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Lacto-N-fucopentaoses (LNFPs) of type I to V are representative components of human milk oligosaccharides (HMOs) and have garnered increasing attention due to their multi-functional activities. These activities include regulating intestinal flora, resisting pathogen adhesion, and promoting the development and repair of the nervous system. Due to the limited resource of HMOs, artificial synthesis of HMOs can provide an alternative pathway to circumvent this limitation. Currently, LNFPs can be produced using various methods, including biosynthesis, chemical synthesis, and enzymatic synthesis. Currently, emphasis is placed on the last two methods. Chemical synthesis-based methods typically involve strict reaction conditions, cumbersome steps, and low yields. On the other hand, enzymatic synthesis offers several advantages, including mild reaction conditions, high yield, and good selectivity. However, only a few reports have focused on in vivo fermentation as a means to produce LNFPs, despite its cost advantage. In vivo fermentation presents an opportunity to supply the key substrates for fucosyl transfer reactions, namely LNnT and GDP-Fuc, along with the required biosynthesis enzymes. Further exploration of this approach is warranted.This paper aims to review the synthesis methods of LNFPs, their functional activities, and emerging trends in their development. By evaluating the different synthesis approaches, this review seeks to contribute to the advancement of LNFPs production and utilization.

The flavor of cigar tobacco leaf determines the quality of finished cigar tobacco, and the enhancement of flavor generally relies on microbial fermentation. In this paper, the correlation between the dominant microorganisms and the main flavor substances of cigar tobacco leaves during fermentation and the correlation between the two were investigated to reveal the correlation between microorganisms and flavor and the metabolic pathways of microorganisms affecting the flavor substances. During the fermentation process, the main flavors of cigar tobacco leaves were sweet, light and grassy, with hexanal, 2,6-dimethylpyridine, nonanal, phenylacetaldehyde, naphthalene, and methyl benzoate as the main constituents, and the key microorganisms Haloferax mediterranei, Haloterrigena limicola, Candidatus Thorarchaeota archaeon SMTZ-45, the genera Methyloversatilis, Sphingomonas, Thauera, Pseudomonas, Penicillium, and Aspergillus. Correlation analysis revealed that fungi were negatively correlated with the main aroma and inhibited the main flavor substances, while bacteria were positively correlated with Benzoic acid, methyl ester in the main flavor substances, which was conducive to the accumulation of green aroma. Functional analysis revealed that the dominant bacterial population was producing aroma by metabolizing glycoside hydrolases and glycosyltransferases, performing amino acid metabolism, carbohydrate metabolism and film transport metabolism. The present study showed that the bacterial and fungal dominant microorganisms during the fermentation of cigar tobacco were influencing the production and degradation of the main flavor substances through the enzyme metabolism by the occurrence of the Merad reaction.

Leukemia encompasses a group of highly heterogeneous diseases that pose a serious threat to human health. The long-term outcome of patients with leukemia still needs to be improved and new effective therapeutic strategies continue to be an unmet clinical need. Shikonin (SHK) is a naphthoquinone derivative that shows multiple biological function includes anti-tumor, anti-inflammatory, and anti-allergic effects. Numerous studies have reported the anti-leukemia activity of SHK during the last 3 decades and there are studies showing that SHK is particularly effective towards various leukemia cells compared to solid tumors. In this review, we will discuss the anti-leukemia effect of SHK and summarize the underlying mechanisms. Therefore, SHK may be a promising agent to be developed as an anti-leukemia drug.

Objective: To rapidly assess the effectiveness, safety, economy, and applicability of Shaoma Zhijing granule (SZG) for the treatment of children with tic disorders (TD), and provide currently available best evidence for decision-makers of health policies. Methods: We conducted a rapid health technology assessment (RHTA) to explore the value of SZG. A systematic literature search in eight literature databases and on three clinical trial registration platforms was performed. The literature was screened according to eligibility criteria. The screening process and data extraction were conducted by two reviewers, and the quality of the literature was also assessed. The results were summarized, analyzed, and presented in tables or figures. Results: A total of five randomized controlled trials (RCTs) were included in this study, of which one was published in English (in the Journal of Child Psychology and Psychiatry) and four in Chinese journals. The overall risk of bias for the five RCTs was evaluated as “some concerns.” SZG monotherapy or in combination with tiapride was better than tiapride alone in improving traditional Chinese medicine (TCM) syndromes and tic symptoms, with a daily cost of ¥67.50–107.22. Adverse events were mainly related to the digestive, respiratory, and neurological systems, but all were mild. Conclusion: Overall, the current RHTA of published, peer-reviewed literature has located a small body of evidence evaluating the use of SZG for the treatment of TD in children. SZG has effects on improving TCM syndromes and tic symptoms; the daily cost is ¥67.50–107.22; and all adverse events are mild. High-quality studies with long-term follow-up should be conducted, so as to provide local evidence and consistently guide and improve scientific decision-making.

Abstract Background Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR‐LFD have not been studied in the Asian cancer population. Method Here we retrospectively analyzed the targeted sequencing data from a large cancer database. Results EGFR‐LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR‐LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal‐level and arm‐level CNV in this cohort. EGFR exon2–17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. Conclusion Our study provided valuable insights into the distribution and molecular characteristics of EGFR‐LFD, hoping to shed light on the treatment management for EGFR‐LFD carriers.

Abstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Abstract The aim of this study was to explore the feasibility of Raman spectroscopy combined with computer algorithms in the diagnosis of primary Sjögren syndrome (pSS). In this study, Raman spectra of 60 serum samples were acquired from 30 patients with pSS and 30 healthy controls (HCs). The means and standard deviations of the raw spectra of patients with pSS and HCs were calculated. Spectral features were assigned based on the literature. Principal component analysis (PCA) was used to extract the spectral features. Then, a particle swarm optimization (PSO)-support vector machine (SVM) was selected as the method of parameter optimization to rapidly classify patients with pSS and HCs. In this study, the SVM algorithm was used as the classification model, and the radial basis kernel function was selected as the kernel function. In addition, the PSO algorithm was used to establish a model for the parameter optimization method. The training set and test set were randomly divided at a ratio of 7:3. After PCA dimension reduction, the specificity, sensitivity and accuracy of the PSO-SVM model were obtained, and the results were 88.89%, 100% and 94.44%, respectively. This study showed that the combination of Raman spectroscopy and a support vector machine algorithm could be used as an effective pSS diagnosis method with broad application value.

Abstract Background Kinase domain duplications (KDDs) have recently been recognized as oncogenic mutations and possible association with drug resistance in cancers. Method Here, targeted sequencing was performed with the tumor tissue and/or plasma from 65 cancer patients with KDDs. Result Intact KDDs were identified in approximately 0.1% of the total population across multiple cancer types. EGFR KDD was first identified in colorectal cancer and breast cancer, whereas FGFR2 KDD was first identified in gastric cancer. Tumors with EGFR KDD displayed lower concurrent TP53 gene alterations (p = 0.03) and slightly higher chromosome instability (p = 0.27) compared to tumors with non‐EGFR‐KDDs. Immune pathway analysis further revealed the enrichment of the cytokine receptors pathway (93%) in the KDD carriers. Hyperprogression‐related gene mutations were identified in four cases. Conclusion Collectively, our data revealed the genomic features of KDD alterations in a multi‐cancer cohort, providing more information for the potential treatment application in the KDD carriers.

