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Flying fishes, which use their wing-like pectoral fins and hypocercal caudal fin to glide through the air to avoid underwater predators, have independently evolved flight behavior, making them ideal for the study of adaptive evolution. To investigate the adaptation of flight behavior in flying fishes and the origin of Beloniformes fishes, this study obtained the complete mitochondrial genomes of Cheilopogon nigricans and Oxyporhamphus micropterus and constructed the DNA sequences extracted from these newly sequenced mitochondrial genomes with the DNA sequences of 32 previously published mitochondrial genomes into a dataset for reconstructing the phylogenetic relationships of Beloniformes fishes. The phylogeny that emerged strongly supported the possibility that flying fishes developed from halfbeaks and the progressive transition of flying fishes from two-wing to four-wing gliding. The divergence time analysis showed that the split between the suborder Belonidei and the family Adrianichthyidae occurred roughly 77.08 Mya, which fell within the period of evolution of the Indian plate in the late Cretaceous. Selection analyses revealed that flying fishes have a lower dN/dS ratio than the other members of Beloniformes, indicating that flying fishes experienced stronger purifying selection to eliminate deleterious mutations to maintain efficient energy metabolism to adapt to flight behavior. Moreover, this work found the positively selected signal in the ND4 gene, suggesting that different mitogenomic genes might have undergone different selective patterns during adaptive evolution.

Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.

Chimeric antigen receptor-T (CAR-T) cell therapy based on functional immune cell transfer is showing a booming situation. However, complex manufacturing processes, high costs, and disappointing results in the treatment of solid tumors have limited its use. Encouragingly, it has facilitated the development of new strategies that fuse immunology, cell biology, and biomaterials to overcome these obstacles. In recent years, CAR-T engineering assisted by properly designed biomaterials has improved therapeutic efficacy and reduced side effects, providing a sustainable strategy for improving cancer immunotherapy. At the same time, the low cost and diversity of biomaterials also offer the possibility of industrial production and commercialization. Here, we summarize the role of biomaterials as gene delivery vehicles in the generation of CAR-T cells and highlight the advantages of in-situ construction in vivo. Then, we focused on how biomaterials can be combined with CAR-T cells to better enable synergistic immunotherapy in the treatment of solid tumors. Finally, we describe biomaterials’ potential challenges and prospects in CAR-T therapy. This review aims to provide a detailed overview of biomaterial-based CAR-T tumor immunotherapy to help investigators reference and customize biomaterials for CAR-T therapy to improve the efficacy of immunotherapy.

Background: Immune cell death (ICD) is a type of tumor cell death that has recently been shown to activate and regulate tumor immunity. However, the role of ICD-related long non-coding RNAs (lncRNAs) in gastric cancer remains to be clarified.Methods: We obtained 375 tumor samples from the Cancer Genome Atlas (TCGA) database and randomly assigned them to training and verification groups. LASSO and Cox regression analysis were utilized to identify ICD-related lncRNAs and establish a risk model. The changes in the immune microenvironment of the two groups were compared by examining the tumor-infiltrating immune cells.Results: We established a tumor signature based on nine ICD-related lncRNAs. In light of the receiver operating characteristic and Kaplan–Meier curves, the prognostic values of this risk model were verified. Multivariate regression analysis showed that the risk score was an independent risk factor for the prognosis of patients in both the training cohort (HR 2.52; 95% CI: 1.65–3.87) and validation cohort (HR 2.70; 95% CI: 1.54–4.8). A nomogram was developed to predict the 1-, 3-, and 5-year survival of patients with gastric cancer, and the signature was linked to high levels of immunological checkpoint expression (B7-H3, VSIR).Conclusions: An ICD-related lncRNA signature could predict the immune response and prognosis of patients with gastric cancer. This prognostic signature could be employed to independently monitor the efficacy of immunotherapy for gastric cancer patients.

Abstract Despite the application of conventional strategies including chemotherapy, radiotherapy, surgery, or immunotherapy, the mortality of gastric cancer (GC) patients remains high. Often, GC is not diagnosed until it has reached late stage, resulting in a missed surgical window. Therefore, a new therapeutic intervention for GC is necessary. Here, the combined application of Kuwanon‐A (KA) and 5‐fluorouracil (5‐FU) was evaluated for its potential to combat GC for the first time. To determine the anticancer activity of KA (from Morus alba) along with 5‐FU against GC, and their mechanism via GADD153, we examained anticancer potential of KA along with 5‐FU via in vitro assays with GC cells, namely MKN‐45, SGC‐7901, HGC‐27, and BGC‐823, and in vivo assays with mouse xenograft of GC. KA alone could induce G2/M phase arrest and apoptosis in GC cells by activating GADD153 through the PERK/elF2α/ATF4 and IRE1/XBP1 signaling pathways, suggesting a critical role of increased endoplasmic reticulum stress in KA‐induced apoptosis of GC cells. Moreover, the combination of KA and 5‐FU showed an enhanced synergistic anticancer effect against GC both in vitro and in vivo. Conclusively, the combination of KA and 5‐FU can act as an effective anticancer regimen in combating GC.

