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Abstract Background WRKY transcription factors are plant-specific and play essential roles in growth, development, and stress responses, including reactions to salt, drought, and cold. Despite their significance, the WRKY genes in the wild sweet potato ancestor, Ipomoea pes-caprae, remain unexplored. Results In this study, 65 WRKY genes were identified in the I. pes-caprae transcriptomic data. A phylogenetic tree incorporating Arabidopsis thaliana and Ipomoea batatas revealed seven major groups, each characterized by conserved gene structural features. Transcriptome data of I. pes-caprae under salt stress conditions identified 17 highly expressed WRKY genes, whose promoter regions contain cis-acting elements associated with plant growth, stress responses, and hormone signaling. Further analysis revealed that the 17 IpWRKY genes exhibited differential expression patterns under various abiotic stresses, suggesting their potential roles in specific stress responses. The gene IpWRKY16 was significantly up-expressed under salt stress, drought, salicylic acid (SA), and abscisic acid (ABA) treatments. Subcellular localization analysis confirmed that IpWRKY16 is located in the nucleus. Under salt stress, IpWRKY16 overexpressing roots showed high activity in superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and low content in malondialdehyde (MDA). Using non-invasive micro-test technology (NMT), a significant efflux of Na+ was observed in the elongation zones of sweet potato adventitious roots that overexpressed IpWRKY16. Quantitative reverse transcription PCR (qRT-PCR) revealed that several ion transporter genes were responsive to IpWRKY16 expression, with IbSOS3, IbAHA4-1, and IbAHA4-2 showing the highest expression levels. We hypothesize that IpWRKY16 responds to salt stress by forming a complex regulatory network involving these key genes. Conclusions This study provides a foundational understanding of WRKY transcription factors in I. pes-caprae, offering insights into their potential role in enhancing salt-tolerance in sweet potato. Our findings contribute valuable genetic knowledge that could aid in the molecular breeding of stress-resilient sweet potato varieties.

Abstract Lactate is a major metabolic product of tumor cells in microenvironment. Increasing evidence has indicated that lactate accumulation could alter the immune response in human cancers, including cervical cancer. However, the function and significance of N6-methyladenosine (m6A) reader YTHDF1 in cervical cancer cells’ lactate metabolism and immunotherapy remain obscure. Results illustrated that YTHDF1 predicted unfavorable clinical outcomes of cervical cancer, which was negatively correlated with CD8+ T cell infiltration. In the co-culture of tumor cells with CD8+ T cells, YTHDF1 overexpression promoted the lactate accumulation and attenuated the cytotoxic CD8+ T cell’s killing effect. Correspondingly, YTHDF1 knockdown exerted the opposite effects. Mechanistically, YTHDF1 targeted the m6A site on SLC16A1 gene (MCT1) to determine its fate. YTHDF1 upregulated MCT1 expression by enhancing MCT1 stability mediated by m6A-modified manner. Collectively, our results revealed an oncogenic role played by YTHDF1 in cervical cancer through m6A/MCT1-dependent manner. In conclusion, these findings unveil the immune escape-promoting effect of YTHDF1 in cervical cancer by boosting the lactate accumulation, which might illuminate a novel target for more precise immunotherapy.

Instruction: Synchronous multiple primary lung cancer (sMPLC) constitutes a distinct subtype of NSCLC, where accurate diagnosis and prognostic evaluation remain challenging. Case Presentation: The case involves a 70-year-old male patient admitted to the hospital due to bilateral pulmonary nodules. The patient underwent staged resection. Molecular pathological examination revealed that tumor A harbored concurrent mutations in MET exon 14 skipping and PIK3CA (p.E545K), while tumor B exhibited a KRAS exon 2 (p.G12S/D) mutation. Postoperatively, the patient demonstrated a favorable recovery, with no evidence of recurrence for 1 year. Conclusion: This study presents a case of sMPLC in early-stage lung cancer, illustrating the genetic heterogeneity in early-stage lung adenocarcinoma and underscoring the significance of precise evaluation of sMPLC and intrapulmonary metastases.

Allergic inflammation is closely related to the activation of mast cells (MCs), which is regulated by its intracellular Ca2+ level, but the intake and effects of the intracellular Ca2+ remain unclear. The Ca2+ influx is controlled by members of Ca2+ channels, among which calcium voltage-gated channel subunit alpha1 C (CaV1.2) is the most robust. This study aimed to reveal the role and underlying mechanism of MC CaV1.2 in allergic inflammation. We found that CaV1.2 participated in MC activation and allergic inflammation. Nimodipine (Nim), as a strong CaV1.2-specific antagonist, ameliorated allergic inflammation in mice. Further, CaV1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C (PKC), which calcium/calmodulin-dependent protein kinase II (CaMKII) catalyzed. Overexpression or knockdown of MC CaV1.2 influenced MC activation. Importantly, CaV1.2 expression in MC had detrimental effects, while its deficiency ameliorated allergic pulmonary inflammation. Results provide novel insights into CaV1.2 function and a potential drug target for controlling allergic inflammation.