AIM: To illustrate clinicopathological features of orbital non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), and to compare the treatment outcome between postoperative radiotherapy (RT) and chemotherapy in a retrospective analysis nearly 20y. METHODS: A retrospective cohort study of 56 patients with orbital NRSTS were reviewed, 34 of whom received postoperative RT, and 22 received postoperative chemotherapy. The clinicopathological features, local recurrence, metastases, and survival data were recorded. Survival analysis was performed using the Kaplan-Meier method. RESULTS: During follow-up (111.8mo, ranged 8-233mo) for 56 patients, 19 patients of them developed local recurrence, and 7 patients developed distant metastases. Fifteen patients died during follow-up period. Overall survival rates considering the whole study group was 78.57% at 5y, and 72.16% at 10y after the initial diagnosis. Compared with chemotherapy, RT was associated with lower risk of local recurrence [hazard ratio for RT vs chemotherapy, 0.263, 95% confidence interval (CI), 0.095-0.728, P=0.0015]; with lower risk of distant metastasis (hazard ratio for RT vs chemotherapy, 0.073, 95%CI, 0.015-0.364, P=0.0014); and with lower risk of death from disease (hazard ratio for RT vs chemotherapy, 0.066, 95%CI, 0.022-0.200, P

Abstract The classification of multifocal lung adenocarcinomas (MLAs), including multiple primary lung adenocarcinomas (MPLAs) and intrapulmonary metastases (IPMs), has great clinical significance in staging and treatment determination. However, the application of molecular approaches in pN0M0 MLA diagnosis has not been well investigated. Here, we performed next‐generation sequencing (NGS) analysis in 45 pN0M0 MLA patients (101 lesion pairs) who were initially diagnosed as having MPLA by comprehensive histologic assessment (CHA). Five additional patients with intrathoracic metastases were used as positive controls, while 197 patients with unifocal lung adenocarcinomas (425 random lesion pairs) were used as negative controls. By utilizing a predefined NGS criterion, all IPMs in the positive control group could be accurately classified, whereas 13 lesion pairs (3.1%) in the negative control cohort were misdiagnosed as IPMs. Additionally, 14 IPM lesion pairs were diagnosed in the study group, with at least 7 misdiagnoses. We thus developed a refined algorithm, incorporating both NGS and histologic results, that could correctly diagnose all the known MPLAs and IPMs. In particular, all IPMs identified by the refined algorithm were diagnosed to be IPMs or suspected IPMs by CHA reassessment. The refined algorithm‐diagnosed MPLAs patients also had significantly better progression‐free survival than the refined algorithm‐diagnosed IPMs (p

Abstract This study analyses the influence of the Asian summer monsoon on volcanic aerosol transport. Realistic, altitude-resolved SO2 emissions of a middle-latitude volcanic eruption (Sarychev 2009) and a tropical volcanic eruption (Nabro 2011) were retrieved and used to initialize the simulations of the long-range transport and dispersion of the sulfate aerosol plumes. The barrier effect of the Asian summer monsoon anticyclone (ASMA) isolated the Sarychev eruption plume outside of the ASMA but constrained the Nabro eruption plume inside of the ASMA, which is most evident in the UTLS region between isotropic surfaces of 360–420 K. Meanwhile, the ASMA could transport a fraction of the plume outside of ASMA quasi-horizontally to the tropical tropopause layer along the southeastern periphery of the anticyclonic circulation, and lift the volcanic plume inside the ASMA anticyclonically across the tropopause with an ascent rate of approximately 0.8 K/day. By enhancing the meridional transport in the UTLS region and lifting volcanic aerosols across the tropopause, the ASMA significantly expanded the potential effects of volcanic eruptions.

Abstract Background Compound epidermal growth factor receptor (EGFR) mutations are less responsive to tyrosine kinase inhibitors (TKIs) than single EGFR mutations in non-small cell lung cancer (NSCLC). However, the detailed clinical characteristics and prognosis of various compound EGFR mutations remain to be elucidated. Methods We retrospectively studied the next-generation sequencing (NGS) data of treatment-naïve tumors from 1025 NSCLC patients with compound EGFR mutations, which were sub-categorized into different combinations of common mutations (19-Del and EGFR exon 21 p.L858R), rare mutations, and variants of uncertain significance (VUSs). Prognosis and drug resistance to first-line TKIs were analyzed in 174 and 95 patients, respectively. Results Compound EGFR mutations were enriched with EGFR exon 21 p.L858R and rare mutations, but not 19-Del (P

Nanotechnology-enhanced photodynamic therapy (PDT) and immunotherapy are emerging as exciting cancer therapeutic methods with significant potential for improving patient outcomes. By combining these approaches, synergistic effects have been observed in preclinical studies, resulting in enhanced immune responses to cancer and the capacity to conquer the immunosuppressive tumor microenvironment (TME). Despite challenges such as addressing treatment limitations and developing personalized cancer treatment strategies, the integration of nanotechnology-enabled PDT and immunotherapy, along with advanced photosensitizers (PSs), represents an exciting new avenue in cancer treatment. Continued research, development, and collaboration among researchers, clinicians, and regulatory agencies are crucial for further advancements and the successful implementation of these promising therapies, ultimately benefiting cancer patients worldwide.

Groundwater plays a crucial role in regulating plant growth in arid regions and has significant effects on plant physiological mechanisms. However, research on the influence of groundwater change on plant ecological stoichiometry is still limited. Therefore, this study was carried out to obtain the variations in assimilated branches and soil ecological stoichiometry of two dominant species in the Gurbantunggut Desert (Haloxylon ammodendron and Haloxylon persicum) at different groundwater depths to reveal the responses of desert plants to groundwater depth changes. The results showed that (1) H. persicum branches’ stress tolerance indicators (C:N, C:P) are higher, while nutritional indicators (N:P) are lower. The soil nutrient of H. ammodendron is richer. (2) The ecological stoichiometry varied significantly along the groundwater gradient. With the deepening of groundwater, the branches C, N and P increased, and the variation in element ratio was inconsistent. Most of the soil properties was inversely proportional to the depth of groundwater. (3) Groundwater depth was a vital environmental factor affecting the assimilated branches ecological stoichiometry. Soil properties also had a significant influence on element accumulation in assimilated branches. (4) Regulating the allocation of branches ecological stoichiometry is an adaptation of two Haloxylon species to cope with local hydrological conditions changes. These findings provide novel insights into desert plant responses to different groundwater conditions within fragile desert ecosystems and may have implications for the implementation of effective measures related to the stability and sustainability of desert ecosystems.