In this research, a dielectric barrier discharge (DBD) reactor is used to study the cracking of the toluene into C1–C6 hydrocarbons. The combined effect of parameters such as temperature (20–400 °C) and plasma power (10–40 W) was investigated to evaluate the DBD reactor performance. The main gaseous products from the decomposition of toluene include lower hydrocarbon (C1–C6). The cracking of toluene increases with power at all temperatures (20–400 °C). On the otherhand, it decreases from 92.8 to 73.1% at 10 W, 97.2 to 80.5% at 20, 97.5 to 86.5% at 30 W, and 98.4 to 93.7% at 40 W with raising the temperature from 20 to 400 °C. Nonetheless, as the temperature and plasma input power increase, the methane yield increases. At 40 W, the maximum methane yield was 5.1%. At 10 and 20 W, the selectivity to C2 increases as the temperature rises up to 400 °C. At 30 and 40 W, it began to drop after 300 °C due to the formation of methane and the yield of methane increases significantly beyond this temperature.

Autophagy is a self-recycling and conserved process, in which the senescent cytoplasmic components are degraded in cells and then recycled to maintain homeostatic balance. Emerging evidence has suggested the involvement of autophagy in oncogenesis and progression of various cancers, such as ovarian cancer (OC). Meanwhile, the non-coding RNAs (ncRNAs) frequently regulate the mRNA transcription and other functional signaling pathways in cell autophagy, displaying promising roles in human cancer pathogenesis and therapeutic response. This article mainly reviews the cutting-edge research advances about the interactions between ncRNAs and autophagy in OC. This review not only summarizes the underlying mechanisms of dynamic ncRNA-autophagy association in OC, but also discusses their prognostic implications and therapeutic biomarkers. The aim of this review was to provide a more in-depth knowledge framework exploring the ncRNA-autophagy crosstalk and highlight the promising treatment strategies for OC patients.

Discoidin domain receptors (DDRs) are receptor tyrosine kinases on the membrane surface that bind to extracellular collagens, but they are rarely expressed in normal liver tissues. Recent studies have demonstrated that DDRs participate in and influence the processes underlying premalignant and malignant liver diseases. A brief overview of the potential roles of DDR1 and DDR2 in premalignant and malignant liver diseases is presented. DDR1 has proinflammatory and profibrotic benefits and promotes the invasion, migration and liver metastasis of tumour cells. However, DDR2 may play a pathogenic role in early-stage liver injury (prefibrotic stage) and a different role in chronic liver fibrosis and in metastatic liver cancer. These views are critically significant and first described in detail in this review. The main purpose of this review was to describe how DDRs act in premalignant and malignant liver diseases and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for cancer treatment and accelerate translation from bench to bedside.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

As a confirmed carcinogen, Helicobacter pylori (H. pylori) is the main cause of inflammatory diseases of the upper digestive tract and even gastric cancer. There is a high prevalence of H. pylori infection among the elderly population, which may cause adverse clinical outcomes. Particularly noteworthy is that guidelines or expert consensus presently available on H. pylori infection overlook the management of the elderly population as a special group. A brief overview of H. pylori in the elderly is as follows. The detection of H. pylori infection can be divided into invasive and non-invasive techniques, and each technique has its advantages and shortcomings. There may be more side effects associated with eradication treatment in elderly individuals, especially for the frail population. Physical conditions and risk-benefit assessments of the elderly should be considered when selecting therapeutic strategies for H. pylori eradication. Unless there are competing factors, elderly patients should receive H. pylori eradication regimens to finally reduce the formation of gastric cancer. In this review, we summarize the latest understanding of H. pylori in the elderly population to provide effective managements and treatment measures.

Objectives: Hip inflammation is one of the most common complications in patients with spondyloarthritis (SpA). Herein, we employed use of a deep learning-based magnetic resonance imaging (MRI) evaluation model to identify irregular and multiple inflammatory lesions of the hip.Methods: All of the SpA patients were enrolled at the Xijing Hospital. The erythrocyte sediment rate (ESR), C-reactive protein (CRP), hip function Harris score, and disease activity were evaluated by clinicians. Manual MRI annotations including bone marrow edema (BME) and effusion/synovitis, and a hip MRI scoring system (HIMRISS) assessment was performed by experienced musculoskeletal radiologists. The segmentation accuracies of four deep learning models, including U-Net, UNet++, Attention-Unet, and HRNet, were compared using five-fold cross-validation. The clinical agreement of U-Net was evaluated with clinical symptoms and HIMRISS results.Results: A total of 1945 MRI slices of STIR/T2WI sequences were obtained from 195 SpA patients with hip involvement. After the five-fold cross-validation, U-Net achieved an average segmentation accuracy of 88.48% for the femoral head and 69.36% for inflammatory lesions, which are higher than those obtained by the other three models. The UNet-score, which was calculated based on the same MRI slices as HIMRISS, was significantly correlated with the HIMRISS scores and disease activity indexes (p values

Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.