IntroductionThe advent of bevacizumab has considerably transformed the therapeutic landscape for non-small cell lung cancer (NSCLC) patients devoid of specific genetic mutations. A pivotal milestone has been reached with the recent approval of a bevacizumab biosimilar, following rigorous phase III clinical investigations, poised to augment NSCLC therapeutic strategies.MethodsThis retrospective analysis encompasses a large-scale study conducted between January 2021 and December 2023, involving 1058 NSCLC patients (metastatic or locally advanced stages). The research design entailed a comparative assessment of the safety and efficacy profiles of combined therapies using the original bevacizumab and its biosimilar, adhering to RECIST v1.1 criteria. Adverse event grading was standardized using the National Cancer Institute’s CTCAE v5.0.ResultsNotably, the biosimilar demonstrated an objective response rate (ORR) of 29.79% in 606 patients, closely paralleling the 27.41% ORR observed in 452 patients receiving the original drug, with insignificant risk differences (-0.03) and a risk ratio of 0.987, affirming equivalence. Progression-free survival (PFS) was influenced by radiation status, treatment lines, and regimen combinations, while dosage intensity and genetic factors had negligible impacts. The incidence of treatment-emergent adverse events (TEAEs) was slightly higher in the biosimilar group (75.11%) versus the original drug group (72.78%), with grade 3 or more severe TEAEs occurring in 23.6% and 18.5% of patients, respectively (Detailed criteria for the definition and assessment of TEAEs have been added to the Methods section, including the use of the National Cancer Institute’s CTCAE v5.0 for grading).ConclusionsThe study affirms that bevacizumab biosimilars offer equivalent therapeutic efficacy and a similar safety profile to the originator product in the management of locally advanced or metastatic NSCLC. The tolerability of the toxicity profile, coupled with the absence of unforeseen adverse reactions, underscores the viability of biosimilar bevacizumab as a valuable addition to NSCLC treatment regimens. These findings also imply potential benefits for a broader patient population beyond clinical trial confines through the adoption of biosimilar beta-adrenergic blocking agents.

Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Treatment for lung cancer continues to rapidly evolve. Here, we describe trends in the initial treatment of adults with newly diagnosed primary non-small-cell lung cancer in Japan. This retrospective cohort study used data from JMDC Inc. Claims Database from 2015 to 2023. Adults with lung cancer, confirmed using a combination of diagnosis, treatment, or procedure codes, were enrolled. A total of 9373 patients were included, with a mean age of approximately 59 years. The median time from diagnosis to treatment initiation ranged from 38 days in patients treated surgically to 25 days in patients with distant metastases. The observed trends were a decrease in the percentage of newly diagnosed patients with distant metastases, a decline in chemotherapy use in patients with early-stage disease, and in advanced disease, a more than doubling in the use of targeted therapy, including checkpoint inhibitors, while radiotherapy and chemotherapy tended to decrease. The observed changes in treatment were driven mainly by the increased use of targeted therapies including checkpoint inhibitors and are aligned with current treatment guidelines in Japan. The observation of fewer patients with distant metastases over time possibly indicates earlier detection. Additional research is needed to understand if new therapies are being extended to older and frail patients with lung cancer in Japan.

Abstract Human–machine interactive platforms that can sense mechanical stimuli visually and digitally are highly desirable. However, most existing interactive devices cannot satisfy the demands of tactile feedback and extended integration. Inspired by the mechanoluminescence (ML) function of cephalopod skin and the sensitive perception of microcracked slit‐organs, a bioinspired stretchable interactive platform is developed by designing a stretchable poly(styrene‐block‐butadiene‐block‐styrene)/fluorescent molecule (SFM) composite followed by the in situ polymerization of pyrrole (Py) and deposition of carbon nanotubes (CNTs), which possesses a simple multilayered structure and quantitatively senses the applied strains via the variations of digital electrical resistance and visual fluorescence intensity. Using the strain‐dependent microstructures derived from the synergistic interactions of the rigid PPy/CNTs functional layer and SFM, the SFM/PPy/CNTs‐based platforms exhibit excellent strain‐sensing performance manifested by a high gauge factor (GF = 2.64 × 104), wide sensing range (~270%), fast response/recovery time (~155/195 ms), excellent stability (~15,000 cycles at 40% strain), and sensitive ML characteristics under ultraviolet illumination. Benefiting from the novel fusion of digital data and visual images, important applications, including the detection of wrist pulses and human motions, and information dual‐encryption, are demonstrated. This study demonstrates the superiority of advanced structures and materials for realizing superior applications in wearable electronics.