Abstract Background Functional mutations or polymorphisms affecting forkhead box P3 (FOXP3) can lead to their abnormal FOXP3 gene expression and/or defective Treg cells generation, thus resulting in autoimmune disease and inflammatory disorders. FOXP3 also plays a key role in Type 2 diabetes mellitus (T2DM) and its complications, because the disease usually involves chronic low-grade inflammatory disorders and is associated with long-term immune system imbalance. This study aimed to investigate the association between FOXP3 polymorphisms and the susceptibility to T2DM and type 2 diabetes nephropathy (T2DN) within the Han Chinese populations. Methods Polymorphisms in rs3761548C/A and rs2294021C/T were examined in 400 patients (which include an equal number of T2DM and T2DN groups) and 200 healthy controls using PCR-HRM and sequence analysis. Results The genotype and allelic frequencies of the two single nucleotide polymorphisms (SNPs) were significantly different in T2DM and the progression of diabetes developing to T2DN. The further gender-based evaluation showed that in female subjects, rs3761548C/A was associated with an approximately 3-fold higher threat for T2DM and 4.5-fold for T2DN, while there was no noticeable association with rs2294021C/T; in males, the promoter polymorphism showed an increased predisposition of 5.4-fold and 3.4-fold predisposition to T2DM and T2DN, respectively, while rs2294021 polymorphism could impart a nearly 2-fold risk of developing T2DN. An additional analysis of combined genotypes (rs3761548 C/A-rs2294021C/T) revealed that CC-CC and CC-CT can be considered protective combinations in the predisposition of males with diabetes towards T2DN, while AA-CC and AA-TT have the opposite effect. Conclusions This study demonstrated the possible involvement of individual and combined genetic associations of rs3761548C/A and rs2294021C/T polymorphisms with the susceptibility to diabetes and diabetic nephropathy in the Han Chinese population, as well as gender bias.

Abstract BRAF mutations are the oncogenic drivers in colorectal cancer and V600 mutations (Class1), which lead to RAS-independent active monomers, are the most common mutation types. BRAF non-V600 mutants can be further classified as RAS-independent active dimers (Class2) and RAS-dependent impaired kinase (Class3). We retrospectively reviewed the mutational profiles of 328 treatment-naïve colorectal tumors with BRAF mutations detected using capture-based hybrid next-generation sequencing targeting 400 + cancer-related genes. The clinical and genetic distinctions of patients harboring Class1/2/3 BRAF mutations were investigated, which revealed that tumors with Class1 BRAF mutations showed more unique genomic profiles than those with Class2/3 mutations. Also, by using an external dataset from cBioPortal, we demonstrated that patients with Class3 BRAF mutations had the best survival outcomes compared to the other two subgroups. These findings promoted the development of anti-BRAF strategies by distinguishing BRAF mutant subgroups.

Abstract Objective To investigate the characteristics and associations of MRI-visible perivascular spaces (PVS) with clinical progression and longitudinal cognitive decline across the Alzheimer’s disease spectrum. Methods We included 1429 participants (641 [44.86%] female) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. PVS number and grade in the centrum semiovale (CSO-PVS), basal ganglia (BG-PVS), and hippocampus (HP-PVS) were compared among the control (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups. PVS were tested as predictors of diagnostic progression (i.e., CN to MCI/AD or MCI to AD) and longitudinal changes in the 13-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 13), Mini-Mental State Examination (MMSE), memory (ADNI-MEM), and executive function (ADNI-EF) using multiple linear regression, linear mixed-effects, and Cox proportional hazards modeling. Results Compared with CN subjects, MCI and AD subjects had more CSO-PVS, both in number (p < 0.001) and grade (p < 0.001). However, there was no significant difference in BG-PVS and HP-PVS across the AD spectrum (p > 0.05). Individuals with moderate and frequent/severe CSO-PVS had a higher diagnostic conversion risk than individuals with no/mild CSO-PVS (log-rank p < 0.001 for all) in the combined CN and MCI group. Further Cox regression analyses revealed that moderate and frequent/severe CSO-PVS were associated with a higher risk of diagnostic conversion (HR = 2.007, 95% CI = 1.382–2.914, p < 0.001; HR = 2.676, 95% CI = 1.830–3.911, p < 0.001, respectively). A higher CSO-PVS number was associated with baseline cognitive performance and longitudinal cognitive decline in all cognitive tests (p < 0.05 for all). Conclusions CSO-PVS were more common in MCI and AD and were associated with cognitive decline across the AD spectrum.

Digital finance, as a new financial model, is increasingly attracting attention for its potential influence on regional innovation. By focusing on the nexus between digital finance and regional innovation efficiency, we first analyze the mechanism by which digital finance affects regional innovation efficiency, and then we empirically investigate its spatial spillover effect by employing the dynamic spatial Durbin model on the basis of a sample set of 31 Chinese provinces from 2011 to 2020. The results reveal that regional innovation efficiency had a significant spatial correlation and time dependence, globally, during the study period. Digital finance significantly contributes to regional innovation efficiency improvement, and such an effect has a significant positive spatial spillover. The spatial effect decomposition results report that the spatial spillover effect of digital finance affecting regional innovation efficiency is stronger than the direct effect. Besides, all three sub-dimensions of digital finance have spatial spillover effects, and the heterogeneity between eastern and central-western regions is mainly reflected in the spatial spillover effects of digital finance.

Abstract Background Soft‐tissue sarcoma (STS) is a rare solid malignant tumor with numerous histologic subtypes. Current studies on targeted therapy for STS are in preclinical and early‐phase trials. Genomic differences largely influence the prognosis of patients even with the same subtype. To investigate the genomic alterations (GAs) and the potential of targeted therapy in STS, we analyzed the genomic landscape, the therapeutic GAs, and biomarkers of immunotherapy in Chinese STS patients. Methods Targeted sequencing covering 425 genes was performed, from which we obtained the results of tissue samples from 351 Chinese STS patients of all ages covering different histologic subtypes. Bioinformatics analysis of altered genes with nonsynonymous mutations, copy‐number variations, and gene fusions were performed. OncoKB therapeutic GAs and relevant biomarkers including TMB, MSI, and HRD were further examined for potential targeted therapy. Results In total, 2743 GAs were identified in 330 genes with a median of 6 (1–38) per case. The top 11 frequently altered genes were: TP53, MCL1, MDM2, CDK4, MYC, CDKN2A, GNAS, RB1, ATRX, CDKN2B, and FGFR1. OncoKB defined therapeutic GAs were found in 23 genes in 43% of the patients. In general, 9.4% of the patients had high‐TMB, 2.8% had MSI, and 13.7% had HRD. A significant difference in the percentage of patients with OncoKB therapeutic GAs were observed between the most frequent two subtypes, leiomyosarcoma and liposarcoma. Altogether, 54% of the patients had the potential to respond to a targeted therapy. Conclusion This study indicated the potential efficacy of targeted therapy on many STS patients, and also provided insight for novel precision therapy. The clinical efficacy of combining targeted therapy and immunotherapy can be further investigated.

