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Understanding the impacts of land use and vegetation carbon sequestration under varying climate scenarios is essential for optimizing regional ecosystem services and shaping sustainable socioeconomic policies. This study presents a novel research framework that integrates a system dynamics (SD) model, a patch generation land use simulation (PLUS) model, and the random forest algorithm, coupled with SSP-RCP scenarios from Coupled Model Intercomparison Project Phase 6 (CMIP6), to simulate future vegetation net primary production (NPP). A case study in Hubei Province, central China, demonstrates the framework’s effectiveness in elucidating the interactions between land use change, climate change, topography, and vegetation conditions on carbon sequestration. The integration of SSP-RCP scenarios provides a clear understanding of how different climate conditions influence regional carbon sinks, offering valuable scientific insights for regional carbon neutrality and sustainable development policymaking. The simulation results for Hubei Province across the years 2030, 2040, 2050, and 2060, under three pathways—SSP1-1.9, SSP2-4.5, and SSP5-8.5—reveal that SSP1-1.9 leads to the highest carbon sequestration, while SSP5-8.5 results in the lowest. The annual total carbon sink ranges from 115.99 TgC to 117.59 TgC, with trends varying across scenarios, underscoring the significant impact of policy choices on local ecosystems. The findings suggest that under low-carbon emission scenarios, there is greater potential for NPP growth, making carbon neutrality goals more achievable.

As a layered material with single/multi-atom thickness, two-dimensional transition metal sulfide WS2 has attracted extensive attention in the field of science for its excellent physical, chemical, optical, and electrical properties. The photoelectric properties of WS2 are even more promising than graphene. However, there are many existing preparation methods for WS2, but few reports on its direct growth on tungsten films. Therefore, this paper studies its preparation method and proposes an innovative two-dimensional material preparation method to grow large-sized WS2 with higher quality on metal film. In this experiment, it was found that the reaction temperature could regulate the growth direction of WS2. When the temperature was below 950 °C, the film showed horizontal growth, while when the temperature was above 1000 °C, the film showed vertical growth. At the same time, through Raman and band gap measurements, it is found that the different thicknesses of precursor film will lead to a difference in the number of layers of WS2. The number of layers of WS2 can be controlled by adjusting the thickness of the precursor.

This paper looks at 3D model retrieval techniques for digital virtual workshops in cloud computing. The global D2 shape distribution features are first used to sort the models for initial retrieval. Then the local curvature features are used to further optimize the sorted results to obtain the final retrieval results. Through the historical and cultural theme scene design, stage performance scene design, and interactive performance design to enhance the immersive experience of the corresponding cultural creations, the creative inheritance and dissemination mode of Dabie Mountain culture in the new period is created. The results show that the difference in the percentage of attention points in the landscape node area is significant, P=0.032, indicating that the virtual reality experience group is better able to meet the needs of the experience. The weights of the three evaluation dimensions of the virtual experience of Dabie Mountain folk song culture are, in order, mood design (0.4073) > scene design (0.3814) > context design (0.2113). Designing multi-sensory (visual, auditory, olfactory, tactile) is of the highest importance. In terms of interactive experience, more attention is paid to the timeliness and accuracy of feedback, as well as the guidance of operations. In terms of emotional experience, more attention is paid to the sense of pleasure, surprise, and satisfaction. In the cultural experience, more attention is paid to traditional folk songs and historical architectural displays.

ABSTRACT Facial skin is more exposed to the outside environment, and it is usually affected by environmental factors. Characterization of the skin microbiome and metabolome of individuals from different geographic regions will help to understand the factors behind the prevalence of skin disorders and support skincare product development. In the current study, volunteers from northern, southern, and northwestern China were recruited. Facial skin samples were collected for amplicon sequencing and metabolomic liquid chromatography‒mass spectrometry (LC–MS/MS) analyses. We demonstrated significant alterations in the abundances of multiple microorganisms and skin lipid compositions between individuals. People living in the northwest, which has a dry climate and high altitude, showed lower level of total lipids, and lower abundance of Malassezia, but higher levels of ceramides and fatty acids. Malassezia had a positive correlation with eicosanoids and a negative correlation with ceramides. This work highlights the effects of geographic factors on the skin microbial structures and skin lipids. IMPORTANCE Characterization of the skin microbiome and metabolome across geography will help uncover the climate factors behind the prevalence of skin disorders and provide suggestions for skincare products for people living in different geographic regions.

Summary: Background: Macrophage infiltration and polarization are integral to the progression of heart failure and cardiac fibrosis after ischemia/reperfusion (IR). Interleukin 34 (IL-34) is an inflammatory regulator related to a series of autoimmune diseases. Whether IL-34 mediates inflammatory responses and contributes to cardiac remodeling and heart failure post-IR remains unclear. Methods: IL-34 knock-out mice were used to determine the role of IL-34 on cardiac remodeling after IR surgery. Then, immunofluorescence, flow cytometry assays, and RNA-seq analysis were performed to explore the underlying mechanisms of IL-34-induced macrophage recruitment and polarization, and further heart failure after IR. Findings: By re-analyzing single-cell RNA-seq and single-nucleus RNA-seq data of murine and human ischemic hearts, we showed that IL-34 expression was upregulated after IR. IL-34 knockout mitigated cardiac remodeling, cardiac dysfunction, and fibrosis after IR and vice versa. RNA-seq analysis revealed that IL-34 deletion correlated negatively with immune responses and chemotaxis after IR injury. Consistently, immunofluorescence and flow cytometry assays demonstrated that IL-34 deletion attenuated macrophage recruitment and CCR2+ macrophage polarization. Mechanistically, IL-34 deficiency repressed both the canonical and noncanonical NF-κB signaling pathway, leading to marked reduction of P-IKKβ and P-IκBα kinase levels; downregulation of NF-κB p65, RelB, and p52 expression, which drove the decline in chemokine CCL2 expression. Finally, IL-34 and CCL2 levels were increased in the serum of acute coronary syndrome patients, with a positive correlation between circulating IL-34 and CCL2 levels in clinical patients. Interpretation: In conclusion, IL-34 sustains NF-κB pathway activation to elicit increased CCL2 expression, which contributes to macrophage recruitment and polarization, and subsequently exacerbates cardiac remodeling and heart failure post-IR. Strategies targeting IL-34-centered immunomodulation may provide new therapeutic approaches to prevent and reverse cardiac remodeling and heart failure in clinical MI patients after percutaneous coronary intervention. Funding: This study was supported by the National Nature Science Foundation of China (81670352 and 81970327 to R T, 82000368 to Q F).