Whole genome duplication (WGD) and tandem duplication (TD) are important modes of gene amplification and functional innovation, and they are common in plant genome evolution. We analyzed the genomes of three Solanaceae species (Solanum lycopersicum, Capsicum annuum, and Petunia inflata), which share a common distant ancestor with Vitis vinifera, Theobroma cacao, and Coffea canephora but have undergone an extra whole genome triplication (WGT) event. The analysis was used to investigate the phenomenon of tandem gene evolution with (S. lycopersicum) or without WGT (V. vinifera). Among the tandem gene arrays in these genomes, we found that V. vinifera, which has not experienced the WGT event, retained relatively more and larger tandem duplicated gene (TDG) clusters than the Solanaceae species that experienced the WGT event. Larger TDG clusters tend to be derived from older TD events, so this indicates that continuous TDGs (absolute dosage) accumulated during long-term evolution. In addition, WGD and TD show a significant bias in the functional categories of the genes retained. WGD tends to retain dose-sensitive genes related to biological processes, including DNA-binding and transcription factor activity, while TD tends to retain genes involved in stress resistance. WGD and TD also provide more possibilities for gene functional innovation through gene fusion and fission. The TDG cluster containing the tomato fusarium wilt resistance gene I3 contains 15 genes, and one of these genes, Solyc07g055560, has undergone a fusion event after the duplication events. These data provide evidence that helps explain the new functionalization of TDGs in adapting to environmental changes.

A new species of the genus Gammarus Fabricius, 1775 is described and illustrated from Xinjiang Uygur Autonomous Region, China. Gammarus zhouqiongi sp. nov. is characterized by pereopods III–IV with long straight setae on posterior margins; inner ramus of uropod III more than twice as long as peduncle, reaching 0.7 times the length of outer ramus; inner ramus with plumose setae, and outer ramus with both plumose setae and long simple setae. Detailed morphological comparisons with related species are discussed. The K2P distances for each marker (CO1, 16S, 28S, and EF1α) of the new species differ from those of other Gammarus species in Xinjiang. Both phylogenetic trees based on separate (CO1, 16S, 28S, and EF1α) and combined (CO1+16S+28S+EF1α) markers show that the new species is an independent branch. A key to identify Gammarus species in Xinjiang is provided.

The Pearl River Estuary (PRE), an important place provides natural spawning ground and migration channel to multiple fish species located in the northern South China Sea. Keeping in mind limited data available on the taxonomic diversity of fishes from this region, we compiled time-series data on fish species from the PRE collected since the 1980s, and analyze diversity at different taxonomic levels using an inclusion index at the taxonomic level, and indexes of taxonomic diversity. Species inventory includes 18 orders, 79 families and 167 genera. Average numbers of (families, genera, species), (genera, species), and (species) per order, family, and genus, (4.39, 9.28, 14.94), (2.11, 3.41), and (1.61) were recorded. An average taxonomic distinctness of 75.0, and variation in taxonomic distinctness 99.8 were calculated. Whereas, an average taxonomic distinctness reveals genetic relationships between PRE fish species to be closer than in the East China Sea continental shelf (65.7) and Daya Bay (62.2), and more distant for the Dongsha Islands (55.2). Based on the overall results of the present study it is concluded that species abundance and taxonomic diversities in the PRE reflects healthy ecosystem of PRE. [ABSTRACT FROM AUTHOR]

Despite the consensus on the constructive effect of LPSO (long-period stacking-ordered) phases, the true effect of bulk LPSO phases on strengthening and toughening in deformed magnesium alloys is still controversial. This article, which introduces the alloys Mg-8Gd-4Y-0.6Zn-0.5Zr, without bulk LPSO phases, and Mg-8Gd-4Y-1.6Zn-0.5Zr, containing bulk LPSO phases, details a systematically comparative analysis conducted to clarify the true contribution of bulk LPSO phases to the properties of as-extruded alloys. The results indicate that bulk LPSO phases significantly improve strength by refining grain sizes remarkably. But contrary to expectations, bulk LPSO phases themselves only provide a small strengthening effect and deteriorate plasticity, ascribed to the poor compatible plastic deformation of bulk LPSO phases. More importantly, this work may offer new insights into the strengthening and toughening of LPSO phases for further research and engineering applications of this series of alloys. Additionally, an example of a design strategy for Mg-Gd-Y-Zn alloys with superior strength and excellent plasticity is proposed at the end of this article.

During acute reperfusion, the expression profiles of long noncoding RNAs in adult rats with focal cerebral ischemia undergo broad changes. However, whether long noncoding RNAs are involved in neuroprotective effects following focal ischemic stroke in rats remains unclear. In this study, RNA isolation and library preparation was performed for long noncoding RNA sequencing, followed by determining the coding potential of identified long noncoding RNAs and target gene prediction. Differential expression analysis, long noncoding RNA functional enrichment analysis, and co-expression network analysis were performed comparing ischemic rats with and without ischemic postconditioning rats. Rats were subjected to ischemic postconditioning via the brief and repeated occlusion of the middle cerebral artery or femoral artery. Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of differentially expressed long noncoding RNAs after ischemic postconditioning in a rat model of ischemic stroke. The results showed that ischemic postconditioning greatly affected the expression profile of long noncoding RNAs and mRNAs in the brains of rats that underwent ischemic stroke. The predicted target genes of some of the identified long noncoding RNAs (cis targets) were related to the cellular response to ischemia and stress, cytokine signal transduction, inflammation, and apoptosis signal transduction pathways. In addition, 15 significantly differentially expressed long noncoding RNAs were identified in the brains of rats subjected to ischemic postconditioning. Nine candidate long noncoding RNAs that may be related to ischemic postconditioning were identified by a long noncoding RNA expression profile and long noncoding RNA-mRNA co-expression network analysis. Expression levels were verified by quantitative real-time reverse transcription-polymerase chain reaction. These results suggested that the identified long noncoding RNAs may be involved in the neuroprotective effects associated with ischemic postconditioning following ischemic stroke. The experimental animal procedures were approved by the Animal Experiment Ethics Committee of Kunming Medical University (approval No. KMMU2018018) in January 2018.