Extracellular vesicles (EVs) are secreted by both eukaryotes and prokaryotes, and are present in all biological fluids of vertebrates, where they transfer DNA, RNA, proteins, lipids, and metabolites from donor to recipient cells in cell-to-cell communication. Some EV components can also indicate the type and biological status of their parent cells and serve as diagnostic targets for liquid biopsy. EVs can also natively carry or be modified to contain therapeutic agents (e.g., nucleic acids, proteins, polysaccharides, and small molecules) by physical, chemical, or bioengineering strategies. Due to their excellent biocompatibility and stability, EVs are ideal nanocarriers for bioactive ingredients to induce signal transduction, immunoregulation, or other therapeutic effects, which can be targeted to specific cell types. Herein, we review EV classification, intercellular communication, isolation, and characterization strategies as they apply to EV therapeutics. This review focuses on recent advances in EV applications as therapeutic carriers from in vitro research towards in vivo animal models and early clinical applications, using representative examples in the fields of cancer chemotherapeutic drug, cancer vaccine, infectious disease vaccines, regenerative medicine and gene therapy. Finally, we discuss current challenges for EV therapeutics and their future development.

Abstract Background Circulating tumor DNA (ctDNA) has been proven as a marker for detecting minimal residual diseases following systemic therapies in mid-to-late-stage non-small-cell lung cancers (NSCLCs) by multiple studies. However, fewer studies cast light on ctDNA-based MRD monitoring in early-to-mid-stage NSCLCs that received surgical resection as the standard of care. Methods We prospectively recruited 128 patients with stage I–III NSCLCs who received curative surgical resections in our Lung Cancer Tempo-spatial Heterogeneity prospective cohort. Plasma samples were collected before the surgery, 7 days after the surgery, and every 3 months thereafter. Targeted sequencing was performed on a total of 628 plasma samples and 645 matched tumor samples using a panel covering 425 cancer-associated genes. Tissue clonal phylogeny of each patient was reconstructed and used to guide ctDNA detection. Results The results demonstrated that ctDNA was more frequently detected in patients with higher stage diseases pre- and postsurgery. Positive ctDNA detection at as early as 7 days postsurgery identified high-risk patients with recurrence (HR = 3.90, P

The application of predicting bus travel time with real-time information, including Global Positioning System (GPS) and Electronic Smart Card (ESC) data is effective to advance the level of service by reducing wait time and improving schedule adherence. However, missing information in the data stream is inevitable for various reasons, which may seriously affect prediction accuracy. To address this problem, this research proposes a Long Short-Term Memory (LSTM) model to predict bus travel time, considering incomplete data. To improve the model performance in terms of accuracy and efficiency, a Genetic Algorithm (GA) is developed and applied to optimise hyperparameters of the LSTM model. The model performance is assessed by simulation and real-world data. The results suggest that the proposed approach with hybrid data outperforms the approaches with ESC and GPS data individually. With GA, the proposed model outperforms the traditional one in terms of lower Root Mean Square Error (RMSE). The prediction accuracy with various combinations of ESC and GPS data is assessed. The results can serve as a guideline for transit agencies to deploy GPS devices in a bus fleet considering the market penetration of ESC.

This paper selected six representative Landsat, SPOT-5 and GF-1 satellite remote sensing images in the past 50 years between 1970 and 2018. The digital shoreline analysis system was used to analyze the change of continental shoreline in Zhejiang Province by using the area method and the baseline method. Besides, the driving force of shoreline change was also analyzed. The results showed that: (1) The seaward extension of the shoreline mainly occured in Hangzhou Bay, Xiangshan Port, Sanmen Bay, Taizhou Bay, Yueqing Bay and Oujiang Port. The reclamation area was 147 700 hectares, and the average change rate of coastline was 26.72 m/a. (2) Over the past 50 years, the continental coastline of Zhejiang Province had shown an obvious decreasing trend. The coastline had decreased by 184.27 km while the natural coastline decreased by 381.37 km and the artificial coastline increased by 197.10 km. (3) The continental coastline of Zhejiang Province was dominated by artificial coastline with the serious straightness and the decrease of natural shoreline retention. (4) Human activities such as reclamation and reclamation were the main driving factors of shoreline change.

Abstract A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.

Introduction: Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. Objectives: The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. Methods: ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. Results: PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. Conclusion: In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.

Abstract As one of the most common malignancies, gastric cancer (GC) is the third leading cause of cancer-related deaths in China. GC is asymptomatic in early stages, and the majority of GC mortality is due to delayed symptoms. It is an urgent task to find reliable biomarkers for the identification of GC in order to improve outcomes. A combination of dried blood spot sampling and direct infusion mass spectrometry (MS) technology was used to measure blood metabolic profiles for 166 patients with GC and 183 healthy individuals, and 93 metabolites including amino acids, carnitine/acylcarnitines and their derivatives, and related ratios were quantified. Multiple algorithms were used to characterize the changes of metabolic profiles in patients with GC compared to healthy individuals. A biomarker panel was identified in training set, and assessed by tenfold cross-validation and external test data set. After systematic selection of 93 metabolites, a biomarker panel consisting of Ala, Arg, Gly, Orn, Tyr/Cit, Val/Phe, C4-OH, C5/C3, C10:2 shows the potential to distinguish patients with GC from healthy individuals in tenfold cross-validation model (sensitivity: 0.8750, specificity: 0.9006) and test set (sensitivity: 0.9545, specificity: 0.8636). This metabolomic analysis makes contribution to the identification of disease-associated biomarkers and to the development of new diagnostic tools for patients with GC.

BackgroundLung cancer is the deadliest and most diagnosed type of cancer worldwide. The 5-year survival rate of lung adenocarcinoma (LUAD) dropped significantly when tumor stages advanced. Patients who received surgically resecting at the pre-invasive stage had a 5-year survival rate of nearly 100%. However, the study on the differences in gene expression profiles and immune microenvironment among pre-invasive LUAD patients is still lacking.MethodsIn this study, the gene expression profiles of three pre-invasive LUAD stages were compared using the RNA-sequencing data of 10 adenocarcinoma in situ (AIS) samples, 12 minimally invasive adenocarcinoma (MIA) samples, and 10 invasive adenocarcinoma (IAC) samples.ResultsThe high expression levels of PTGFRN (Hazard Ratio [HR] = 1.45; 95% Confidence Interval [CI]: 1.08-1.94; log-rank P = 0.013) and SPP1 (HR = 1.44; 95% CI: 1.07-1.93; log-rank P = 0.015) were identified to be associated with LUAD prognosis. Moreover, the early LUAD invasion was accompanied by the enhancement of antigen presentation ability, reflected by the increase of myeloid dendritic cells infiltration rate (Cuzick test P < 0.01) and the upregulation of seven important genes participating in the antigen presentation, including HLA-A (Cuzick test P = 0.03), MICA (Cuzick test P = 0.01), MICB (Cuzick test P = 0.01), HLA-DPA1 (Cuzick test P = 0.04), HLA-DQA2 (Cuzick test P < 0.01), HLA-DQB1 (Cuzick test P = 0.03), and HLA-DQB2 (Cuzick test P < 0.01). However, the tumor-killing ability of the immune system was inhibited during this process, as there were no rising cytotoxic T cell activity (Cuzick test P = 0.20) and no increasing expression in genes encoding cytotoxic proteins. ConclusionIn all, our research elucidated the changes in the immune microenvironment during early-stage LUAD evolution and may provide a theoretical basis for developing novel early-stage lung cancer therapeutic targets.