Summary: Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive lymphoid malignancy with a poor prognosis and lacks standard treatment. Targeted therapies are urgently needed. Here we systematically investigated the druggable mechanisms through chemogenomic screening and identified that Bcl-xL-specific BH3 mimetics effectively induced ENKTL cell apoptosis. Notably, the specific accumulation of Bcl-xL, but not other Bcl-2 family members, was verified in ENKTL cell lines and patient tissues. Furthermore, Bcl-xL high expression was shown to be closely associated with worse patient survival. The critical role of Bcl-xL in ENKTL cell survival was demonstrated utilizing selective inhibitors, genetic silencing, and a specific degrader. Additionally, the IL2-JAK1/3-STAT5 signaling was implicated in Bcl-xL dysregulation. In vivo, Bcl-xL inhibition reduced tumor burden, increased apoptosis, and prolonged survival in ENKTL cell line xenograft and patient-derived xenograft models. Our study indicates Bcl-xL as a promising therapeutic target for ENKTL, warranting monitoring in ongoing clinical trials by targeting Bcl-xL.

IntroductionThe pathogenic gene CDH23 plays a pivotal role in tip links, which is indispensable for mechanoelectrical transduction in the hair cells. However, the underlying molecular mechanism and signal regulatory networks that influence deafness is still largely unknown.MethodsIn this study, a congenital deafness family, whole exome sequencing revealed a new mutation in the pathogenic gene CDH23, subsequently; the mutation has been validated using Sanger sequencing method. Then CRISPR/Cas9 technology was employed to knockout zebrafish cdh23 gene. Startle response experiment was used to compare with wide-type, the response to sound stimulation between wide-type and cdh23−/−. To further illustrate the molecular mechanisms underlying congenital deafness, comparative transcriptomic profiling and multiple bioinformatics analyses were performed.ResultsThe YO-PRO-1 assay result showed that in cdh23 deficient embryos, the YO-PRO-1 signal in inner ear and lateral line neuromast hair cells were completely lost. Startle response experiment showed that compared with wide-type, the response to sound stimulation decreased significantly in cdh23 mutant larvae. Comparative transcriptomic showed that the candidate genes such as atp1b2b and myof could affect hearing by regulating ATP production and purine metabolism in a synergetic way with cdh23. RT-qPCR results further confirmed the transcriptomics results. Further compensatory experiment showed that ATP treated cdh23−/− embryos can partially recover the mutant phenotype.ConclusionIn conclusion, our study may shed light on deciphering the principal mechanism and provide a potential therapeutic method for congenital hearing loss under the condition of CDH23 mutation.

WTe2 has attracted much attention because of its layered structure and special electronic energy band structure. However, due to the difficulty of evaporating the W element itself and the inactivity of the Te element, the obtained large-area WTe2 thin films are usually accompanied by many defects. In this paper, WTe2 nanocrystalline films were successfully prepared on quartz substrates using magnetron sputtering and chemical vapor deposition techniques. Various analytical techniques such as X-ray Diffraction, Raman spectra, X-ray Photoelectron Spectroscopy, Scanning Electron Microscope, and photoluminescence spectra are employed to analyze the crystal structure, composition, and morphology. The effects of different tellurization temperatures and tellurization times on the properties of WTe2 thin films were investigated. WTe2 nanocrystalline films with good crystallinity were obtained at 600 °C for 30 min. The thermal conductivity of the WTe2 films prepared under this condition was 1.173 Wm−1K−1 at 300 K, which is significantly higher than that of samples prepared using other methods.

Abstract Aims To explore the associations between serum phenylacetylglutamine (PAGln) and chronic heart failure (HF). Methods and results Totally 956 subjects were enrolled consecutively from the Department of Cardiovascular Medicine, Ruijin Hospital. Baseline data were obtained from all participants, and 471 stable chronic HF subjects were followed up. Serum PAGln was analysed by liquid chromatography–tandem mass spectrometry. The association between PAGln and basic renal indicators was assessed by simple correlation analysis. Logistic regression analysis was conducted to measure the association between PAGln and HF risk. Event‐free survival was determined by Kaplan–Meier curves, and differences in survival were assessed using log‐rank tests. Cox proportional hazards analysis was used to assess the prognostic value of PAGln in HF. Serum PAGln levels were increased in patients with chronic HF (3.322 ± 8.220 μM vs. 1.249 ± 1.168 μM, P

Background: Limited research has been conducted to investigate the impact of secondary mitral regurgitation (MR) in heart failure (HF) patients with different levels of estimated pulmonary artery systolic pressure (ePASP). Methods: A total of 468 patients suffering from HF and secondary MR were enrolled and categorized into non-severe and severe MR groups based on the degree of MR. The primary endpoint of the study was a composite of cardiovascular death and a first-heart-failure hospitalization. The secondary endpoints were the primary outcomes, individually. The outcomes of the two groups were compared. Patients were further classified based on whether their ePASP was ≥50 mmHg or