Federated learning enables the collaborative training of machine learning models across multiple organizations, eliminating the need for sharing sensitive data. Nevertheless, in practice, the data distributions among these organizations are often non-independent and identically distributed (non-IID), which poses significant challenges for traditional federated learning. To tackle this challenge, we present a hierarchical federated learning framework based on blockchain technology, which is designed to enhance the training of non-IID data., protect data privacy and security, and improve federated learning performance. The framework builds a global shared pool by constructing a blockchain system to reduce the non-IID degree of local data and improve model accuracy. In addition, we use smart contracts to distribute and collect models and design a main blockchain to store local models for federated aggregation, achieving decentralized federated learning. We train the MLP model on the MNIST dataset and the CNN model on the Fashion-MNIST and CIFAR-10 datasets to verify its feasibility and effectiveness. The experimental results show that the proposed strategy significantly improves the accuracy of decentralized federated learning on three tasks with non-IID data.

Abstract Epidermal dry electrodes with high skin‐compliant stretchability, low bioelectric interfacial impedance, and long‐term reliability are crucial for biopotential signal recording and human–machine interaction. However, incorporating these essential characteristics into dry electrodes remains a challenge. Here, a skin‐conformal dry electrode is developed by encapsulating kirigami‐structured poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS)/polyvinyl alcohol (PVA)/silver nanowires (Ag NWs) film with ultrathin polyurethane (PU) tape. This Kirigami‐structured PEDOT:PSS/PVA/Ag NWs/PU epidermal electrode exhibits a low sheet resistance (≈3.9 Ω sq−1), large skin‐compliant stretchability (>100%), low interfacial impedance (≈27.41 kΩ at 100 Hz and ≈59.76 kΩ at 10 Hz), and sufficient mechanoelectrical stability. This enhanced performance is attributed to the synergistic effects of ionic/electronic current from PEDOT:PSS/Ag NWs dual conductive network, Kirigami structure, and unique encapsulation. Compared with the existing dry electrodes or standard gel electrodes, the as‐prepared electrodes possess lower interfacial impedance and noise in various conditions (e.g., sweat, wet, and movement), indicating superior water/motion‐interference resistance. Moreover, they can acquire high‐quality biopotential signals even after water rinsing and ultrasonic cleaning. These outstanding advantages enable the Kirigami‐structured PEDOT:PSS/PVA/Ag NWs/PU electrodes to effectively monitor human motions in real‐time and record epidermal biopotential signals, such as electrocardiogram, electromyogram, and electrooculogram under various conditions, and control external electronics, thereby facilitating human–machine interactions.

Abstract Background Carbon nanoparticles (CNPs) are a new tracer for lymph node mapping, which can quickly reach and develop lymph nodes through a lymphatic network. This research investigated the characteristics of systematic lymph node dissection and sentinel lymph node biopsy mapped with CNPs in endometrial carcinoma. Methods We first applied CNPs to systematic lymph node dissection in 18 endometrial carcinoma patients as the study group and another 18 endometrial carcinoma patients who were not injected with anything served as the control group. Then, we applied CNPs to sentinel lymph nodes biopsy in 54 endometrial carcinoma patients. All 54 patients received systematic lymph node dissection after sentinel lymph node biopsy. The detection rate, sensitivity, specificity, and accuracy of systematic lymph node dissection and sentinel lymph node biopsy by CNPs were respectively analyzed. A nomogram model for predicting the success of sentinel lymph node mapping was established. Results The average number of lymph nodes removed in the CNP-labeled study group was higher than that in the control group (p

Abstract Background Osmotic release oral system methylphenidate (OROS-MPH) is one of the most commonly used medication for attention-deficit hyperactivity disorder (ADHD), however, real-world knowledge on OROS-MPH dose titration has been limited. This study aims to summarize and visualise the OROS-MPH titration patterns in children and adolescents with ADHD in the United States (US) and Japan. Methods This retrospective cohort study used the US IBM® MarketScan® Commercial Claims and Encounters database from 2000 to 2019 and the Japan Medical Data Centre database from 2008 to 2019. New OROS-MPH users with ADHD were identified and split into child (6 to

Objective The present study investigated the province-level distribution and drivers of infant mortality rate (IMR) in mainland China.Design Ecological analysis based on publicly available data for all 31 provinces in mainland China.Data sources Data on province-level IMRs in 2020 were obtained from the official websites of the healthcare commissions within each province and from the China Health Statistics Yearbook 2021. Data on potential IMR drivers were retrieved from the China Statistical Yearbook 2021.Data analysis GeoDa V.1.12.1 and ArcMap V.10.2 software were used to examine province-level distribution of IMR. Global and local spatial autocorrelations were performed, and Getis-ord G* hotspots and coldspots were identified. Geodetector was used to analyse the individual and joint influence of drivers on IMR.Results IMRs in 2020 varied from 1.91 to 7.60 per 1000 live births across provinces. The following statistically significant drivers with q values >0.5 were identified: health literacy of the population (0.6673), male illiteracy rate (0.6433), proportion of the population older than >65 years (0.6369), per capita government health expenditure (0.6216), forest coverage rate (0.5820), per capita disposable income (0.5785), per capita number of hospitals (0.5592), per capita gross regional product (0.5410) and sulfur dioxide concentration in the atmosphere (0.5158). The following three interactions among these drivers emerged as strongest influences on province-level IMR: proportion of population >65 years ∩ per capita gross regional product (q=0.9653), forest coverage rate ∩ per capita gross regional product (0.9610) and per capita government health expenditure ∩ sulfur dioxide (0.9295).Conclusion IMR in mainland China varies substantially across the country, being generally high-west and low-east. Several factors, on their own and interacting together, contribute to IMR. Policies and programmes to reduce IMR should be formulated according to local conditions and should focus on western provinces of the country.