BackgroundEsophageal cancer (EC) is an aggressive neoplasm of the gastrointestinal tract that is usually treated with a combination of chemotherapy, radiotherapy (RT), and/or surgery, according to disease status. Despite the availability of multimodal therapeutic strategies, local recurrence is frequently observed. However, there is no standard treatment or promising therapeutic approach for local recurrence or metastatic esophageal carcinoma after the RT. This study tended to investigate the efficacy and safety of sintilimab maintenance after concurrent chemoradiotherapy (CCRT) for local/regional recurrent esophageal squamous carcinoma.MethodsThis study was a single-arm, phase Ib/II trial conducted in a single site in China. Patients previously radically treated (surgery or CCRT), histologically confirmed, local or regional recurrence esophageal squamous carcinoma, qualified for the study design, were treated with 25–28 times radiotherapy plus raltitrexed once every 3 weeks for up to two cycles. Patients who have not progressed after CCRT received sintilimab as maintenance once every 3 weeks up to 1 year. Primary endpoints were overall survival (OS) and safety. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).ResultsBetween September 2019 and March 2022, in a total of 36 enrolled patients, 34 pts completed CCRT. Three patients excluded due to violation of the exclusion criteria (1 pt) and consent withdrawal (2 pts). Finally, 33 pts were included in the final analysis, in which 3 pts had disease progression, and the remaining 30 entered maintenance therapy with sintilimab. The median follow-up time was 12.3 months. Median OS was 20.6 months (95%CI 10.5–NA) and the 1-year OS rate was 64%. Median PFS was 11.5 months (95%CI 5.29–21.3) and the 1-year PFS rate was 43.6%. The ORR was 63.6% (95%CI 44.6–77.8), including 2 cases of CR and 19 cases of PR. The DCR was 19.9%, the median DOR was 19.5 months, and the median TTR was 2.4 months. The rate of any grade TRAEs was 96.7%; ≥Grade 3 TRAE was 23.4%. The incidence of immune-related AE was 60%, most of which were grade 1–2, and only one case of thyroid-stimulating hormone increased was irAE with grade 3 or above.ConclusionSintilimab has shown promising clinical efficacy and a manageable safety profile as maintenance therapy after CCRT for local/regional recurrent esophageal squamous carcinoma. In addition, further confirmation from a large-scale real-world study is still needed.

Three severe droughts impacted the Amazon in 2005, 2010, and 2015, leading to widespread above-average land surface temperature (LST) (i.e. positive thermal anomalies) over the southern Amazon in the dry season (Aug–Sep) of these years. Below-average dry-season incoming solar radiation (SW↓) and terrestrial water storage anomaly (TWSA) were simultaneously observed in 2005 and 2010, whereas the opposite was observed in 2015. We found that anomalies in precipitation (P), SW↓, and TWSA combined can well explain dry-season thermal anomalies during these droughts (average R ^2 –0.51). We investigated the causes for opposing anomalies in dry-season SW↓ and TWSA, and found different hydro-climatological conditions preceding the drought-year dry seasons. In 2005 and 2010, P was considerably below average during the wet-to-dry transition season (May–July), causing below-average TWSA in the dry season that was favorable for fires. Increased atmospheric aerosols resulting from fires reduced solar radiation reaching the ground. In 2015, although below-average dry-season P was observed, it was above the average during the wet-to-dry transition season, leading to reduced fires and aerosols, and increased dry-season SW↓. To further examine the impact of opposite hydro-climatological processes on the drought severity, we compared dry-season LST during droughts with the maximum LST during non-drought years (i.e. LST _max ) for all grid cells, and a similar analysis was conducted for TWSA with the minimum TWSA (i.e. TWSA _min ). Accordingly, the regions that suffered from concurrent thermal and water stress (i.e. LST > LST _max and TWSA < TWSA _min ) were identified. These regions are mainly observed over the southeast in 2005 and southern Amazon in 2010. In 2015, large-scale dry-season thermal stress was found over central and southeast Amazon with little water stress. This study underlines the complex interactions of different hydro-climatological components and the importance of understanding the evolution of droughts to better predict their possible impacts on the Amazon rainforest.

Vaccinium corymbosum L., commonly known as blueberry, is a valuable small fruit tree in terms of its economic significance and is primarily found in China within the regions of Heilongjiang and Jilin provinces. Additionally, it thrives in the areas spanning the middle and lower reaches of the Yangtze River. Beyond their economic value, blueberries play a crucial role within forest ecosystems, serving as a significant energy source and source of nutrients. Their presence contributes significantly to fostering stability, enhancing biodiversity, and acting as an indicator of environmental quality within forest ecosystems. Since August 2022, an unknown leaf disease has been found on a large scale in blueberry fields in Nanjing, Jiangsu Province, China. The disease causes leaf curling, wilting, and even early defoliation, severely reducing the yield and production value of blueberries. The pathogenicity test confirmed the virulence of the isolates (NG5-1, NG5-2, NG5-3, NG5-4, N2-1, and N2-2) against V. corymbosum. The two pathogens were identified as Colletotrichum fructicola and C. aenigma by observing the morphological characteristics of the isolates and combined with multilocus phylogenetic analyses (ITS, CAL, ACT, TUB2, ApMat, and GAPDH). Blueberry anthracnose, caused by C. aenigma, is the first report of this disease in China. The biological characteristics of C. aenigma were investigated under different conditions, including temperature, pH, light conditions, culture medium, and carbon and nitrogen sources. The optimal temperature for growth was determined to be within the range of 25–30 °C; C. aenigma exhibits optimal growth at a pH of 7–8. Mycelial growth is favored under conditions of partial light, whereas complete darkness promotes spore production. It was found that PDA medium was the most favorable medium for C. aenigma mycelial growth, and MM medium was the best medium for spore production; the most suitable carbon sources for colony growth and spore production were sorbitol and glucose, respectively, and the most suitable nitrogen source was peptone. This study furnishes a theoretical foundation for a more scientifically informed approach to the prevention and control of anthracnose on V. corymbosum.