Abstract This study (ORIENT-4) aimed to assess the efficacy and safety of sintilimab, a humanized anti-PD-1 antibody, in patients with relapsed/refractory extranodal NK/T cell lymphoma (r/r ENKTL). ORIENT-4 is a multicenter, single-arm, phase 2 clinical trial (NCT03228836). Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 months. The primary endpoint was the objective response rate (ORR) based on Lugano 2014 criteria. Twenty-eight patients with r/r ENKTL were enrolled from August 31, 2017 to February 7, 2018. Twenty-one patients (75.0%, 95% CI: 55.1–89.3%) achieved an objective response. With a median follow-up of 30.4 months, the median overall survival (OS) was not reached. The 24-month OS rate was 78.6% (95% CI, 58.4–89.8%). Most treatment-related adverse events (TRAEs) were grade 1–2 (71.4%), and the most common TRAE was decreased lymphocyte count (42.9%). Serious adverse events (SAEs) occurred in 7 (25.0%) patients, and no patient died of adverse events. Sintilimab is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

PurposeEpstein-Barr virus (EBV) infection has been shown to contribute to oncogenesis and often causes acute clinical manifestation of Infectious mononucleosis (IM). It is unknown whether IM could increase the risk of subsequent malignancies. We aimed to evaluate the association of IM caused by EBV (EBV-IM) with overall and subtypes of malignancy in a large population-based cohort study.MethodsThis study included 1,419,407 individuals born in Denmark between 1973 and 2016 identified from national registers and 23,057 individuals had IM. The 5,394 of them had confirmed EBV-IM and they were birth date- and sex- matched (1:63) to 1,396,350 non-IM individuals. Cox regression was used to examine the associations of EBV-IM with malignancy.ResultsIndividuals with a history of confirmed EBV-IM had an 88% increased overall risk of malignancy (hazard ratio [HR]:1·88, 95% confidence interval [CI]: 1·42–2·49) and a five-fold risk of hematologic malignancies (HR 5·04, 95% CI: 3·07–8·25), compared to those without IM. Similar estimates were observed in the sibling analysis. The overall risk of malignancy was greater for EBV-IM with complications (HR 8·93, 95% CI: 3·35–23·81) than that for EBV-IM without complications (HR 1·35, 95% CI: 1·20–1·53). EBV-IM duration was related to increased risk of malignancy in a dose-response way. Notably, the significant elevated risk of overall malignancy was observed in the first two years after EBV-IM onset (rate ratio [RR] 4·44, 95% CI: 2·75–7·17) and attenuated thereafter.ConclusionEBV-IM was associated with an increased risk in malignancy, particularly hematologic malignancies and in the first two years following IM exposure. Our findings suggest an important time-window for early screening of the EBV-attributed malignancy.

Depression is common among patients with acute coronary syndrome (ACS). Although multiple studies have confirmed that depression is an independent risk factor for poor outcomes in ACS, general awareness of this issue is still limited. Ongoing research has described detailed aspects of depression in ACS, with various mechanistic hypotheses put forward to explain the complexity of this comorbidity. Several investigations have explored management strategies in this subgroup of patients, including screening for depression, antidepressant treatment, and cardiac rehabilitation. However, evidence of long-term improvement in clinical outcomes is still scarce, and a more comprehensive understanding of the underlying mechanisms that link depression with ACS is required to further improve disease management.

Adverse cardiac remodeling, including cardiac fibrosis, after myocardial infarction (MI) is a major cause of long-term heart failure. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that regulates glucose metabolism, also plays an important role in various fibrotic and cardiovascular diseases. However, its effects on MI remain unknown. Here, PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) and a permanent left anterior descending ligation mouse model were used to explore the functional role of PFKFB3 in MI. We showed that PFKFB3 expression increased significantly in the area of cardiac infarction during the early phase after MI, peaking on day 3. 3PO treatment markedly improved cardiac function, accompanied by decreased infarction size and collagen density in the infarct area. Meanwhile, 3PO attenuated cardiac fibrosis after MI by reducing the expression of collagen and fibronectin in murine hearts. Notably, 3PO reduced PFKFB3 expression and inhibited the transforming growth factor-beta 1/mothers against the decapentaplegic homolog 2/3 (TGF-β1/SMAD2/3) signaling pathway to inhibit cardiac fibrosis after MI. Moreover, PFKFB3 expression in neonatal rat cardiac fibroblasts (NRCFs) increased significantly after MI and under hypoxia, whereas 3PO alleviated the migratory capacity and activation of NRCFs induced by TGF-β1. In conclusion, 3PO effectively reduced fibrosis and improved adverse cardiac remodeling after MI, suggesting PFKFB3 inhibition as a novel therapeutic strategy to reduce the incidence of chronic heart failure following MI.