Abstract Background Aortic valve replacement (AVR) for chronic aortic regurgitation (AR) with a severe dilated left ventricle and dysfunction leads to left ventricle remodeling. But there are rarely reports on the left ventricle reverse remodeling (LVRR) after AVR. This study aimed to investigate the LVRR and outcomes in chronic AR patients with severe dilated left ventricle and dysfunction after AVR. Methods We retrospectively analyzed the clinical datum of chronic aortic regurgitation patients who underwent isolated AVR. The LVRR was defined as an increase in left ventricular ejection fraction (LVEF) at least 10 points or a follow-up LVEF ≥ 50%, and a decrease in the indexed left ventricular end-diastolic diameter of at least 10%, or an indexed left ventricular end-diastolic diameter ≤ 33 mm/m2. The changes in echocardiographic parameters after AVR, survival analysis, the predictors of major adverse cardiac events (MACE), the association between LVRR and MACE were analyzed. Results Sixty-nine patients with severe dilated left ventricle and dysfunction underwent isolated AVR. LV remodeling in 54 patients and no LV remodeling in 15 patients at 6–12 months follow-up. The preoperative left ventricular dimensions and volumes were larger, and the EF was lower in the LV no remodeling group than those in the LV remodeling group (all p

The decline of coral reefs and their fish has attracted worldwide attention. The South China Sea is the important center of coral reefs. Reef-fish is a crucial component in coral reef ecosystem. However, studies on the long-term variation in the biololgy of coral reef fish in the South China Sea are very lacking. To enhance our understanding of variation in reef fish biology in the South China Sea, we investigated long-term changes in some biological indicators of three dominant coral reef fishes (Lutjanus kasmira, Gnathodentex aureolineatus, and Cephalopholis urodeta) at the Yongshu Reef of the South China Sea between 1998–1999 and 2016–2019, and examined the effects of fishing and sea surface temperature on their biology. Compared with 1998–1999, average body length, average body mass, large fish indicator, feeding level and relative fatness of Lutjanus kasmira and Gnathodentex aureolineatus decreased in 2016–2019, but Cephalopholis urodeta did not. The relative fatness was positively correlated with the feeding level, which indicated that the decline of feeding level decreased the relative fatness. Fishing had the most important negative impact on biological changes. In the past two decades, Lutjanus kasmira had the most obvious decline in size and relative fatness, followed by Gnathodentex aureolineatus, but Cephalopholis urodeta had almost no decline. We hypothesized that different coral reef fishes have different abilities to maintain population stability under external pressures, and the differences in vulnerability of three fish species were the main reasons for their different responses to external pressures. To promote the conservation of coral reef fish, we recommend taking rigorous management to protect habitat.

BackgroundThe gut-brain axis has been potentially proposed as a link between the intake of fermented dairy foods and depression. We carried out this meta-analysis on published cohort studies to estimate the overall depression risk of fermented dairy foods intake.MethodsWe searched the CNKI (China National Knowledge Infrastructure) and PubMed databases for all articles within a range of published years from 2010 to 2022 on the association between fermented dairy foods intake and depression.ResultsFinally, 8 studies met the inclusion criteria for this study, with 83,533 participants. Overall, there was statistical evidence of significantly decreased depression risk was found to be associated with fermented dairy foods intake (OR = 0.89, 95% CI = 0.81-0.98). In subgroup analysis, cheese and yogurt consumptions were significantly associated with decreased depression risk (OR = 0.91, 95% CI = 0.84-0.98 for cheese and OR = 0. 84, 95% CI = 0.72-0.99 for yogurt). However, we failed to find superabundant intake of fermented dairy foods intake decreased the risk of depression.ConclusionOur meta-analysis indicated that fermented dairy foods intake may have potential beneficial effect on depression via the gut-brain axis.

Data reconstruction and data denoising are two critical preliminary steps in seismic data processing. Compressed Sensing states that a signal can be recovered by a series of solving algorithms if it is sparse in a transform domain, and has been well applied in the field of reconstruction, when, sparse representation of seismic data is the key point. Considering the complexity and diversity of seismic data, a single mathematical transformation will lead to incomplete sparse expression and bad restoration effects. Morphological Component Analysis (MCA) decomposes a signal into several components with outstanding morphological features to approximate the complex internal data structure. However, the representation ability of combined dictionaries is constrained by the number of dictionaries, and cannot be self-adaptively matched with the data features. Dictionary learning overcomes the limitation of fixed base function by training dictionaries that are fully suitable for processed data, but requires huge amount of time and considerable hardware cost. To solve the above problems, a new dictionary library (K-Singluar Value Decomposition learning dictionary and Discrete Cosine Transform dictionary) is hereby proposed based on the efficiency of fixed base dictionary and the high precision of learning dictionary. The self-adaptive sparse representation is achieved under the Morphological Component Analysis framework and is successfully applied to the reconstruction and denoising of seismic data. Real data tests have proved that the proposed method performs better than single mathematical transformation and other combined dictionaries.

