Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion.

Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with 177Lu. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [177Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.

Dimerized Nonfused Electron Acceptor Based on a Thieno[3,4-c]pyrrole-4,6-dione Core for Organic Solar Cells.

In this work, the first dimerized nonfused electron acceptor (NFEA), based on thieno[3,4-c]pyrrole-4,6-dione as the core, has been designed and synthesized. The dimerized acceptor and its single counterpart exhibit similar energy levels but different absorption spectra due to their distinct aggregation behavior. The dimerized acceptor-based organic solar cells (OSCs) demonstrate a higher power conversion efficiency of 11.05%, accompanied by enhanced thermal stability. This improvement is attributed to the enhancement of the short-circuit current density and fill factor, along with an increase in the glass transition temperature. Characterizations of exciton dynamics and film morphology reveal that a dimerized acceptor-based device possesses an enhanced exciton dissociation efficiency and a well-established charge transport pathway, explaining its improved photovoltaic performance. All these results indicate that the dimerized NFEA as a promising candidate can achieve efficiency-stability-cost balance in OSCs.

Improving new energy subsidy efficiency considering learning effect: A case study on wind power.

Subsidy policies are instrumental in driving the development of new energy. However, the effective allocation of new energy subsidies over time is challenging given fiscal constraints. This study addresses this challenge by considering the learning effect associated with the new energy industry. A two-stage dynamic programming model is proposed to capture the investment decision-making process of companies under new energy subsidy policies and government subsidy setups. Theoretical findings suggest that company investment decisions in new energy are influenced by a guiding principle: The subsidy rate should be negatively correlated with the variation rate of production scale increment (VRPSI). We calibrate this investment decision principle using wind power data from 14 countries. According to this principle, excessive subsidy rates may result in a low VRPSI, thereby diminishing future investment profitability in the new energy industry and leading to subsidy inefficiency. Upon investigating the efficiency of annual subsidy allocation, we find that the subsidy rates were potentially set too high in 2014, 2016, and 2017. Furthermore, the government should exercise caution regarding an inefficient subsidy pattern whereby companies invest in new energy only when the subsidy rate exceeds a certain threshold, neglecting traditional power sources. It is crucial to note that although this study uses wind power industry data for calibration and simulation, the theoretical model can be broadly applied to other new energy industries and emerging industries with increasing marginal net profit.

Matrine reverses the resistance of Haemophilus parasuis to cefaclor by inhibiting the mutations in penicillin-binding protein genes (ftsI and mrcA).

Introduction: Matrine (MT) is a potential resistance reversal agent. However, it remains unclear whether MT can reverse the resistance of Haemophilus parasuis (H. parasuis) to ß-lactams, and, if so, by what mechanism MT works. Methods: We screened one cefaclor (CEC)-resistant strain (clinical strain C7) from eight clinical (H. parasuis) strains and determined the underlying resistance mechanism. Then, we investigated the reversal effect of MTon the resistance of this strain to CEC. Results and Discussion: The production of ß-lactamase, overexpression of AcrAB-TolC system, and formation of biofilm might not be responsible for the resistance of clinical strain C7 to CEC. Fourteen mutation sites were found in four PBP genes (ftsI, pbp1B, mrcA, and prcS) of clinical strain C7, among which the mutation sites located in ftsI (Y103D and L517R) and mrcA (A639V) genes triggered the resistance to CEC. The minimum inhibitory concentration (MIC) of CEC against clinical strain C7 was reduced by two to eight folds after MT treatment, accompanied by the significant down-regulated expression of mutated ftsI and mrcA genes. Based on such results, we believed that MT could reverse the resistance of H. parasuis to CEC by inhibiting the mutations in ftsI and mrcA genes. Our research would provide useful information for restoring the antimicrobial activity of ß-lactams and improving the therapeutic efficacy of Glässer's disease.

Constructing a P2W18O626--Containing Hybrid Photocatalyst via Noncovalent Interactions for Enhanced H2 Production.