Background and aimsIntestinal flora metabolites are associated with cardiovascular (CV) diseases including heart failure (HF). The carnitine precursor trimethyllysine (TML), which participates in the generation of the atherogenic-related metabolite trimethylamine N-oxide (TMAO), was found to be related to poor prognosis in patients with CV diseases. The aim of the present study was to examine the relationship between TML and stable chronic HF.Methods and resultsIn total, 956 subjects including 471 stable chronic HF and 485 non-HF patients were enrolled in the present cohort study and subjects with stable HF were followed up for 2.0 ± 1.1 years. Serum levels of TML and TMAO were measured by liquid chromatography mass spectrometry in tandem. TML levels were significantly elevated in patients with HF compared with non-HF patients and were positively correlated with N-terminal pro-brain natriuretic peptide (NTproBNP) levels (r = 0.448, P < 0.001). TML was associated with the presence of HF after adjusting for age, sex, complications, traditional clinical factors, and TMAO (tertile 3 (T3), adjusted odds ratio (OR) 1.93, 95% confidence interval (CI) 1.19–3.13, and P = 0.007). In patients with HF, increased TML levels were associated with a composite endpoint of CV death and HF hospitalization during follow-up (T3, adjusted hazard ratio (HR) 1.93, 95% CI 1.27–2.93, and P = 0.002). Increased TML levels indicated a higher risk of CV death, re-hospitalization, and all-cause mortality.ConclusionSerum TML levels were associated with the presence and severity of HF in all subjects. High levels of TML can indicate complications and poor prognosis in HF patients.

Background Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on the clinical features and prognostic factors. Patients and Methods A consecutive cohort of patients with PB-DLBCL was retrospectively analyzed in our hospital from February 1997 through July 2018. The primary endpoint is overall survival (OS) contributing to any cause. Results A total of 76 patients were diagnosed with PB-DLBCL. The median age at diagnosis was 51 years (range: 25-80 years), with female prevalence (98.7%). Forty (52.6%) patients had right-sided breast involvement but no bilateral breast involvement at diagnosis. Overall, disease stages IE and IIE were seen in 55 (72.4%) and 21 (27.6%) patients, respectively. According to the stage-modified International Prognostic Index (IPI), 37 (48.7%) patients were classified in the very good risk group (IPI 0). Of the 72 patients available, the non-germinal center B-cell (non-GCB) subtype of DLBCL was observed in 66 (91.6%) patients. All patients received anthracycline-based chemotherapy, 56 (73.7%) with rituximab, 31 (40.8%) also with additional radiation therapy, and 14 (18.4%) patients received a prophylactic intrathecal injection. Seven (9.2%) patients had refractory disease. With a median follow-up of 6.8 years (range 0.4-25.0 years), 10 (13.2%) patients had a relapse in the central nervous system (CNS) site. The 5-year and 10-year OS of all the patients was 97.2% (95% CI: 99.3-89.5) and 84.8% (95% CI: 70.0-93.5), respectively. The median OS was not reached. The median progression-free survival (PFS) was 10.3 years for patients with PB-DLBCL(Figure 2B). The 5-year PFS of all the patients was 76.3% (95% CI: 64.6-84.6). Univariate analysis revealed several prognostic factors, including stage-modified IPI, breast surgery, refractory disease, and CNS relapse. Multivariate analyses produced two independent prognostic factors for patients with PB-DLBCL, including stage-modified IPI score (2-3 versus 0) (hazard ratio: 19.114, 95% CI 1.841 to 198.451, p=0.013) and CNS relapse (hazard ratio: 5.522, 95% CI 1.059 to 28.788, p=0.043). Conclusion In our cohort, PB-DLBCL clinical features are similar to prior literature reports. Stage-modified IPI score and CNS relapse were associated with overall survival.

To explore the relationship between soluble ST2 (sST2) and metabolic syndrome (MetS) and determine whether sST2 levels can predict the presence and severity of MetS. We evaluated 550 consecutive subjects (58.91 ± 9.69 years, 50% male) with or without MetS from the Department of Vascular & Cardiology, Shanghai Jiao Ton g University-Affiliated Ruijin Hospital. Serum sST2 concentrations were measured. The participants were divided into three groups according to the sST2 tertiles. Univariate and multivariable logistic regression models were used to evaluate the association between serum sST2 concentrations and the presence of MetS. Serum sST2 concentrati ons were significantly higher in the MetS group than in those in the no MetS group (14.80 ± 7.01 vs 11.58 ± 6.41 ng/mL, P < 0.01). Subjects with more MetS components showed higher levels of sST2. sST2 was associated with the occurrence of MetS after multivariable adjustment as a continuous log-transformed variable (per 1 SD, odds ratio (OR): 1.42, 95% CI: 1.13–1.80, P < 0.01). Subgroup analysis showed that individuals with MetS have signifi cantly higher levels of sST2 than those without MetS regardless of sex and age. High serum sST2 levels were significantly and independently associated with the presence and severity of MetS. Thus, sST2 levels may be a novel biomarker and clinical predictor of MetS.

Abstract Background Circular RNAs (circRNAs) play crucial roles in the development and progression of human cancers, including non-small cell lung cancer (NSCLC). However, most of these circRNAs, such as hsa_circ_0014235, are not fully identified in functions and mechanisms. Methods The isolated exosomes from serum specimens were identified using transmission electron microscopy (TEM). The expression of hsa_circ_0014235, miR-520a-5p and cyclin-dependent kinase 4 (CDK4) was detected by real-time quantitative polymerase chain reaction (qPCR). For functional assays, cell proliferation, colony formation ability, migration, invasion, cell apoptosis and cell cycle progression were determined using cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay, transwell assay and flow cytometry assay, respectively. The expression of CDK4 and other indicated marker proteins was detected by western blot. The predicted target relationship between miR-520a-5p and hsa_circ_0014235 or cyclin-dependent kinase 4 (CDK4) was verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP) assay. Results The expression of hsa_circ_0014235 was notably elevated in NSCLC serum-derived exosomes, tumor tissues and cells. NSCLC serum-derived exosomes promoted NSCLC cell resistance to cisplatin (DDP), cell proliferation, migration and invasion in vitro, as well as tumor growth and DDP resistance in vivo. Hsa_circ_0014235 overexpression enhanced DDP resistance and facilitated cell malignant behaviors. MiR-520a-5p was a target of hsa_circ_0014235, and rescue experiments showed that miR-520a-5p restoration reversed the effects of hsa_circ_0014235 overexpression. Moreover, CDK4 was a target of miR-520a-5p, and rescue experiments showed that CDK4 knockdown reversed the aggressive effects of miR-520a-5p inhibition on NSCLC progression. Conclusions Exosome-transmitted hsa_circ_0014235 promoted NSCLC malignant development by mediating the miR-520a-5p/CDK4 regulatory axis.