Glioma is the most common primary malignant intracranial tumor. Owing to highly aggressive invasiveness and metastatic properties, the prognosis of this disease remains poor even with surgery, radiotherapy, and chemotherapy. Rutin is a glycoside natural flavonoid that modulates microglia inflammatory profile and improves anti-glioma activity. Here, a glycoside flavonoid was extracted and named purple sweet potato delphinidin-3-rutin (PSPD3R). In an experiment using the subcutaneous xenograft model of human glioblastoma (GBM) and alamar blue assay, we found that PSPD3R suppressed the glioma proliferation both in vitro and in vivo. Flow cytometry assay and transmission electron microscopy observation revealed that PSPD3R stimulated glioma cell autophagy and apoptosis. High-throughput microRNA (miRNA) sequencing showed that PSPD3R substantially affected the miRNA expression of U251 cells. Acridine orange staining and immunoblotting indicated that PSPD3R regulated autophagy via Akt/Creb/miR-20b-5p in glioma cells. Luciferase reporter assays showed that autophagy-related gene 7 (Atg7) mRNA was the target gene of miR-20b-5p. The downregulation of miR-20b-5p inhibited glioma proliferation in vivo. In summary, PSPD3R regulated autophagy in glioma via the Akt/Creb/miR-20b-5p/Atg7 axis. This work unraveled the molecular mechanism of PSPD3R-induced autophagy in glioma and revealed its potential as a therapeutic agent for glioma treatment.

Background: One of the features of tumor immunity is the immunosuppressive tumor microenvironment (TME). In this study, TME gene signatures were used to define the characteristics of Cervical squamous cell carcinoma (CESC) immune subtypes and construct a new prognostic model.Methods: Single sample gene set enrichment analysis (ssGSEA) was used to quantify pathway activity. RNA-seq of 291 CESC were obtained from the Cancer Genome Atlas (TCGA) database as a training set. Microarray-based data of 400 cases of CESC were obtained from the Gene Expression Compilation (GEO) database as an independent validation set. 29 TME related gene signatures were consulted from previous study. Consensus Cluster Plus was employed to identify molecular subtype. Univariate cox regression analysis and random survival forest (RSF) were used to establish the immune-related gene risk model based on the TCGA data set of CESC, and the accuracy of prognosis prediction was verified by GEO data set. ESTIMATE algorithm was used to perform immune and matrix scores on the data set.Results: three molecular subtypes (C1, C2, C3) were screened in TCGA-CESC on account of 29 TME gene signatures. Among, C3 with better survival outcome had higher immune related gene signatures, while C1 with worse prognosis time had enhanced matrix related features. Increased immune infiltration, inhibition of tumor related pathways, widespread genomic mutations and prone immunotherapy were observed in C3. Furthermore, a five immune genes signature was constructed and predicted overall survival for CESC, which successfully validated in GSE44001 dataset. A positive phenomenon was observed between five hub genes expressions and methylation. Similarly, high group enriched in matrix related features, while immune related gene signatures were enriched in low group. Immune cell, immune checkpoints genes expression levels were negatively, while most TME gene signatures were positively correlated with Risk Score. In addition, high group was more sensitive to drug resistance.Conclusion: This work identified three distinct immune subtypes and a five genes signature for predicting prognosis in CESC patients, which provided a promising treatment strategy for CESC.