Stable carbon isotopes (δ13C) and elemental stoichiometry characteristics are important ways to research the water and nutrient use strategies of plants. Investigating the variation patterns inof δ13C and the major nutrient elements in different organs of plants and the correlation among them can reveal the ecological strategies of desert plants in extreme arid environments. In this study, two typical desert plants, Alhagi sparsifolia and Karelinia caspia, were studied in the Tarim Basin. By analyzing the changes in δ13C, carbon (C), nitrogen (N), and phosphorus (P) and the ecological stoichiometry of their roots, stems, and leaves, the distribution patterns among different organs and their correlation with soil environmental factors were revealed. The results showed the following: (1) The δ13C of the two plants differed significantly among different organs (p < 0.01). The root and stem of Alhagi sparsifolia had significantly greater δ13C than the leave, while the δ13C of Karelinia caspia showed a root > stem > leaf gradient; (2) the C content in the leaves of the two plants was significantly lower than that of the root (p < 0.01), whereas the N content showed the opposite trend (p < 0.01); (3) the average N:P of Alhagi sparsifolia was >16.00, indicating it was mainly limited by P elements, while the average N:P of Karelinia caspia was Alhagi sparsifolia and Karelinia caspia, the N content and C:N and the P content and C:P showed a significantly negative correlation (p < 0.01), and δ13C was negatively correlated with C:P; (5) soil total phosphorus (TP) is an important soil environmental factor affecting δ13C and the nutrient elements in Alhagi sparsifolia and Karelinia caspia. This study demonstrates that Alhagi sparsifolia and Karelinia caspia are able to effectively coordinate and regulate their water, N, and P use strategies in response to environmental stress. These results can provide scientific reference for the evaluation of plant physiological and ecological adaptations for ecological conservation in arid areas.

Salinity stands as a significant environmental stressor, severely impacting crop productivity. Plants exposed to salt stress undergo physiological alterations that influence their growth and development. Meanwhile, plants have also evolved mechanisms to endure the detrimental effects of salinity-induced salt stress. Within plants, Calcineurin B-like (CBL) proteins act as vital Ca2+ sensors, binding to Ca2+ and subsequently transmitting signals to downstream response pathways. CBLs engage with CBL-interacting protein kinases (CIPKs), forming complexes that regulate a multitude of plant growth and developmental processes, notably ion homeostasis in response to salinity conditions. This review introduces the repercussions of salt stress, including osmotic stress, diminished photosynthesis, and oxidative damage. It also explores how CBLs modulate the response to salt stress in plants, outlining the functions of the CBL-CIPK modules involved. Comprehending the mechanisms through which CBL proteins mediate salt tolerance can accelerate the development of cultivars resistant to salinity.

The release of algal toxins in algae-containing water sources poses a serious threat to drinking water safety and human health. The conventional water treatment processes of water plants have a limited ability to remove algae and algal toxins, especially algal toxins with a molecular weight (MW) of less than 1000 Da. To eliminate algal pollution from a water source, a two-stage ultrafiltration (UF) process with a large polysulfone hollow fiber membrane with a MW cut-off of 200 kDa and a small aromatic polyamide roll membrane with a MW cut-off of 1 kDa were applied after a traditional sand filter in a water treatment plant. UF operation conditions, including the operating time, pressure, and membrane flux, were investigated. With an operating pressure of 0.05–0.08 MPa, the polysulfone hollow fiber membrane removed algae effectively, as the influent algal cell concentration ranged from 1–30 cells/mL but exhibited a limited removal of algal toxins. With an operating pressure of 0.3–0.4 MPa, the elimination of microcystins (MCs) reached 96.3% with the aromatic polyamide roll membrane. The operating pressure, membrane flux, and operating time were selected as the experimental factors, and the effects on the UF efficiency to remove algal toxins and biodegradable dissolved organic carbon were investigated by the response surface methodology. The model showed that the order of influence on the membrane operating efficiency was operating pressure > membrane flux > running time. The optimal UF operating conditions were an operating pressure of 0.3 MPa, a membrane flux of 17.5 L/(m2·h), and a running time of 80 min.

Continuous cropping can lead to an excessive accumulation of nitrate in facility-cultured soil. Excessive accumulation of nitrate gradually becomes the main reason for crop failure in vegetables and endangers human health. Therefore, the exploration of effective measures to decrease abundant nitrate accumulation in Chinese flowering cabbage is indispensable. In this study, a kind of plant growth regulator, fulvic acid (FA), was used to study its positive effect on alleviating the growth inhibition induced by excessive Ca(NO3)2 in Chinese flowering cabbage. Meanwhile, we conducted hydroponic cultivation and measured the growth indices, photosynthetic and oxidation-reduction characteristics of Chinese flowering cabbage with different treatments. After determining the optimal treatment concentration, we mainly designed four treatment groups, including Con, FA, Ca(NO3)2 and FA + Ca(NO3)2 cotreatment, to explore the regulatory mechanism by which FA alleviates Ca(NO3)2 stress in Chinese flowering cabbage. The results showed that FA can effectively alleviate the inhibitory effect of excessive Ca(NO3)2 on the growth of Chinese flowering cabbage seedlings. FA recovered the photosynthetic capacity of seedlings under Ca(NO3)2 stress. In addition, FA depressed the accumulation of O2·−, H2O2, malondialdehyde (MDA) and relative electrical conductivity, but increased the activity of antioxidant enzymes, including SOD, POD, CAT and APX, which finally enhanced the stress resistance of Chinese flowering cabbage to Ca(NO3)2. The expression of nitrate-related transporters, BcNRT1.1 and BcNRT1.5, was depressed by FA, which inhibited redundant nitrate absorption and restricted more nitrate from being stored in the roots instead of being transferred to the shoot. Ultimately, nitrate accumulation in the edible part was reduced in Chinese flowering cabbage seedlings. In general, exogenous FA may alleviate nitrate stress by improving oxidation resistance, photosynthetic capacity and redundant Ca(NO3)2 accumulation in Chinese flowering cabbage.

In order to reduce the number of road side unit (RSU) and meet the needs of mobile vehicle users for processing latency-sensitive and computation-intensive tasks, a context-aware resource allocation algorithm was proposed based on parked cars.Road side parked vehicles were selected to serve the vehicle users instead of RSU using parking time as a factor for determining whether a parked vehicle could become a parked car roadside unit (PCRSU).In order to further reduce the system response time, a mechanism was designed considering content caching and distribution.In respect to user content caching, PCRSU made personalized content recommendation for vehicle users with awareness by using two elements of user historical search data and point of interest (PoI) area type.In respect to content distribution, PCRSU allocated bandwidth efficiently by sensing the data transmission needs of vehicle users.Extensive experiments show that compared with the existing benchmark methods, the proposed algorithm can select PCRSU more reasonably, effectively reduce the demand response delay, improve the stability of the network while ensuring network coverage, and provide more accurate service content for vehicle users.