Background and Aims: Acute coronary syndrome (ACS) has become one of the most common causes of disability. It is thus important to identify ACS early in the disease course of patients using novel biomarkers for prompt management. Decorin (DCN) was well-acknowledged for its effect on collagen fibrillogenesis and maintaining tissue integrity. Additionally, DCN could release as secreted proteoglycan under pathological conditions. Hence, we aimed to determine the relationship between serum DCN concentration and ACS.Methods: A total of 388 patients who underwent coronary angiography (CAG) in the cardiovascular center of Ruijin Hospital between June 2016 and December 2017 were enrolled in this study. Blood samples were drawn during CAG surgery to determine the serum DCN level of patients with ACS (n = 210) and control subjects (n = 178) using enzyme-linked immunosorbent assay.Results: We found that the serum DCN levels of ACS patients were elevated compared with those of the control subjects (13.59 ± 0.50 vs. 13.17 ± 0.38, respectively, p < 0.001). Furthermore, the serum DCN level, after being adjusted with other cardiovascular factors, was independently associated with ACS. Moreover, an increased serum DCN level was positively correlated with the number of white blood cells and the level of high-sensitivity C-reactive protein (R = 0.3 and 0.11, respectively). Mechanistically, DCN might have elicited an imbalanced inflammatory response during cardiac ischemia by suppressing the expression of anti-inflammatory genes.Conclusion: Serum DCN is a novel biomarker of ACS and contributes to the increased inflammatory response in ischemic heart disease.

Background: Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy.Methods and Results: Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency.Conclusions: Collectively, these findings reveal the indispensable roles of the FABP3–PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.

Abstract Extranodal natural killer/T‐cell lymphoma (ENKL), nasal‐type is a rare but highly aggressive disease with poor prognosis. Optimal treatment strategies for newly diagnosed localized ENKL have not been fully defined. Here we retrospectively analyzed 72 patients with newly diagnosed stage IE/IIE ENKL treated with gemcitabine, dexamethasone, and cisplatin (GDP) regimen chemotherapy with sandwiched radiotherapy in our department between May 2012 and September 2014. After 2 cycles of GDP induction chemotherapy, the complete response rate (CRR) and overall response rate (ORR) were 30.6% (22/72) and 91.7% (66/72). After whole treatment completion, the CRR and ORR were 81.9% (59/72) and 91.7% (66/72), respectively. With a median follow‐up of 57.8 months (Interquartile Range 54.0‐64.5 months), the 5‐year progression‐free survival rate was 70.9% (95% CI, 60.1% to 81.7%), and the 5‐year overall survival rate was 72.0% (95% CI, 61.6% to 82.4%), respectively. Patients with CRR after treatment had better prognosis than their counterparts. The major adverse events were myelosuppression, liver dysfunction, gemcitabine‐related skin rash, and digestive tract toxicities. Grade 3 to 4 neutropenia and thrombocytopenia were 18.0% (13/72) and 15.3% (11/72), respectively. No treatment related deaths were observed. It is concluded that the GDP regimen with sandwiched radiotherapy was an effective and well‐tolerated treatment for newly diagnosed stage IE/IIE ENKL, nasal‐type.

Aims: Limited information exists regarding optimal revascularization options for patients with triple-vessel coronary artery disease (TVD), heart failure (HF), and different degrees of mitral regurgitation (MR). Thus, we aimed to compare the effect of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) surgery in the indicated patients.Methods and Results: In the real-world prospective study, 1190 patients with multi-vessel disease and decreased left ventricular systolic function but without severe MR, who underwent PCI or CABG, were enrolled and followed-up for 4.7 ± 1.8 years. The primary endpoint was a composite of cardiovascular death and HF hospitalization. Secondary endpoints were the individual components of the primary outcome. Risk of the primary endpoint was higher in the PCI than in the CABG group (HR = 1.38, 95%CI: 1.14–1.67, and P < 0.01), particularly in patients with moderate MR (HR = 1.85, 95%CI: 1.35–2.55, and P < 0.01). In patients with no-mild MR, the risk of the primary endpoint did not differ significantly between PCI and CABG (P = 0.09). Treatment with PCI was associated with an increased risk for cardiovascular death and HF hospitalization in the moderate MR cohort, while PCI was comparable to CABG in the no-mild MR cohort.Conclusions: In this real-world study, for patients with HF and TVD, CABG was related to lower adverse outcome rates compared to PCI. Assessment of MR can aid in selecting optimal revascularization therapies and in risk stratification.

The tender shoots of Chinese toon are one of the most popular vegetables, although the chemical basis of its edible value is still unknown. Guided by antioxidant and α-glucosidase inhibitory activities, the main constituents and their function and content in Chinese toon buds were studied. Six main flavonoid glycosides based on quercetin (1–3) and kaempferol (4–6), kaempferol (7), and a methyl gallate (8) with antioxidant and α-glucosidase inhibition activities were isolated and identified using chromatographic and spectrometric techniques and methods. The contents of the seven main flavonoids determined by high-performance liquid chromatography method were ranged from 0.5 to 5.1 mg/g, and the total flavonoids content measured by ultraviolet spectrophotometry was 17.1 mg rutin equivalent/g dry weight, which was higher than that found in 11 other common vegetables. Correlating the activities and contents of these flavonoids, Chinese toon bud is a potentially rich source of dietary antioxidants and hypoglycemics.