BackgroundSmall cell carcinoma of ovary (SCCO) is a rare and aggressive cancer primarily reported in the form of case reports. Due to limited epidemiological and prognostic analyses based on large populations, SCCO has varied considerably without prognostic models and a recognized first-line treatment strategy. The study aimed to compare the clinical characteristics, treatment methods, and prognosis of SCCO and high-grade serous ovarian cancer (HGSOC), the most prevalent subtype of ovarian cancer, in a large sample and develop a predictive model for these two subtypes.MethodsData from the Surveillance, Epidemiology, and End Results program were analyzed for patients with SCCO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between the two groups. Propensity-score matching, Cox risk regression analysis, and Kaplan-Meier survival curves were used to assess the data. Finally, a nomogram was developed to predict the patient survival time.ResultsA total of 32,185 women, including 31,979 (99.4%) diagnosed with HGSOC and 206 (0.6%) diagnosed with SCCO, were identified. Age ≤ 51 years, single, median house income less than $70,000, early stage, and unilateral disease were more common characteristics of patients with SCCO than those with HGSOC. Patients with SCCO were more likely to receive radiotherapy (6.8% vs. 0.8%, p

ObjectivesTo evaluate the efficacy of Optical Coherence Tomography (OCT) for detecting cervical lesions in women with minor abnormal cytology results (atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL)).MethodsA prospective study was conducted at gynecologic clinic from Mar 2021 to Sep 2021. The recruited women with cervical cytological findings of ASC-US or LSIL were inspected with OCT before colposcopy-directed cervical biopsy. The diagnostic performance of OCT, alone and in combination with high-risk human papillomavirus (hrHPV) testing were evaluated to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+)/CIN3 or worse (CIN3+). The rate of colposcopy referral and the immediate risk of CIN3+ of OCT were calculated.ResultsA total of 349 women with minor abnormal cervical cytology results were enrolled. For detection of CIN2+/CIN3+, the sensitivity and NPV of OCT were lower than those of hrHPV testing (CIN2+: 71.3% vs. 95.4%, 89.0% vs. 91.1%, P < 0.001; CIN3+: 75% vs. 93.8%, 96.5% vs. 95.6%, P < 0.001), but the specificity, accuracy and PPV were higher than those of hrHPV testing (CIN2+: 77.5% vs. 15.6%, 75.9% vs. 35.5%, 51.2% vs. 27.3%, P < 0.001; CIN3+: 69.4% vs. 13.6%, 69.9% vs. 20.9%, 19.8% vs. 9.9%, P < 0.001). OCT combined with hrHPV testing (CIN2+: 80.9%; CIN3+: 72.6%) showed higher specificity than that of OCT alone (P < 0.001). The colposcopy referral rate base on OCT classification was lower than that based on hrHPV testing (34.7% vs. 87.1%, P < 0.001). Patients with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology, the immediate CIN3+ risk in OCT negative cases was less than 4%.ConclusionsOCT alone or combination with hrHPV testing shows good performance for detecting CIN2+/CIN3+ in patients with ASC-US/LSIL cytology. OCT is an effective method for colposcopy triage in women with hrHPV-positive ASC-US and hrHPV-negative LSIL cytology.

BackgroundOver the last 2 decades, patients with low rectal cancer have had better outcomes from improvements in surgical techniques in sphincter preservation. We aimed to quantify the trends in sphincter-preserving surgeries for low rectal cancer over 20 years in a top tertiary hospital in China.MethodsBetween 1999 and 2021, a cohort of patients with primary malignant rectal tumor ≤5cm from the anal verge and who received elective surgeries at Changhai Hospital, Shanghai, China, was identified. Data were extracted from electronic medical records. A Joinpoint Regression Model was used to analyze trends in surgical procedures by average annual percentage change (AAPC). Adjusted Cox proportional hazards regression model was used to assess overall survival.ResultsAmong a total of 4,172 patients during the study period, 3,111 (74.6%) underwent a sphincter-preserving surgery and 1,061 (25.4%) received APR. Sphincter-preserving surgery increased 3.6% per year (95%CI, 2.3-4.9). Low anterior resection was the most performed procedure (86.3%) and maintained a steady trend, while intersphincteric resection increased 49.4% annually (95%CI, 19.5-86.7) after initiation. Laparoscopic techniques increased 15.1% per year (95%CI, 8.4-43.4) after initiation. Sphincter-preserving surgery increased annually for tumors ≤2cm, 2-≤3cm and 3-≤4cm from the anal verge (AAPC 7.1, 4.5-9.8; 4.7, 3.1-6.3; 2.7, 1.7-3.6, respectively). Furthermore, patients with sphincter-preserving surgery had a better overall survival than abdominoperineal resection (APR) patients (adjusted HR 0.78, 95% CI, 0.65-0.93, p=.01).ConclusionsUtilization of sphincter-preserving surgeries increased significantly over the last 20 years. Patients with low rectal cancer who underwent sphincter preservation had better survival than similar patients who underwent APR.