Polyoxometalates (POMs) have gained significant research attention because of their excellent properties in photocatalytic (PC) hydrogen production. Exploring POM-based compounds for heterogeneous photocatalysis is an ongoing task. Here, we obtain a water-insoluble inorganic-organic hybrid compound, (P2W18O62)3(C12N3H10)6(C12N3H11)6·9.5H2O (P-PW), formed by Dawson-type POM P2W18O626- (P2W18) anions and protonated 2-(pyridin-4-yl)-1H-benzo[d]imidazole (PHB) cations via noncovalent interactions. In the presence of the sacrificial agent triethanolamine, P-PW exhibits a PC H2 generation rate of 0.418 mmol/g/h, surpassing that of P2W18 and PHB by 15 and 17 times, respectively. This enhancement in PC performance of P-PW can be attributed to its band structure change from the precursor compounds, leading to increased light absorption and therefore more efficient PC hydrogen production.

Comprehensive assessment of drought resistance and recovery in kiwifruit genotypes using multivariate analysis.

As global climate change persists, ongoing warming exposes plants, including kiwifruit, to repeated cycles of drought stress and rewatering, necessitating the identification of drought-resistant genotypes for breeding purposes. To better understand the physiological mechanisms underlying drought resistance and recovery in kiwifruit, moderate (40-45% field capacity) and severe (25-30% field capacity) drought stresses were applied, followed by rewatering (80-85% field capacity) to eight kiwifruit rootstocks in this study. We then conducted a multivariate analysis of 20 indices for the assessment of drought resistance and recovery capabilities. Additionally, we identified four principal components, each playing a vital role in coping with diverse water conditions. Three optimal indicator groups were pinpointed, enhancing precision in kiwifruit drought resistance and recovery assessment and simplifying the evaluation system. Finally, MX-1 and HW were identified as representative rootstocks for future research on kiwifruit's responses to moderate and severe drought stresses. This study not only enhances our understanding of the response mechanisms of kiwifruit rootstocks to progressive drought stress and recovery but also provides theoretical guidance for reliable screening of drought-adaptive kiwifruit genotypes.

Soaking the Rare-Earth Carbonates for a Change: An Alternative Approach to Explore Carbonate Nonlinear Optical Crystals.

Alkali-metal rare-earth carbonates (ARECs) find great potential in nonlinear optical applications. As the most common method, the hydrothermal reaction is widely used in synthesizing ARECs. The black-box nature of the hydrothermal reaction makes it difficult for understanding the formation processes and therefore may slow down the pace of structural discovery. Here, by simply soaking the rare-earth carbonates in Na2CO3 solutions, we successfully obtain a series of noncentrosymmetric Na3RE(CO3)3·6H2O (RE = Tb 1, Sm 2, Eu 3, Gd 4, Dy 5, Ho 6, and Er 7) compounds without using the high-temperature hydrothermal method. The transformation process, investigated by powder X-ray diffraction and scanning electron microscopy, is governed by the concentration of the soaking solutions. Na3Tb(CO3)3·6H2O, as an example, is studied structurally, and its physical properties are characterized. It exhibits a second harmonic generation effect of 0.5 × KDP and a short UV cutoff edge of 222 nm (5.8 eV). Our study provides insights for exploring new AREC structures, which may further advance the development of carbonate nonlinear optical crystals.

Functions and novel regulatory mechanisms of key glycolytic enzymes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the pulmonary vasculature and elevated pulmonary arterial pressure, ultimately leading to right heart failure and death. Despite its clinical significance, the precise molecular mechanisms driving PAH pathogenesis warrant confirmation. Compelling evidence indicates that during the development of PAH, pulmonary vascular cells exhibit a preference for energy generation through aerobic glycolysis, known as the "Warburg effect", even in well-oxygenated conditions. This metabolic shift results in imbalanced metabolism, increased proliferation, and severe pulmonary vascular remodeling. Exploring the Warburg effect and its interplay with glycolytic enzymes in the context of PAH has yielded current insights into emerging drug candidates targeting enzymes and intermediates involved in glucose metabolism. This sheds light on both opportunities and challenges in the realm of antiglycolytic therapy for PAH.

A single cell atlas of circulating immune cells involved in diabetic retinopathy.