Skipjack tuna (Katsuwonus pelamis) is a highly migratory species of significant value in global marine fisheries. The South China Sea (SCS) is the largest marginal sea in the northwestern Pacific Ocean, and many tuna and tuna-like species occur within it. Although a recent Western and Central Pacific Fisheries Commission report identified skipjack tuna in the western and central Pacific to be sustainably fished, the exploitation status of skipjack tuna in the SCS is still unclear, due to limited data. We apply two data-poor methods, length-based Bayesian biomass estimation (LBB) and length-based spawning potential ratio (LBSPR), to assess the status of skipjack tuna stock in the SCS. We use electronic length frequency analysis to estimate von Bertalanffy growth parameters (asymptotic length Linf and growth coefficient K) to serve as priors for LBB and LBSPR estimation. Estimates are calculated for SCS skipjack tuna Linf (68.3 cm), K (0.325 year−1), natural mortality (0.49 year−1) and mean fork length at 50% sexual maturity (36.7 cm). LBB analysis reveals the estimated relative stock size (0.29) indicates that the SCS skipjack tuna stock maybe heavily overfished. LBSPR analysis reveals the estimated spawning potential ratio for this fishery to be 3%, which is significantly below the limit reference point of 20%. Accordingly, for the SCS skipjack tuna stock we identify a need to reduce fishing mortality by controlling fishing effort and increasing catchable size.

Kimura's disease (KD) is a rare chronic progressive immune inflammatory disease. The etiology is unknown and manifests as a chronic inflammatory process, which is more common in young Asian men. The clinical manifestations are painless subcutaneous swelling of the head and neck and periauricular lymphadenopathy, which is slow growing and has a benign course. KD may involve the kidney, and pathological examination revealed eosinophil infiltration in the renal tissue. Proteinuria has been reported in 12–16% of KD cases, and about 60–70% of KD patients will develop nephrotic proteinuria. KD is easily confused with nephrotic syndrome, because KD does not have specific clinical manifestations, laboratory and imaging, and early misdiagnosis is easy. We report a case of KD that was biopsy-proven to have minimal lesion glomerulopathy after ~11 years. In this report, we describe a clinical case of KD with nephrotic syndrome, but there's no eosinophil infiltration in the kidneys. The clinical manifestations of KD recurrence were bilateral eyelid edema, bilateral lower limb swelling, and massive proteinuria in response to mycophenolate mofetil treatment (1.5 g).

Background: A high-dose proton pump inhibitor (PPI)-amoxicillin dual therapy has been investigated for treatment of patients with Helicobacter pylori ( H. pylori ) infection. Currently, the efficacy of this dual therapy remains inconclusive, with controversial findings from various single-center clinical trials. Objectives: To assess the efficacy and safety of high-dose dual therapy (HDDT) compared with the bismuth-containing quadruple therapy (BQT) in treatment-naive patients with H. pylori infection. Design: A multicenter, open-label, randomized controlled clinical trial. Methods: Three hundred and forty treatment-naïve patients with H. pylori infection were prospectively recruited from seven participating hospitals. The enrolled patients were randomized into one of two treatment groups: the HDDT group (esomeprazole, 20 mg four times daily; amoxicillin, 750 mg four times daily) and the BQT group (esomeprazole, 20 mg, twice daily; bismuth potassium citrate, 600 mg, twice daily; amoxicillin, 1 g, twice daily; metronidazole, 400 mg, four times daily). The primary outcome was eradication rate, and secondary outcomes were safety and patient compliance. Results: The eradication rates in the HDDT group versus the BQT group were 86.47% versus 87.06% on intention-to-treat (ITT) analysis, 91.88% versus 92.50% on modified ITT (MITT) analysis, and 91.77% versus 93.04% on per-protocol (PP) analysis, with no significant differences between the two groups. The patient compliance rates in the HDDT group versus the BQT group were 97.02% versus 95.86%, and no significant difference was found between the two groups. Notably, the HDDT group exhibited significantly lower incidence in the drug-induced adverse events (AEs) compared to the BQT group (16.67% versus 47.94%). Conclusion: HDDT is equally efficacious in eradicating H. pylori infection and resulted in good patient compliance and safety compared with BQT. These findings provide evidence in support of HDDT as a first-line treatment for H. pylori infection. Registration: This clinical trial was registered at The Chinese Clinical Trial Registry (trial registration number: ChiCTR2000039096).

With the rapid modernization of methods for monitoring fishing vessels, different ways of obtaining data on large-size light falling-net vessels have developed. In particular, the vessel monitoring system (VMS) may be used to track fishing activities in the South China Sea (SCS). In this study, we used VMS data to show the characterize and differences in the information transmitted when monitoring large-size falling-net fishing vessels, as well as their advantages and disadvantages. We investigated the spatial distribution of large-size light falling-net fisheries in the SCS using Beidou VMS data from 2017 to 2020. We also compared trajectories of fishing vessels from various provinces. According to these data, vessels operate in the Nansha Islands and the waters of the Pearl River Estuary, Beibu Gulf, Zhongsha, and Xisha Islands, and there is a clear seasonal pattern of fishing in the SCS. There are the differences of vessels in terms of distribution areas and ports of entry and exit. Additionally, we found the operation area of the large-size falling-net fishing vessels divided into four main fishing zones. The analysis compares the number of days of operation in the different fishing areas as well as seasonal variations. Our study shows that the operating area of large-size light falling-net vessels has extended southwards and that the number of days for which fishing vessels operate has increased compared with the last decade. Using the Beidou VMS to study the large-size light falling-net vessels in the SCS can provide more detailed scientific reference data for the SCS fisheries.