Ceratocystis fimbriata (C. fimbriata) is a notorious pathogenic fungus that causes sweet potato black rot disease. The APSES transcription factor Swi6 in fungi is located downstream of the cell wall integrity (CWI)-mitogen-activated protein kinase (MAPK) signaling pathway and has been identified to be involved in cell wall integrity and virulence in several filamentous pathogenic fungi. However, the specific mechanisms by which Swi6 regulates the growth and pathogenicity of plant pathogenic fungi remain elusive. In this study, the SWI6 deletion mutants and complemented strains of C. fimbriata were generated. Deletion of Swi6 in C. fimbriata resulted in aberrant growth patterns. Pathogenicity assays on sweet potato storage roots revealed a significant decrease in virulence in the mutant. Non-targeted metabolomic analysis using LC-MS identified a total of 692 potential differentially accumulated metabolites (PDAMs) in the ∆Cfswi6 mutant compared to the wild type, and the results of KEGG enrichment analysis demonstrated significant enrichment of PDAMs within various metabolic pathways, including amino acid metabolism, lipid metabolism, nucleotide metabolism, GPI-anchored protein synthesis, and ABC transporter metabolism. These metabolic pathways were believed to play a crucial role in mediating the growth and pathogenicity of C. fimbriata through the regulation of CWI. Firstly, the deletion of the SWI6 gene led to abnormal amino acid and lipid metabolism, potentially exacerbating energy storage imbalance. Secondly, significant enrichment of metabolites related to GPI-anchored protein biosynthesis implied compromised cell wall integrity. Lastly, disruption of ABC transport protein metabolism may hinder intracellular transmembrane transport. Importantly, this study represents the first investigation into the potential regulatory mechanisms of SWI6 in plant filamentous pathogenic fungi from a metabolic perspective. The findings provide novel insights into the role of SWI6 in the growth and virulence of C. fimbriata, highlighting its potential as a target for controlling this pathogen.

Abstract IL6 is one of the most elevated cytokines during chimeric antigen receptor (CAR) T cell cytokine release syndrome (CRS), and IL6R blockade by Tocilizumab has successfully relieved the most life-threatening aspects of CRS in patients. In addition, latest studies demonstrated the essential role of IL1 in driving CART induced neurotoxicity in mouse models. Here we present a clinical investigation (ChiCTR2000032124; ChiCTR2000031868) of anti-CD19 and anti-BCMA CART (41BBζ) secreting an anti-IL6 scFv and IL1 receptor antagonist (IL1RA) in treating patients with hematologic malignancy. Our results revealed that IL6 and IL1B were maintained at low levels without significant elevation during CRS, rendering Tocilizumab dispensable. Moreover, treated patients did not show neurotoxicity during CRS and exhibited mild to moderate CRS. Notably, we observed high rate of complete response (CR) and significant CART expansion during treatment. In sum, we conclude that CART-secreting anti-IL6 scFv and IL1RA could self-neutralize IL6 storm and maintain low levels of IL1B during CART therapy to minimize IL6- and IL1-associated cytokine toxicity and neurotoxicity without impairing therapeutic efficacy.

Recent legislations, such as the European General Data Protection Regulation (GDPR), require user data holders to guarantee the individual’s right to be forgotten. This means that user data holders must completely delete user data upon request. However, in the field of machine learning, it is not possible to simply remove these data from the back-end database wherein the training dataset is stored, because the machine learning model still retains this data information. Retraining the model using a dataset with these data removed can overcome this problem; however, this can lead to expensive computational overheads. In order to remedy this shortcoming, we propose two effective methods to help model owners or data holders remove private data from a trained model. The first method uses an elastic weight consolidation (EWC) constraint term and a modified loss function to neutralize the data to be removed. The second method approximates the posterior distribution of the model as a Gaussian distribution, and the model after unlearning is computed by decreasingly matching the moment (DMM) of the posterior distribution of the neural network trained on all data and the data to be removed. Finally, we conducted experiments on three standard datasets using backdoor attacks as the evaluation metric. The results show that both methods are effective in removing backdoor triggers in deep learning models. Specifically, EWC can reduce the success rate of backdoor attacks to 0. IMM can ensure that the model prediction accuracy is higher than 80% and keep the success rate of backdoor attacks below 10%.

With the increasing demand for medicinal plants and the increasing shortage of resources, improving the quality and yield of medicinal plants and making more effective use of medicinal plants has become an urgent problem to be solved. During the growth of medicinal plants, various adversities can lead to nutrient loss and yield decline. Using traditional chemical pesticides to control the stress resistance of plants will cause serious pollution to the environment and even endanger human health. Therefore, it is necessary to find suitable pesticide substitutes from natural ingredients. As an important part of the microecology of medicinal plants, endophytes can promote the growth of medicinal plants, improve the stress tolerance of hosts, and promote the accumulation of active components of hosts. Endophytes have a more positive and direct impact on the host and can metabolize rich medicinal ingredients, so researchers pay attention to them. This paper reviews the research in the past five years, aiming to provide ideas for improving the quality of medicinal plants, developing more microbial resources, exploring more medicinal natural products, and providing help for the development of research on medicinal plants and endophytes.