Cells require some metals, such as zinc and manganese, but excess levels of these metals can be toxic. As a result, cells have evolved complex mechanisms for maintaining metal homeostasis and surviving metal intoxication. Here, we present the results of a large-scale functional genomic screen in Drosophila cultured cells for modifiers of zinc chloride toxicity, together with transcriptomics data for wild-type or genetically zinc-sensitized cells challenged with mild zinc chloride supplementation. Altogether, we identified 47 genes for which knockdown conferred sensitivity or resistance to toxic zinc or manganese chloride treatment, and >1800 putative zinc-responsive genes. Analysis of the ‘omics data points to the relevance of ion transporters, glutathione (GSH)-related factors, and conserved disease-associated genes in zinc detoxification. Specific genes identified in the zinc screen include orthologs of human disease-associated genes CTNS, PTPRN (also known as IA-2), and ATP13A2 (also known as PARK9). We show that knockdown of red dog mine (rdog; CG11897), a candidate zinc detoxification gene encoding an ABCC-type transporter family protein related to yeast cadmium factor (YCF1), confers sensitivity to zinc intoxication in cultured cells, and that rdog is transcriptionally upregulated in response to zinc stress. As there are many links between the biology of zinc and other metals and human health, the ‘omics data sets presented here provide a resource that will allow researchers to explore metal biology in the context of diverse health-relevant processes.

Horticultural lettuce varieties vary considerably in phenotype. Here, via RNA-seq of 240 different lettuce accessions, the authors identify loci and expression patterns associated with flavonoid and anthocyanin content and show that cultivated lettuce likely arose via a single domestication event.

Abstract Background Biomarkers of early plaque progression are still elusive. Myeloid DAP12-associating lectin-1 (MDL-1), also called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. However, the relationship between its level and atherosclerosis is unknown. In this study, we aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression. Methods Immunofluorescence staining, real-time PCR and western blot were performed to analyze MDL-1 expression in aorta or mice macrophages. The role of MDL-1 in macrophage survival was further investigated by adenovirus infection and TUNEL assay. Results Significant MDL-1 expression was found in advanced human and apoE−/− mice atherosclerotic plaques, especially in lesional macrophages. In the model of atherosclerosis regression, we found MDL-1 expression was highly downregulated in lesional macrophages from ldlr−/− mouse regressive plaques, coincident with a reduction in lesional macrophage content and marker of M1 proinflammatory macrophages. Furthermore, we found MDL-1 was significantly expressed in inflammatory M1 subtype polarized bone marrow-derived macrophages. In vitro experiments, the level of MDL-1 was remarkably elevated in macrophages treated with pathophysiological drivers of plaque progression, such as oxidized low-density lipoprotein (ox-LDL) and hypoxia. Mechanistically, we demonstrated that MDL-1 overexpression notably promoted macrophage survival and decreased cleaved caspase-3 expression under ox-LDL stimulation, which suggested that it could maintain lesional macrophage survival and cause its accumulation. Conclusions This study firstly demonstrated that MDL-1 is mainly expressed in atherosclerotic lesional macrophages and increased macrophage MDL-1 expression is associated with early plaque progression and promotes macrophage survival.

Background/Aims: Tr1 cells can induce peripheral tolerance to self- and foreign antigens, and have been developed as a therapeutic tool for the induction of tolerance to transplanted tissue. We explored the feasibility of generating Tr1 cells by using IL-10 gene-modified recipient DCs (DCLV-IL-10) to stimulate donor naive CD4+ T cells. We also investigated some biological properties of Tr1 cells. Methods: DCLV-IL-10 were generated through DCs transduced with a lentivirus vector carrying the IL-10 gene, and Tr1 cells were produced by using DCLV-IL-10 to stimulate naive CD4+ T cells. The effects of Tr1 cells on T-cell proliferation and the occurrence of graft versus host disease (GVHD) following allogeneic stem-cell transplantation (allo-HSCT) were investigated. Results: The DCLV-IL-10-induced Tr1 cells co-expressed LAG-3 and CD49b. Moreover, they also expressed CD4, CD25, and IL-10, but not Foxp3, and secreted significantly higher levels of IL-10 (1,729.36 ± 185.79 pg/mL; P < 0.001) and INF-γ (1,524.48 ± 168.65 pg/mL; P < 0.01) than the control T cells upon the stimulation by allogeneic DCs. Tr1 cells markedly suppressed T-lymphocyte proliferation and the mixed lymphocytic response (MLR) in vitro. The mice used in the allo-HSCT model had longer survival times and lower clinical and pathological GVHD scores than the control mice. Conclusion: IL-10 gene-modified DC-induced Tr1 cells may be used as a potent cellular therapy for the prevention of GVHD after allo-HSCT.

In this paper, we have constructed an all-fiberized bi-directional pumping fiber amplifier. The output time domain signals and limitations of copumping and counterpumping schemes were experimentally investigated. The power scaling of copumping and counterpumping scheme is restricted by stimulated Raman scattering (SRS) and transverse modal instability (TMI), respectively. The highest output power of 3.06 kW was achieved by using bi-directional pumping. Finally, we tested the relationship between SRS threshold and injected seed power.