Marine ecosystems are a primary conservation concern because of the separate and synergistic effects of overfishing and climate change on their productivity and biodiversity. For the purpose of implementing ecosystem-based fisheries management, it is essential to understand how fish stocks respond to climate change in marine ecosystems, especially those that have been overexploited. The Beibu Gulf in the northwestern part of the South China Sea has long been one of China’s major fishing grounds. After the collapse of the demersal ecosystem in 1990 s, small pelagic fishes, including Japanese jack mackerel (Trachurus japonicus) and Japanese scad (Decapterus maruadsi), have occupied a more-important ecological niche in this gulf. However, insufficient research on how small pelagic fish respond to climate change creates great uncertainty for implementing the current management measures. This study used fish data of trawl surveys and environmental data to investigate possible mechanisms leading to dramatic fluctuations in small pelagic fish populations and their possible effects on the Beibu Gulf marine ecosystem. Abnormal blooms of small pelagic fish, especially T. japonicus and D. maruadsi, occurred following four La Niña events (in 2007/2008, 2010/2011, 2011/2012, and 2020/2021). Moreover, the dominant fish species shifted observably and regularly, Shannon–Wiener diversity and Pielou’s evenness decreased significantly in the northeastern coastal waters of the gulf, and the spatial pattern of the fish community was reorganized in this ecosystem. The small pelagic fish blooms in summers probably resulted from a combination of climate change, overfishing, and a summer fishing moratorium, which thereby caused a series of responses in the marine ecosystem. Fluctuations in the small pelagic fish populations after La Niña events seemed more dramatic after the collapse of demersal fish stocks. Therefore, we emphasize the need for implementing ecosystem-based, preventive, and adaptive fisheries management.

Abstract SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

Abstract Carbon dots are zero‐dimensional carbon nanomaterials with quantum confinement effects and edge effects, which have aroused great interests in many disciplines such as energy, chemistry, materials, and environmental applications. They can be prepared by chemical oxidation, electrochemical synthesis, hydrothermal preparation, arc discharge, microwave synthesis, template method, and many other methods. However, the raw materials' high cost, the complexity and environmental‐unfriendly fabrication process limit their large‐scale production and commercialization. Herein, we review the latest developments of coal‐based carbon dots about selecting coal‐derived energy resources (bituminous coal, anthracite, lignite, coal tar, coke, etc.) the developments of synthesis processes, surface modification, and doping of carbon dots. The coal‐based carbon dots exhibit the advantages of unique fluorescence, efficient catalysis, excellent water solubility, low toxicity, inexpensive, good biocompatibility, and other advantages, which hold the potentiality for a wide range of applications such as environmental pollutants sensing, catalyst preparation, chemical analysis, energy storage, and medical imaging technology. This review aims to provide a guidance of finding abundant and cost‐effective precursors, green, simple and sustainable production processes to prepare coal‐based carbon dots, and make further efforts to exploit the application of carbon dots in broader fields.

Introduction: Antibody–drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies.Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis.Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses.Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p

ObjectiveWe aimed to investigate the secular prevalence of gestational diabetes mellitus (GDM) and evaluate its adverse pregnancy outcomes among pregnant women in Hebei province, China.MethodsWe analyzed the data from the monitoring information management system for pregnant women in 22 hospitals of Hebei province, China. In this study, 366,212 individuals with singleton live births from 2014 to 2021 were included, of whom 25,995 were diagnosed with gestational diabetes. We described the incidence of common complications and further analyzed the clinical characteristics in GDM patients and the relationship between GDM and adverse pregnancy outcomes.ResultsThe top 3 pregnancy complications in Hebei province are anemia, gestational hypertension, and GDM. The average incidence of GDM was 7.10% (25,995/366,212). The incidence rate of GDM significantly increased from 2014 to 2021 (χ2trend = 7,140.663, P < 0.001). The top 3 regions with GDM incidence were Baoding (16.60%), Shijiazhuang (8.00%), and Tangshan (3.80%). The incidence of GDM in urban pregnant women (10.6%) is higher than that in rural areas (3.7%).The difference between the GDM and Non-GDM groups was statistically significant in terms of maternal age, gravidity, parity, education level, and incidence of pregnancy complications (gestational hypertension, heart diseases, and anemia) (P < 0.05). GDM individuals were at significantly increased risk of most assessed adverse pregnancy outcomes, including premature delivery, Cesarean delivery, uterine inertia, neonatal intensive care unit (NICU) admission, Apgar (activity-pulse-grimace-appearance-respiration) score at 1 min, and macrosomia (P < 0.05). The multivariate logistic regression analysis showed that GDM was an independent risk factor in terms of premature birth, Cesarean delivery, uterine inertia, placental abruption, NICU admission, and macrosomia.ConclusionThe risk of adverse pregnancy outcome in pregnant women with GDM is significantly increased. In order to reduce the occurrence of adverse pregnancy outcomes, effective interventions are needed.