Abstract TRK fusions are rare but targetable mutations which occur across a wide variety of cancer types. We report the prevalence of approximately 0.7% for NTRK‐positive colorectal cancer (CRC) by genetically profiling 2519 colonic and rectal tumors. The aberrations of APC and TP53 frequently co‐occurred with NTRK gene fusions, whereas RAS/BRAF oncogenic alterations and NTRK fusions were almost always mutually exclusive. NTRK‐driven colorectal cancer patients demonstrated increased TMB (median = 53 mut/MB, 95% CI: 36.8–68.0 mut/MB), high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to molecularly unstratified colorectal cancer population. These data shed light on possible future approach of multimodality treatment regimen including TRK‐targeted therapy and immune checkpoint inhibitor therapy in NTRK‐positive CRCs.

Abstract Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

Abstract Background Homologous recombination deficiency (HRD) is a molecular biomarker for administrating PARP inhibitor (PARPi) or platinum-based (Pt) chemotherapy. The most well-studied mechanism of causing HRD is pathogenic BRCA1/2 mutations, while HRD phenotype is also present in patients without BRCA1/2 alterations, suggesting other unknown factors. Methods The targeted next-generation sequencing (GeneseeqPrime® HRD) was used to evaluate the HRD scores of 199 patients (Cohort I). In Cohort II, a total of 85 Pt-chemotherapy-treated high-grade serous ovarian cancer (HGSOC) patients were included for investigating the role of HRD score in predicting treatment efficacy. The concurrent genomic features analyzed along HRD score evaluation were studied in a third cohort with 416 solid tumor patients (Cohort III). Results An HRD score ≥ 38 was predefined as HRD-positive by analyzing Cohort I (range: 0–107). Over 95% of the BRCA1/2-deficient cases of Cohort I were HRD-positive under this threshold. In Cohort II, Pt-sensitive patients have significantly higher HRD scores than Pt-resistant patients (median: 54 vs. 34, p = 0.031) and a significantly longer PFS was observed in HRD-positive patients (median: 548 vs. 343 days, p = 0.003). Furthermore, TP53, NCOR1, and PTK2 alterations were enriched in HRD-positive patients. In Cohort III, impaired homologous recombination repair pathway was more frequently observed in HRD-positive patients without BRCA1/2 pathogenic mutations. The alteration enrichment of TP53, NCOR1, and PTK2 observed in Cohort II was also validated by the ovarian subgroup in Cohort III. Conclusions Using an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.

Anthropogenic heat release is the release of heat generated by anthropogenic energy consumption. The regional mean Anthropogenic heat release flux in Southwest China grew quickly from 0.06 Wm-2 in 1992 to a peak of 0.37 Wm-2 in 2019. This study examines the climatic effects and feedbacks of Anthropogenic heat release due to energy consumption in Southwest China during the boreal summer using simulations from the Community Earth System Model. The modeling results show that Anthropogenic heat release impacts on the lower-troposphere stability and affects large-scale atmospheric circulation in Southwest China, which transports more water vapor and consequently increases the humidity and low cloud cover in Southwest China. This effect impacts the energy balance at the surface by reducing the amount of incoming shortwave radiation that reaches the ground. Anthropogenic heat release decreases the average 2-m air temperature in Southwest China by 0.10 ± 0.01 K (1σ uncertainty) and also decreases the minimum and maximum air temperatures in Southwest China as well. Anthropogenic heat release contributes to cooler and wetter summers in Southwest China. The results show that Anthropogenic heat release is a non-negligible factor that impacts the climate of Southwest China. This study improves our understanding of the climate change resulting from human activities in Southwest China.

Abstract Background Free circular RNAs(circRNAs) escaping from primary lesion of cancer to brain are strictly regulated by blood–brain barrier and therefore cerebrospinal fluid (CSF) circRNAs have potential advantage in exploring biomarkers and mechanism of brain metastasis in lung cancer. Methods We collected paired cerebrospinal fluid, plasma and tumor tissues from 21 lung adenocarcinoma (ADC) patients with brain metastases (BM) and performed RNA sequencing. Results Compared to tumor tissue and plasma, circRNAs in CSF were characterized by lower number of spieces but higher abundance. Notably, CSF-circRNAs displayed high heterogeneity among different BM lung ADC patients. A total of 60 CSF-circRNAs was identified and associated with shorten overall survival. The circRNA-miRNA-mRNA network analysis revealed that the 60 CSF-circRNAs involved in cancer-associated pathways, and five of them showed strong association with WNT signaling pathway. Validation by RT-PCR of CSF and in vitro experiments of the five candidate circRNAs support their potential roles in cell proliferation and invasion. Conclusions In summary, our results depicted the heterogenous CSF-circRNAs profiles among BM lung ADC and implied that CSF-circRNAs may be promising prognosis-related biomarkers.

Abstract Background A high turnover rate has become a critical issue in the field of nursing and how to tackle the problem of nursing turnover has received increased attention worldwide. Hope, career identity, job satisfaction may be useful for reducing turnover. The aim of this study is to explore the relationships among career identity, hope, job satisfaction, and the turnover intention of nurses, and to test the mediating role of job satisfaction on the associations of hope and career identity with turnover intention. Methods A descriptive cross-sectional design was used. A total of 500 nurses were recruited from five comprehensive tertiary hospitals using convenience sampling. The questionnaire included items about sociodemographic information as well as the Adult Dispositional Hope Scale, Nursing Career Identity Scale, Job Satisfaction Index Scale, and Nurse Turnover Intention Scale. Pearson’s correlation, multiple linear regression, and structural equation modeling were used to analyze the data. We describe the study in accordance with the STROBE statement. Results Hope (r = − 0.227, p

Abstract Purpose To predict miscarriage outcome within 12 weeks of gestational age by evaluating values of serum estradiol, progesterone and β-human chorionic gonadotropin (β-HCG) within 9 weeks of gestation. Methods One hundred sixty-five women with singleton pregnancies were retrospectively studied. Estradiol, progesterone and β-HCG levels were measured at 5–6 weeks of gestation and the measurements were repeated at 7–9 weeks. According to pregnancy outcome at 12 weeks of gestation, 71 cases were categorized into miscarriage group, and 94 cases into group of normal pregnancy. Each group was further divided into 5–6 and 7–9 weeks of gestation sub-group. Predictive values of estradiol, progesterone and β- HCG levels at 5–6 weeks and 7–9 weeks of gestation were analyzed with receiver operating characteristic (ROC) curves and logistic regression. Results Serum levels of estradiol at 7–9 weeks identified miscarriage with an area under the ROC curve (AUC) of 0.866 (95% CI 0. 793 ~ 0.938, P = 0.000), diagnostic cutoff value of 576 pg/ml, sensitivity of 0.804, and specificity of 0.829 respectively at the optimal threshold, according to Youden index. Progesterone levels at 7–9 weeks were with AUC of 0.766 (95% CI 0. 672 ~ 0.861, P = 0.000), cutoff value of 15.27 ng/ml, sensitivity of 0.921, and specificity of 0.558, respectively; Estradiol at 5–6 weeks were with AUC of 0.709 (95% CI 0. 616 ~ 0.801, P