Abstract Revolutionary CART therapy still faces the challenge of severe cytokine release syndrome (CRS). While IL6 and IL1 have been demonstrated as essential contributors, GM-CSF is one of the most abundant inflammatory cytokines secreted by CART and has also been suggested in contributing to CRS. To minimize GM-CSF production from CART to reduce its associated toxicity, we conducted a pilot study (ChiCTR2000032124) of CRISPR-edited GM-CSF knockout (KO) in CART secreting anti-IL6 scFv and IL1RA, with additional TCR KO for tracing edited CART. The initial results of three patients (1 Non-Hodgkin lymphoma (NHL) and 2 multiple myelomas (MMs)) are summarized as: 3/3 complete response, 2/3 none CRS, 1/3 grade 2 CRS, and 0/3 neurotoxicity. The analysis revealed low levels of GM-CSF, IL6 and IL1B at the time of interferon-gamma (IFNG) peaks, and elevated IL1RA. We also observed significant expansion of CD3– CART during treatment and no aberrant expansion of CD3– CART in the follow-up. Re-expansion of CD3– CART was observed in two patients while recurring CD19+ cells were eradicated in the patient with NHL. In summary, our study supported the safety and durable potency of CRISPR-edited CART in patients, providing a novel platform for developing autologous or allogeneic CART to minimize GM-CSF-associated toxicity in addition to autonomous IL6/IL1 blockade.

Background: Antidepressant (AD) algorithm is an important tool to support treatment decision-making and improve management of major depressive disorder (MDD). However, little is known about its concordance with real-world practice. This study aimed to assess the concordance between the longitudinal treatment patterns and AD algorithm recommended by a clinical practice guideline in China.Methods: Data were obtained from the electronic medical records of Shanghai Mental Health Center (SMHC), one of the largest mental health institutions in China. We examined the concordance between clinical practice and the Canadian Network for Mood and Anxiety Treatments (CANMAT) algorithm among a cohort composed of 19,955 MDD patients. The longitudinal characteristics of treatment regimen and duration were described to identify the specific inconsistencies. Demographics and health utilizations of the algorithm-concordant and -discordant subgroups with optimized treatment were measured separately.Results: The overall proportion of algorithm-concordant treatment significantly increased from 84.45% to 86.03% during the year of 2015–2017. Among the patients who received recommended first-line drugs with subsequent optimized treatment (n = 2977), the concordance proportion was 27.24%. Mirtazapine and trazodone were the most used drugs for adjunctive strategy. Inadequate or extended duration before optimized treatment are common inconsistency. The median length of follow-up for algorithm-concordant (n = 811) and algorithm-discordant patients (n = 2166) were 153 days (Q1-Q3 = 79–328) and 368 days (Q1-Q3 = 181–577) respectively, and the average number of clinical visits per person-year was 13.07 and 13.08 respectively.Conclusion: Gap existed between clinical practice and AD algorithm. Improved access to evidence-based treatment is required, especially for optimized strategies during outpatient follow-up.

Objective. Cervical cancer (CC) is a prevalent cancer in women. Hypoxia plays a critical role in CC cell ferroptosis resistance. This study explored the mechanism of hypoxia in CC cell ferroptosis resistance by regulating HIF1α/KDM4A/H3K9me3. Methods. Cultured SiHa and Hela cells were exposed to CoCl2 and treated with Erastin. Cell viability was detected by MTT assay, and concentrations of iron ion, MDA and GSH were determined using corresponding kits. Expressions of KDM4A, HIF1α, TfR1, DMT1, and H3k9me3 were detected by RT-qPCR, Western blot, and ChIP assay. The correlation of KDM4A and HIF1α was analyzed on Oncomine, UALCAN, and Starbase. CC cells were co-transfected with shKDM4A or/and pcDNA3.1-HIF1α. Iron uptake and release were assessed using the isotopic tracer method. The binding relationship between HIF1α and HRE sequence was verified by dual-luciferase assay. Results. Cell viability and GSH were decreased while iron concentration, MDA, KDM4A, and HIF1α levels were increased in hypoxia conditions. The 2-h hypoxia induced ferroptosis resistance. KDM4A and HIF1α were highly-expressed in CC tissues and positively correlated with each other. KDM4A knockdown attenuated cell resistance to Erastin, increased H3K9me3 level in the HIF1α promoter region, and downregulated HIF1α transcription and translation. H3K9me3 level was increased in the HIF1α promoter after hypoxia. HIF1α overexpression abrogated the function of KDM4A knockdown on ferroptosis in hypoxia conditions. Iron uptake/release and TfR1/DMT1 levels were increased after hypoxia. Hypoxia activated HRE sequence in TfR1 and DMT1 promoters. Conclusion. Hypoxia upregulated KDM4A, enhanced HIF1α transcription, and activated HRE sequence in TfR1 and DMT1 promoters via H3K9me3, thus inducing ferroptosis resistance in CC cells.

Metabolic diseases are associated with chronic, low-grade inflammation. Here the authors show that major vault protein (MVP) suppresses NF-κB signalling in macrophages via an IRAK1–TRAF6 axis and that loss of MVP in myeloid cells exacerbates the inflammatory response in mice fed a high fat diet.

