lead to cell growth and survival. It has been revealed that AKT2 play a central role in tumorigenesis, tumor growth as well as metastasis. The aim of this study is to investigate the association between AKT2 and the clinical outcome of non-small cell lung cancer (NSCLC) patients by detecting its expression levels in the tumor tissue samples. Methods We developed an immunohistochemistry (IHC) assay to measure AKT2 protein levels in lung specimens from 80 cases with NSCLC and 10 cases with benign pulmonary disease. Results The positive rate of AKT2 was 57.50% (46/80) in NSCLC, which was higher than that in benign pulmonary (10.0%) samples (χ2=8.038, P=0.006). There was no significant correlation between AKT2 expression and the clinicopathologic profiles. The expression of AKT2 was significantly correlated with the progression free survival (PFS) ( χ2=12.671, P=0.005) and the overall survival (OS) (χ2=9.851, P=0.021) of patients with NSCLC. Conclusion AKT2 may provide a prognostic bio-marker of NSCLC.

Background and objective Recently, Cyberknife is a new flame-less stereotactic radiation therapy technology, which has several advantages, such as large dose, high precision and minimizing exposure to the surrounding normal tissue or adjacent vital structures, so it is successful in the treatment of non-small cell lung cancer (NSCLC). The aim of this study is to determine the effectiveness and safety of robotic stereotactic radiotherapy-Cyberknife with image guidance and realtime respiratory tracking against clinical stage III-IV peripheral NSCLC. Methods A review of treatment details and outcomes for 31 patients, with 34 tumors with histologically proven cancers treated by Cyberknife at the CyberKnife Center of Nanjing general hospital of Nanjing military command between March 2009 and March 2010 is presented. Of the 31patients, 15 were adenocarcinoma and 12 were squamous cell cancer. Twenty-eight patients received other forms of antineoplastic therapy such as chemotherapy. A total dose of 36 Gy-60 Gy was prescribed to the 65%-85% isodose line and given in two to five fractions in less than 1 week using the CyberKnife radiosurgery system. CT scans were performed after one-two months, then patients were followed every 3 months. Results Two patients had complete radiographic responses, 16 patients showed PRs, 7 patients showed SDs. Two patients showed PRs (reduction in tumor size), but developed distant metastases. Response rate was 58% and disease control rate was 81%. All patients tolerated the radiosurgery well, fatigue being the main side effect. No grade 4 or above toxicity was encountered. Conclusion In this small cohort of patients with advanced peripheral NSCLC, Cyberknife seems to be a safe and has good therapeutic effects with slight adverse reaction, but long time follow-up is necessary to evaluate the survival data and late toxicity.

Accumulating evidence shows a tight link between inflammation and cancer. However, comprehensive identification of pivotal transcription factors (i.e., core TFs) mediating the dysregulated links remains challenging, mainly due to a lack of samples that can effectively reflect the connections between inflammation and tumorigenesis. Here, we constructed a series of TF-mediated regulatory networks from a large compendium of expression profiling of normal colonic tissues, inflammatory bowel diseases (IBDs) and colorectal cancer (CRC), which contains 1201 samples in total, and then proposed a network-based approach to characterize potential links bridging inflammation and cancer. For this purpose, we computed significantly dysregulated relationships between inflammation and their linked cancer networks, and then 24 core TFs with their dysregulated genes were identified. Collectively, our approach provides us with quite important insight into inflammation-associated tumorigenesis in colorectal cancer, which could also be applied to identify functionally dysregulated relationships mediating the links between other different disease phenotypes.

BACKGROUND: Lysine specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics, but the pathological roles of its dysfunction in lung cancer remain to be elucidated. The aim of this study was to evaluate the prognostic significance of LSD1 expression in patients with non-small cell lung cancer (NSCLC) and to define its exact role in lung cancer proliferation, migration and invasion. METHODS: The protein levels of LSD1 in surgically resected samples from NSCLC patients were detected by immunohistochemistry or Western blotting. The mRNA levels of LSD1 were detected by qRT-PCR. The correlation of LSD1 expression with clinical characteristics and prognosis was determined by statistical analysis. Cell proliferation rate was assessed by MTS assay and immunofluorescence. Cell migration and invasion were detected by scratch test, matrigel assay and transwell invasion assay. RESULTS: LSD1 expression was higher in lung cancer tissue more than in normal lung tissue. Our results showed that over-expression of LSD1 protein were associated with shorter overall survival of NSCLC patients. LSD1 was localized mainly to the cancer cell nucleus. Interruption of LSD1 using siRNA or a chemical inhibitor, pargyline, suppressed proliferation, migration and invasion of A549, H460 and 293T cells. Meanwhile, over-expression of LSD1 enhanced cell growth. Finally, LSD1 was shown to regulate epithelial-to-mesenchymal transition in lung cancer cells. CONCLUSIONS: Over-expression of LSD1 was associated with poor prognosis in NSCLC, and promoted tumor cell proliferation, migration and invasion. These results suggest that LSD1 is a tumor-promoting factor with promising therapeutic potential for NSCLC.