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is the major subtype of pancreatic cancer and head PDACs show distinct characteristics from body/tail PDACs. With limited studies based on Asian population, the mutational landscape of Asian PDAC remains unclear. Methods One hundred fifty-one Chinese patients with head PDAC were selected and underwent targeted 425-gene sequencing. Genomic alterations, tumor mutational burden, and microsatellite instability were analyzed and compared with a TCGA cohort. Results The genomic landscape of Chinese and Western head PDAC had identical frequently-mutated genes including KRAS, TP53, SMAD4, and CDKN2A. KRAS hotspot in both cohorts was codon 12 but Chinese PDACs containing more G12V but fewer G12R variants. Potentially pathogenic fusions, CHD2-BRAF and KANK1-MET were identified in two KRAS wild-type patients. Serum cancer antigens CA125 and CA19-9 were positively associated with SMAD4 alterations while high CEA was enriched in wild-type CDKN2A subgroup. The probability of vascular invasion was lower in patients with RNF43 alterations. The nomogram developed including histology grade, the mutation status of SMAD4, TGFBR2, and PREX2 could calculate the risk score of prognoses validated by Chinese and TCGA cohort. Conclusions Chinese head PDAC contained more KRAS G12V mutation than Western population. The well-performed nomogram may improve post-operation care in real-world practice.

Abstract Background Premature ovarian insufficiency (POI) plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

Baicalin is a natural active ingredient isolated from Scutellariae Radix that can cross the blood-brain barrier and exhibits neuroprotective effects on multiple central nervous system diseases. However, the mechanism behind the neuroprotective effects remains unclear. In this study, rat models of spinal cord injury were established using a modified Allen’s impact method and then treated with intraperitoneal injection of Baicalin. The results revealed that Baicalin greatly increased the Basso, Beattie, Bresnahan Locomotor Rating Scale score, reduced blood-spinal cord barrier permeability, decreased the expression of Bax, Caspase-3, and nuclear factor κB, increased the expression of Bcl-2, and reduced neuronal apoptosis and pathological spinal cord injury. SH-SY5Y cell models of excitotoxicity were established by application of 10 mM glutamate for 12 hours and then treated with 40 µM Baicalin for 48 hours to investigate the mechanism of action of Baicalin. The results showed that Baicalin reversed tight junction protein expression tendencies (occludin and ZO-1) and apoptosis-related protein expression (Bax, Bcl-2, Caspase-3, and nuclear factor-κB), and also led to up-regulation of PI3K and Akt phosphorylation. These effects on Bax, Bcl-2, and Caspase-3 were blocked by pretreatment with the PI3K inhibitor LY294002. These findings suggest that Baicalin can inhibit blood-spinal cord barrier permeability after spinal cord injury and reduce neuronal apoptosis, possibly by activating the PI3K/Akt signaling pathway. This study was approved by Animal Ethics Committee of Xi’an Jiaotong University on March 6, 2014.

Plant disease diagnosis in time can inhibit the spread of the disease and prevent a large-scale drop in production, which benefits food production. Object detection-based plant disease diagnosis methods have attracted widespread attention due to their accuracy in classifying and locating diseases. However, existing methods are still limited to single crop disease diagnosis. More importantly, the existing model has a large number of parameters, which is not conducive to deploying it to agricultural mobile devices. Nonetheless, reducing the number of model parameters tends to cause a decrease in model accuracy. To solve these problems, we propose a plant disease detection method based on knowledge distillation to achieve a lightweight and efficient diagnosis of multiple diseases across multiple crops. In detail, we design 2 strategies to build 4 different lightweight models as student models: the YOLOR-Light-v1, YOLOR-Light-v2, Mobile-YOLOR-v1, and Mobile-YOLOR-v2 models, and adopt the YOLOR model as the teacher model. We develop a multistage knowledge distillation method to improve lightweight model performance, achieving 60.4% mAP@ .5 in the PlantDoc dataset with small model parameters, outperforming existing methods. Overall, the multistage knowledge distillation technique can make the model lighter while maintaining high accuracy. Not only that, the technique can be extended to other tasks, such as image classification and image segmentation, to obtain automated plant disease diagnostic models with a wider range of lightweight applicability in smart agriculture. Our code is available at https://github.com/QDH/MSKD.

Plant diseases threaten global food security by reducing crop yield; thus, diagnosing plant diseases is critical to agricultural production. Artificial intelligence technologies gradually replace traditional plant disease diagnosis methods due to their time-consuming, costly, inefficient, and subjective disadvantages. As a mainstream AI method, deep learning has substantially improved plant disease detection and diagnosis for precision agriculture. In the meantime, most of the existing plant disease diagnosis methods usually adopt a pre-trained deep learning model to support diagnosing diseased leaves. However, the commonly used pre-trained models are from the computer vision dataset, not the botany dataset, which barely provides the pre-trained models sufficient domain knowledge about plant disease. Furthermore, this pre-trained way makes the final diagnosis model more difficult to distinguish between different plant diseases and lowers the diagnostic precision. To address this issue, we propose a series of commonly used pre-trained models based on plant disease images to promote the performance of disease diagnosis. In addition, we have experimented with the plant disease pre-trained model on plant disease diagnosis tasks such as plant disease identification, plant disease detection, plant disease segmentation, and other subtasks. The extended experiments prove that the plant disease pre-trained model can achieve higher accuracy than the existing pre-trained model with less training time, thereby supporting the better diagnosis of plant diseases. In addition, our pre-trained models will be open-sourced at https://pd.samlab.cn/ and Zenodo platform https://doi.org/10.5281/zenodo.7856293.

Abstract Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA‐seq analysis, and weighted gene co‐expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL‐elicited benefits, if any. A pharmacological protein–protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL‐evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL‐elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG‐governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.

IntroductionTo evaluate the global research results of the catheter ablation and surgical treatment of atrial fibrillation in the past 40 years by bibliometrics, and to explore the hotspots and prospects for future development.MethodsRelevant literatures were selected from the Web of Science Core Collection. VOSviewer 1.6.17, SciMAT 1.1.04, and CiteSpace 5.8.R1 were used to analyze the data objectively, deeply and comprehensively.ResultsAs of July 14, 2021, 11,437 studies for the catheter ablation and surgical treatment of atrial fibrillation have been identified from 1980 to 2021. The Journal of Cardiovascular Electrophysiology and Circulation respectively ranked first in terms of the number of publications and the number of co-citations. A total of 6,631 institutions from 90 countries participated in the study, with USA leading the way with 3,789 documents. Cryoablation, atrial fibrosis, substrate modification, minimally invasive and access surgery will still be the research focus and frontier in the next few years.ConclusionsThe publication information for the catheter ablation and surgical treatment of atrial fibrillation were reviewed, including country, institution, author, journal publications, and so on. Developed countries had the advantage in this research areas, and cooperation with low-income countries should be improved. The former research hotspots in the field of catheter ablation and surgical treatment of atrial fibrillation were analyzed, and the future research direction was predicted.