Melanoma, the most aggressive and deadliest form of skin cancer, has attracted increased attention due to its increasing incidence worldwide. The Cortex Mori (CM) has long been used as a classical traditional Chinese medicine (TCM) to treat various diseases, including cancer. The bioactive components and underlying mechanisms, however, remain largely unknown. The current study aims to investigate the anti-melanoma effects of CM and potential mechanisms through combined network pharmacology and bioinformatic analyses, and validated by in vitro and in vivo experiments. We report here that CM has anti-melanoma activity both in vitro and in vivo. Furthermore, 25 bioactive compounds in CM were found to share 142 melanoma targets, and network pharmacology and enrichment analyses suggested that CM inhibits melanoma through multiple biological processes and signaling pathways, particularly the PI3K-AKT signaling inhibition and activation of apoptotic pathways, which were further confirmed by biochemical and histological examinations. Finally, partial CM-derived bioactive compounds were found to show anti-melanoma effects, validating the anti-melanoma potential of bioactive ingredients of CM. Taken together, these results reveal bioactive components and mechanisms of CM in inhibiting melanoma, providing them as potential anti-cancer natural products for the treatment of melanoma.

This research aims to develop a prognostic glioma marker based on m6A/m5C/m1A genes and investigate the potential role in the tumor immune microenvironment. Data for patients with glioma were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). The expression of genes related to m6A/m5C/m1A was compared for normal and glioma groups. Gene Ontology and Kyoto Encyclopedia of Genes and Gene enrichment analysis of differentially expressed genes were conducted. Consistent clustering analysis was performed to obtain glioma subtypes and complete the survival analysis and immune analysis. Based on TCGA, Lasso regression analysis was used to obtain a prognostic model, and the CGGA database was used to validate the model. The model-based risk scores and the hub genes with the immune microenvironment, clinical features, and antitumor drug susceptibility were investigated. The clinical glioma tissues were collected to verify the expression of hub genes via immunohistochemistry. Twenty genes were differentially expressed, Consensus cluster analysis identified two molecular clusters. Overall survival was significantly higher in cluster 2 than in cluster 1. Immunological analysis revealed statistically significant differences in 26 immune cells and 17 immune functions between the two clusters. Enrichment analysis detected multiple meaningful pathways. We constructed a prognostic model that consists of WTAP, TRMT6, DNMT1, and DNMT3B. The high-risk and low-risk groups affected the survival prognosis and immune infiltration, which were related to grade, gender, age, and survival status. The prognostic value of the model was validated using another independent cohort CGGA. Clinical correlation and immune analysis revealed that four hub genes were associated with tumor grade, immune cells, and antitumor drug sensitivity, and WTAP was significantly associated with microsatellite instability(MSI). Immunohistochemistry confirmed the high expression of WTAP, DNMT1, and DNMT3B in tumor tissue, but the low expression of TRMT6. This study established a strong prognostic marker based on m6A/m5C/m1A methylation regulators, which can accurately predict the prognosis of patients with gliomas. m6A/m5C/m1A modification mode plays an important role in the tumor microenvironment, can provide valuable information for anti-tumor immunotherapy, and have a profound impact on the clinical characteristics.

BackgroundQuantitative flow ratio (QFR) is a new functional index to assess the functional significance of coronary stenosis. While whether there is an association between QFR and transit-time flow measurement (TTFM) parameters of the target coronary artery has not been well addressed.MethodsA total of 89 patients receiving the in situ left internal thoracic artery (LITA) grafts to the left anterior descending artery (LAD), and 19 patients undergoing the saphenous vein grafts (SVG) were enrolled in this retrospective study. The QFR value of the LAD was evaluated preoperatively. According to the QFR values, patients with the LITA to the LAD bypass grafts were divided into two groups (group A1: QFR < 0.75, group A2: QFR ≥ 0.75), and SVG patients were divided into two groups (V1 group: QFR < 0.75, V2 group: QFR ≥ 0.75).ResultsIn groups A1 and A2, respectively, median graft flow (Qm) was 44 (34) mL/minute and 26.5 (30.0) ml/minute; median pulsatility index (PI) was 2.00 (1.00) and 2.65 (0.90). Significant differences were observed in Qm (P = 0.034) and PI (P = 0.030). And the correlation coefficients of the TTFM variables with QFR were Qm: r = r = −0.226, (P = 0.036), PI: r = 0.265 (P = 0.012) among the LITA to LAD population.ConclusionTTFM variables, especially the PI, of the LITA in situ graft to the LAD during Coronary artery bypass grafting (CABG) are strongly affected by preoperative QFR values. Moreover, in functionally mild coronary stenosis, the chance of competitive flow increases.