This study focused on examining the exact role of circulating immune cells in the development of diabetic retinopathy (DR). In vitro co-culture experiments showed that peripheral blood mononuclear cells (PBMCs) from patients with type 1 DR crucially modulated the biological functions of human retinal microvascular endothelial cells (HRMECs), consequently disrupting their normal functionality. Single-cell RNA sequencing (scRNA-seq) study revealed unique differentially expressed genes and pathways in circulating immune cells among healthy controls, non-diabetic retinopathy (NDR) patients, and DR patients. Of significance was the observed upregulation of JUND in each subset of PBMCs in patients with type 1 DR. Further studies showed that downregulating JUND in DR patient-derived PBMCs led to the amelioration of HRMEC dysfunction. These findings highlighted the notable alterations in the transcriptomic patterns of circulating immune cells in type 1 DR patients and underscored the significance of JUND as a key factor for PBMCs in participating in the pathogenesis of DR.

PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

Sast1-mediated manifold effects inhibit Plutella xylostella fertility.

BACKGROUND: Plutella xylostella (Linnaeus) is a destructive pest of cruciferous crops due to its strong reproductive capacity and extensive resistance to pesticides. Seminal fluid proteins (SFPs) are the main effective factors that determine the reproductive physiology and behaviour of both sexes. Although an increasing number of SFPs have been identified, the effects of astacins in SFPs on agricultural pests have not yet been reported. Here, we elucidated the mechanisms by which Sast1 (seminal astacin 1) regulates the fertility of Plutella xylostella (L.). RESULTS: PxSast1 was specifically expressed in the testis and accesssory gland. CRISPR/Cas9-induced PxSast1 knockout successfully constructed two homozygous mutant strains. Sast1 impaired the fertility of P. xylostella by separately regulating the reproductive capacity of males and females. Loss of PxSast1, on the one hand, significantly decreased the ability of males to mate and fertilize, mainly manifested as shortened mating duration, reduced mating competitiveness and decreased eupyrene sperm production; on the other hand, it significantly inhibited the expression of chorion genes in females, resulting in oogenesis deficits. Simultaneously, for mated females, the differentially expressed genes in signalling pathways related to oogenesis and chorion formation were significantly enriched after PxSast1 knockout. CONCLUSION: These analyses of the functions of PxSast1 as the regulator of spermatogenesis and oogenesis establish its importance in the fertility process of P. xylostella, as well as its potential as a promising target for genetic regulation-based pest control. © 2024 Society of Chemical Industry.

Effects of mindfulness-based interventions on cardiovascular risk factors: An umbrella review of systematic reviews and meta-analyses.

OBJECTIVE: Reviews have shown that mindfulness-based interventions (MBIs) were effective in improving cardiovascular risk factors (CVRFs), but the results were contradictory. This umbrella review aimed to summarize and grade the existing reviews on CVRFs associated with MBIs. METHODS: The protocol of this umbrella review had been registered in PROSPERO (CRD42022356812). PubMed, Web of science, Embase, The Cochrane Library, Scopus, Medline, PsycINFO and CINAHL were searched from database inception to 20 July 2022. The quality of evidence was assessed through GRADE. RESULTS: Twenty-seven reviews with 14,923 participants were included. Overall, 45% of reviews had low heterogeneity (I2 < 25%). For the quality of evidence, 31% were rated very low, 42% were rated low, 17% were rated moderate and 10% were rated high. MBIs significantly improved systolic blood pressure [SMD -5.53 mmHg (95% CI -7.81, -3.25)], diastolic blood pressure [SMD -2.13 mmHg (95% CI -2.97, -1.30)], smoking [Cohen's d 0.42 (95% CI 0.20, 0.64)], glycosylated hemoglobin [MD 0.01 (95% CI -0.43, -0.07)], binge eating behavior [SMD -6.49 (95% CI -10.80, -2.18)], depression [SMD -0.72 (95% CI -1.23, -0.21)] and stress [SMD -0.67 (95% CI -1.00, -0.34)]. CONCLUSIONS: In conclusion, this umbrella review provided evidence for the role of MBIs in the improvement of CVRFs.

Adjustable strength and toughness of dual cross-linked nanocellulose films via spherical cellulose as soft-phase.