The characteristics of distribution of Pseudomonas aeruginosa in patients with agranulocytosis and fever in 12 hospitals in Shanghai from 2012 to 2014 were retrospectively analyzed. WHONET 5.6 software was used to analyze the results of drug sensitivity test. Data from different diseases, different sample sources, and drug sensitivity tests were statistically analyzed to investigate the clinical distribution characteristics and drug resistance of Pseudomonas aeruginosa in patients with agranulocytosis and fever in Shanghai, China. This study revealed that, among these 109 strains of P. aeruginosa , they were mainly found in patients with acute myelocytic leukemia (AML; 48 strains, 44.04%) and patients with acute lymphocytic leukemia (ALL; 36 strains, 33.03%). The specimen sources were mainly respiratory tract secretions (58 strains, 53.21%) and blood (21 strains, 19.26%). The P. aeruginosa isolates from neutropenic sepsis patients showed high sensitivity to the following antibiotics: piperacillin/tazobactam, cefepime, ciprofloxacin, ceftazidime, and amikacin with 91.1%, 89%, 89%, 87.9%, and 85.7% of isolates being sensitive, respectively. Furthermore, for P. aeruginosa isolates from the AML group of patients, the lowest antibiotic resistance rates were seen for ciprofloxacin (0%), cefoperazone/sulbactam (2.1%), and cefepime (7.1%), while for the ALL group the lowest antibiotic resistance rates were seen for piperacillin (2.8%), ceftazidime (2.8%), and cefepime (2.8%). Isolates from AML patients (21.3%) were significantly more likely to be piperacillin resistant than those from the ALL patients (2.8%). Therefore, P. aeruginosa infection is relatively common in patients with agranulocytosis and fever. The strains had a certain degree of resistance to commonly used antibiotics.

Background: Several inflammatory factors have been demonstrated with diagnostic or prognostic value in patients with ischemic cardiomyopathy (ICM). Interleukin 34 (IL-34), an additional ligand of colony stimulating factor-1 receptor (CSF-1R), has been identified as a biomarker of coronary artery disease (CAD) and chronic kidney disease (CKD). However, the potential effect of IL-34 in ICM remains unknown.Methods: Serum IL-34 levels were detected in 360 subjects with ICM and in 465 subjects without ICM; the latter group included 233 controls without CAD and 232 patients with CAD and normal cardiac function. Uni- and multivariable logistic regression analyses were conducted to analyze the relationship between IL-34 and ICM.Results: IL-34 levels were significantly increased in patients with ICM compared with both groups of subjects without ICM (122.52 ± 115.30 vs. 95.02 ± 101.43 vs. 82.57 ± 84.24 pg/ml, respectively; P < 0.001). Moreover, serum IL-34 level was significantly positively correlated to NT-proBNP level (r = 0.223, P < 0.001), left ventricular end diastolic diameter and New York Heart Association (NYHA) functional class, indicating that a higher IL-34 level reflects more severe heart failure (HF). Multivariable regression analyses revealed that IL-34 was remarkably associated with the presence and severity of ICM after adjusting for age, sex, conventional risk factors as well as medication [odds ratio (OR): 1.501, 95% confidence interval (CI): 1.249–1.803, P < 0.001, per SD increase]. The predictive value of IL-34 value remained significant in patients already diagnosed with CAD.Conclusion: Increased IL-34 levels are relevant to the presence and severity of ischemic HF in all subjects and in patients with CAD. IL-34 may be used as a novel clinical biomarker of ICM with predictive value.

We generated a library of ~1000 Drosophila stocks in which we inserted a construct in the intron of genes allowing expression of GAL4 under control of endogenous promoters while arresting transcription with a polyadenylation signal 3’ of the GAL4. This allows numerous applications. First, ~90% of insertions in essential genes cause a severe loss-of-function phenotype, an effective way to mutagenize genes. Interestingly, 12/14 chromosomes engineered through CRISPR do not carry second-site lethal mutations. Second, 26/36 (70%) of lethal insertions tested are rescued with a single UAS-cDNA construct. Third, loss-of-function phenotypes associated with many GAL4 insertions can be reverted by excision with UAS-flippase. Fourth, GAL4 driven UAS-GFP/RFP reports tissue and cell-type specificity of gene expression with high sensitivity. We report the expression of hundreds of genes not previously reported. Finally, inserted cassettes can be replaced with GFP or any DNA. These stocks comprise a powerful resource for assessing gene function.

Background: We investigated whether and to what extent the ratio between circulating fibrinogen (Fg) and its degradation products (FDP) reflects the severity of coronary artery disease (CAD) in type 2 diabetic patients. Methods: Plasma levels of Fg and FDP were determined, and Fg/FDP ratio was calculated in 344 consecutive patients with type 2 diabetes and chest pain on exertion undergoing coronary angiography. The severity of CAD was evaluated by the number of significant CAD (>50% luminal diameter narrowing) and Gensini score. Results: Plasma Fg was higher, but Fg/FDP ratio was lower in patients with significant CAD (n = 255) compared with those without (n = 89), due to a disproportionate increase in FDP. Fg and FDP correlated positively, while Fg/FDP ratio negatively, with the number of diseased coronary arteries and the tertile of Gensini score (all P values for trend < 0.01). After adjusting for age, sex, risk factors for CAD, lipid profiles, glycosylated hemoglobin A1c, creatinine, leukocyte count, and high-sensitivity C-reactive protein, Fg/FDP ratio remained an independent determinant for multivessel coronary disease (MVD) (odds ratio [OR], 0.869; 95% confidence interval [CI], 0.788-0.958, P = 0.005) and high tertile of Gensini score (OR, 0.797, 95% CI, 0.682-0.930, P = 0.004). The area under the curve of Fg/FDP ratio was larger than that of Fg for predicting the presence of MVD (0.647 vs. 0.563, P = 0.048) and Gensini score ≥ 30 (0.656 vs. 0.538, P = 0.026). Conclusions: Elevated plasma Fg and FDP level and reduced Fg/FDP ratio are associated with presence of CAD, and Fg/FDP ratio is superior to Fg in reflecting severe coronary atherosclerosis for patients with type 2 diabetes.