Alloys Mg-8Gd-4Y-0.6Zn-0.5Zr (referred to as 0.6Zn) without the bulk long-period stacking ordered (LPSO) phase and Mg-8Gd-4Y-1.1Zn-0.5Zr (referred to as 1.1Zn) containing the bulk LPSO phase were prepared and a series of hot compression tests were conducted to examine and evaluate the influence of the bulk LPSO phase on the thermal deformation behavior and characteristics of the Mg-Gd-Y-Zn-Zr alloy. The bulk LPSO phase affects the dynamic recrystallization behavior, resulting in differences in flow stress between two alloys under different conditions. Specifically, in the temperature range of 380~460 °C, compression at lower strain rates is beneficial for the LPSO phase to promote dynamic recrystallization, while compression at a high strain rate inhibits the dynamic recrystallization due to the severe deformation of the bulk LPSO phase to release the stress concentration instead. The increase in temperature helps the LPSO promote dynamic recrystallization. As a result, the LPSO phase promotes dynamic recrystallization at all experimental strain rates at 500 °C. Furthermore, the thermal processing maps of the 0.6Zn and 1.1Zn alloys are established, and their optimal processing windows are located at 500 °C/0.001~0.01 s−1 and 500 °C/0.01 s−1, respectively. In addition, the instability zones for the 1.1Zn alloy are much larger than that for the 0.6Zn alloy, which corresponds to the microcracks generated at the interfaces between α-Mg and bulk LPSO phases.

To better understand how fish communities respond to environmental changes under extreme climate events, we examine changes in fish communities in Beibu Gulf during strong El Niño and La Niña events. Strong La Niña and El Niño events affect the composition, abundance, and distribution of fish communities in Beibu Gulf. Fish community distribution and composition change before and after La Niña and El Niño events, and dominant species within them change with stable fishing intensity. The abundance and distribution of small pelagic fish such as Japanese jack mackerel (Trachurus japonicus) and Japanese scad (Decapterus maruadsi) are the most affected. Using a generalized additive model (GAM), we explore relationships between the abundance of T. japonicus and D. maruadsi and a suite of environmental variables. The GAM results revealed that sea surface salinity and sea surface temperature best explain changes in catch per unit effort of these two species during a La Niña event; depth, sea surface temperature, and mixed layer depth during an El Niño event. The results obtained in this study will offer support for implementing more-accurate, scientific fisheries management measures.

Abstract Many mycophagous Drosophila species have adapted to tolerate high concentrations of mycotoxins, an ability not reported in any other eukaryotes. Although an association between mycophagy and mycotoxin tolerance has been established in many Drosophila species, the genetic mechanisms of the tolerance are unknown. This study presents the inter‐ and intraspecific variation in the mycotoxin tolerance trait. We studied the mycotoxin tolerance in four Drosophila species from four separate clades within the immigrans‐tripunctata radiation from two distinct locations. The effect of mycotoxin treatment on 20 isofemale lines per species was studied using seven gross phenotypes: survival to pupation, survival to eclosion, development time to pupation and eclosion, thorax length, fecundity, and longevity. We observed interspecific variation among four species, with D. falleni being the most tolerant, followed by D. recens, D. neotestacea, and D. tripunctata, in that order. The results also revealed geographical variation and intraspecific genetic variation in mycotoxin tolerance. This report provides the foundation for further delineating the genetic mechanisms of the mycotoxin tolerance trait.

Event detection plays a crucial role in social media analysis, which usually concludes sub-event detection and correlation. In this article, we present a method for reconstructing the unfolding sub-event relations in terms of external expert knowledge. First, a Single Pass Clustering method is utilized to summarize massive social media posts. Second, a Label Propagation Algorithm is introduced to detect the sub-event according to the expert labeling. Third, a Word Mover’s Distance method is used to measure the correlation between the relevant sub-events. Finally, the Markov Chain Monte Carlo simulation method is presented to regenerate the popularity of social media posts. The experimental results show that the popularity dynamic of the empirical social media sub-events is consistent with the data generated by the proposed method. The evaluation of the unfolding model is 50.52% ∼ 88% higher than that of the random null model in the case of “Shanghai Tesla self-ignition incident.” This work is helpful for understanding the popularity mechanism of the unfolding events for online social media.

Three bottom trawl surveys over the northern continental slope in the South China Sea (18°50′–20°40′N, 112°50′–115°10′E) were carried out, in June 2015, March 2017 and September 2018, to investigate species composition, biodiversity and community structure of demersal fish. Surveys in 2015, 2017 and 2018 captured 97 fish species (representing 77 genera, 52 families, 26 orders), 108 fish species (representing 84 genera, 61 families, 19 orders) and 126 fish species (representing 105 genera, 74 families, 25 orders), respectively. Three surveys captured a total of 252 fish species, representing 164 genera, 97 families, 30 orders. Perciformes dominated. Species richness in station linking shallow continental shelf with deep slope was the lowest among stations. In three surveys, 16 species occurred in the catches of three surveys, accounting for 6.35% of all species. Species replacement rate between stations showed a significant linear relationship with the depth difference and latitude difference. Margalef’s species richness index (D), Shannon–Weiner diversity index (H’) and Pielou’s evenness index (J’) among stations ranged 2.65–6.74, 1.02–4.15 and 0.28–1.14, respectively. Differences of D, H’ and J’ were insignificant among seasons. There were significant positive linear relations between H’ and J’ and latitude. D, H’ and J’ decreased with increasing sampling depth, however the relations were not significant. Based on multivariate statistical analysis, fish community at species level was divided into five groups with average dissimilarities of 95.69%–99.96%. In terms of genus and family, average dissimilarities among groups were more than 88.11% and 82.69%. There were significant differences in species composition between depths, but no significant differences between seasons and temperatures, as well as in genus and family composition.

Abstracts Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood C max and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood–pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.