Nanocellulose films possess numerous merits ascribing to their inherent biocompatibility, non-toxic and biodegradability properties. The potential for practical applications would be improved if their mechanical strength and toughness requirements could be met simultaneously. Herein, dual cross-linked nanocellulose (DC) film was fabricated by the treatments of chemical and physical cross-linking, which was mechanically superior to pure nanocellulose (CNF) films. To further increase the toughness of DC films, spherical cellulose (Sph) was incorporated into DC film (DC-Sph film), and analyzed under different humidity conditions (RH) (from 10 % to 90 %). The changes of functional groups of CNF, DC and DC-Sph films were detected by FTIR and XPS spectrum. The epichlorohydrin and Sph content were optimized, followed by the investigation of RH on the toughness of films. The highest tensile strength (146.6 ± 4.6 MPa) was obtained in DC film at 50 % RH, while the DC-Sph film showed the largest toughness (40.3 ± 3.7 kJ/m2) at 70 % RH. Furthermore, the possible toughening mechanism of DC-Sph film was also discussed.

Potential biopsychosocial factors mediating/moderating the relationship between depressive symptoms and body size among children and adolescents: A systematic review.

The prevalence of depression and obesity in the pediatric population has increased along with multiple adverse health outcomes in later life. However, the mechanisms underlying the bidirectional relationship between obesity and depression have not yet been clarified. We aim to systematically summarize the literature reporting on mediational or moderational biopsychosocial factors in the relationship between depression and body size among children and adolescents. Four electronic databases (PubMed, Web of Science, PsycINFO, and PsychArticles) were systematically searched from inception until December 23, 2021, and subsequently updated until June 9, 2023. The study protocol was registered with PROSPERO (CRD42022301475). A total of 36 unique records reporting 152,513 children and adolescents meeting the inclusion criteria were identified. The results indicate that disparate psychological variables (e.g., body image, victimization and bullying, eating disorders, and sleep problems) may mediate the bidirectional relationship between depressive symptoms and body size. Moreover, the mediational/moderational effect of biological factors has not been well established. The moderational effect of social factors was inconsistently reported. Future research should aim to identify and characterize factors that may impact the bidirectional relationship between depression and obesity to inform prevention intervention strategies for affected children and adolescents.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Stroma-associated FSTL3 is a factor of calcium channel-derived tumor fibrosis.

Hepatocellular carcinoma (HCC) is the most widespread histological form of primary liver cancer, and it faces great diagnostic and therapeutic difficulties owing to its tumor diversity. Herein, we aim to establish a unique prognostic molecular subtype (MST) and based on this to find potential therapeutic targets to develop new immunotherapeutic strategies. Using calcium channel molecules expression-based consensus clustering, we screened 371 HCC patients from The Cancer Genome Atlas to screen for possible MSTs. We distinguished core differential gene modules between varying MSTs, and Tumor Immune Dysfunction and Exclusion scores were employed for the reliable assessment of HCC patient immunotherapeutic response rate. Immunohistochemistry and Immunofluorescence staining were used for validation of predicted immunotherapy outcomes and underlying biological mechanisms, respectively. We identified two MSTs with different clinical characteristics and prognoses. Based on the significant differences between the two MSTs, we further identified Follistatin-like 3 (FSTL3) as a potential indicator of immunotherapy resistance and validated this result in our own cohort. Finally, we found that FSTL3 is predominantly expressed in HCC stromal components and that it is a factor in enhancing fibroblast-M2 macrophage signaling crosstalk, the function of which is relevant to the pathogenesis of HCC. The presence of two MSTs associated with the calcium channel phenotype in HCC patients may provide promising directions for overcoming immunotherapy resistance in HCC, and the promotion of FSTL3 expressed in stromal components for HCC hyperfibrosis may be responsible for the poor response rate to immunotherapy in Cluster 2 (C2) patients.

Lipid Metabolism and Improvement in Oilseed Crops: Recent Advances in Multi-Omics Studies.

Oilseed crops are rich in plant lipids that not only provide essential fatty acids for the human diet but also play important roles as major sources of biofuels and indispensable raw materials for the chemical industry. The regulation of lipid metabolism genes is a major factor affecting oil production. In this review, we systematically summarize the metabolic pathways related to lipid production and storage in plants and highlight key research advances in characterizing the genes and regulatory factors influencing lipid anabolic metabolism. In addition, we integrate the latest results from multi-omics studies on lipid metabolism to provide a reference to better understand the molecular mechanisms underlying oil anabolism in oilseed crops.

LLGL2 Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling via ACTN1.

Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.