ObjectiveInflammation plays a central role in the pathogenesis of metabolic syndrome (MetS). Cyclophilin B (CypB) can be constitutively secreted in response to inflammatory stimuli and oxidative stress, participating in tissue or systemic inflammation. We investigated the relationship between CypB and MetS in both humans and mice.MethodsSerum CypB levels were determined in 211 subjects with MetS and 292 subjects without MetS (non-MetS) (133 healthy controls and 159 high-risk subjects with one to two MetS components). Additionally, CypB expression in metabolic organs was examined in mice fed with high-fat diet (HFD) and genetically obese (ob/ob) mice.ResultsSerum CypB level was significantly higher in MetS subjects compared with both groups of non-MetS subjects (193.80 ± 83.22 vs. 168.38 ± 65.01 vs. 124.26 ± 47.83 ng/mL, P 60 years old with higher CypB levels were more likely to have MetS, and the risk for MetS was higher and more significant in women compared with men. Additionally, CypB expression levels were lower at baseline and dramatically enhanced in metabolic organs (such as the liver) and visceral and subcutaneous adipose tissue from HFD-induced obese mice and ob/ob mice.ConclusionIncreased CypB levels were significantly and independently associated with the presence and severity of MetS, indicating that CypB could be used as a novel biomarker and clinical predictor of MetS.

BackgroundRenal dysfunction, commonly associated with cardiac dysfunction, has predictive value for adverse long‐term outcomes in heart failure (HF). We previously identified a novel renal biomarker, interleukin‐34 (IL‐34), elevated in HF patients and associated with kidney dysfunction and coronary artery disease during HF. However, the prognostic value of IL‐34 in HF remains unclear, so that the present study aimed to determine it. Methods and ResultsThis prospective, observational study included 510 consecutive HF patients with their serum IL‐34 as well as other variables measured at baseline, and they were followed up for 2 years. The primary end point was a composite of cardiovascular death or a first HF hospitalization, with cardiovascular death, HF hospitalization, and all‐cause mortality as secondary outcomes. There was a significant and gradual increase in risk as IL‐34 increased, determined by log‐rank tests with Kaplan–Meier curves. Serum IL‐34 was also a significant prognostic predictor of the primary end point (1.301 [1.115–1.518]; P=0.001), cardiovascular death (1.347 [1.096–1.655]; P=0.005), HF hospitalization (1.234 [1.018–1.494]; P=0.032), and all‐cause mortality (1.343 [1.115–1.618]; P=0.002) in HF as per SD increase in the log IL‐34 level after adjusting for age, sex, traditional risk factors, and N‐terminal pro‐brain natriuretic peptide. Especially, IL‐34 had a more‐significant prognostic value in HF patients with kidney impairment than those without. ConclusionsIL‐34 is a significant predictor of cardiovascular death, HF hospitalization, and all‐cause mortality in chronic HF, especially when concomitant with renal dysfunction. Serum IL‐34 measurement may provide new insights linking kidney impairment to poor HF outcomes beyond other renal markers.

Recent studies have established SIRT1 as an important regulator of lipid metabolism, although the mechanism of its action at the molecular level has not been revealed. Here, we show that knockdown of SIRT1 with the help of small hairpin RNA decreases basal and isoproterenol-stimulated lipolysis in cultured adipocytes. This effect is attributed, at least in part, to the suppression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase (ATGL), at the level of transcription. Mechanistically, SIRT1 controls acetylation status and functional activity of FoxO1 that directly binds to the ATGL promoter and regulates ATGL gene transcription. We have also found that depletion of SIRT1 decreases AMP-dependent protein kinase (AMPK) activity in adipocytes. To determine the input of AMPK in regulation of lipolysis, we have established a stable adipose cell line that expresses a dominant-negative α1 catalytic subunit of AMPK under the control of the inducible TET-OFF lentiviral expression vector. Reduction of AMPK activity does not have a significant effect on the rates of lipolysis in this cell model. We conclude, therefore, that SIRT1 controls ATGL transcription primarily by deacetylating FoxO1.

Given the diversity of autophagy targets and regulation, it is important to characterize autophagy in various cell types and conditions. We used a primary myocyte cell culture system to assay the role of putative autophagy regulators in the specific context of skeletal muscle. By treating the cultures with rapamycin (Rap) and chloroquine (CQ) we induced an autophagic response, fully suppressible by knockdown of core ATG genes. We screened D. melanogaster orthologs of a previously reported mammalian autophagy protein-protein interaction network, identifying several proteins required for autophagosome formation in muscle cells, including orthologs of the Rab regulators RabGap1 and Rab3Gap1. The screen also highlighted the critical roles of the proteasome and glycogen metabolism in regulating autophagy. Specifically, sustained proteasome inhibition inhibited autophagosome formation both in primary culture and larval skeletal muscle, even though autophagy normally acts to suppress ubiquitin aggregate formation in these tissues. In addition, analyses of glycogen metabolic genes in both primary cultured and larval muscles indicated that glycogen storage enhances the autophagic response to starvation, an important insight given the link between glycogen storage disorders, autophagy, and muscle function.

The asymmetric unit of the title compound, C17H23NO, contains two independent molecules. In both molecules, the hydroxy group is involved in the formation of an intramolecular O—H...N hydrogen bond. In the crystal, there are two crystallographically independent chains of the molecules propagating along the c axis and formed by weak intermolecular N—H...O hydrogen bonds.