Background: The present study aimed to investigate the potential association between oral and intestinal microbiotas of pregnant women with periodontitis and/or gestational diabetes mellitus (GDM) in the second trimester.Methods: Four groups were defined: periodontitis (n = 28), GDM (n = 7), periodontitis + GDM (n = 7), and periodontitis- and GDM-free controls (n = 27). The oral and intestinal microbiomes were analyzed using the 16S rRNA sequencing technique.Results: Periodontitis alone significantly decreased the oral microbial diversity (by Shannon index, p = 0.003) and changed the structure of the oral microbial community (by AMOVA, p 0.001). GDM alone significantly increased the oral microbial diversity (by Shannon index, p = 0.049), and when combined with periodontitis, GDM significantly decreased the intestinal microbial richness (by observed species, p = 0.018) and influenced the structure of intestinal microbial community (by AMOVA, p = 0.043). The differentially abundant microbial taxa among different groups in both oral and intestinal samples were identified by LEfSe analysis, and limited taxa showed consistent trends. The numbers and ratios of oral-intestinal shared operational taxonomical units were the least in the periodontitis + GDM group.Conclusions: A close relationship between the oral microbiota and pregnant periodontitis was shown. Significant changes occur in both the oral and intestinal microbiomes when periodontitis was coupled with GDM. A separate influence of periodontitis and GDM on the oral and intestinal microbiotas may be indicated.

ObjectivesAlanine aminotransferase (ALT) level is one of the crucial indexes to evaluate disease status for chronic hepatitis B (CHB) patients. However, whether the ALT level after nucleos(t)ide analog (NA) treatment is associated with hepatocellular carcinoma (HCC) development remains unclear.Materials and MethodsWe evaluated the association between ALT level and HCC occurrence in NA-treated patients and investigated the predictive value of ALT flare for HCC. The associations between ALT level and HCC were analyzed by logistic regression and Cox proportional hazards models.ResultsThere were 21,223 CHB patients at Ruijin Hospital of China and 16,737 CHB patients in the Optum electronic health records (EHR) in the United States (US) treated with NAs between 2010 and 2018. Among them, 8,152 and 4,893 patients who achieved a normal ALT value were included in the study cohorts, respectively. A significant positive dose-dependent correlation between the peak ALT level and HCC was identified in both cohorts. Within the China cohort, ALT flare was significantly associated with increased risks of HCC compared to normal ALT (HR 2.55, 95%CI 1.45–4.50). Stronger increased risks associated with ALT flare were observed in the US cohort (HR 7.62, 95%CI 4.85–11.98).ConclusionsALT flare is a strong predictor for HCC occurrence in the CHB patients treated with NAs. Elevation of ALT, especially ALT flare warrants close monitoring for early HCC detection.

Background: Renal hypokalemia is associated with mutation. This study aimed to investigate the clinical features and pathogenic mutations in patients with renal hypokalemia. Methods: The patients with hypokalemia were enrolled, and the renal function, thyroid function, renin-aldosterone system, urinary potassium excretion, and exome sequencing were performed. The correlation between the clinical phenotypes and causative genes was assessed. Results: Five patients with hypokalemia were enrolled and diagnosed as tubular hypokalemia. The patients with common clinical manifestations were difficult to differentiate based on atypical laboratory findings. The results of the genetic analysis were as follows: both patient 1 and patient 2 were heterozygous for the c.C625T mutation of the KCNJ1 gene, which is responsible for Bartter syndrome. Patient 3 was heterozygous for the c.G298A mutation of the ATP6V1B1 gene, which is responsible for renal tubular acidosis. Patient 4 had a compound heterozygous mutation of c.G893A of the BSND gene, responsible for Bartter syndrome, and c.1029+5G>A, the ATP6V0A4 gene responsible for distal renal tubular acidosis. Patient 5 had Gitelman syndrome and carried the compound heterozygous mutations c.C1963T and c.G2029A of the SLC12A3 gene. All the above loci were known heterozygous mutations. Conclusions: The unusual heterozygous mutations were identified in five renal hypokalemia patients. Molecular diagnosis of tubular hypokalemia was conducive to accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Mast cells (MCs) are important effector cells in anaphylaxis and anaphylactic disease. 3',4',5,7-tetrahydroxyflavone (THF) presents in many medicinal plants and exerts a variety of pharmacological effects. In this study, we evaluated the effect of THF on C48/80-induced anaphylaxis and the mechanisms underlying its effects, including the role of secreted phosphoprotein 1 (SPP1), which has not been reported to IgE-independent MC activation. Results: THF inhibited C48/80-induced Ca2+ flow and degranulation via the PLC/PKC/IP3 pathway in vitro. RNA-seq showed that THF inhibited the expression of SPP1 and downstream molecules. SPP1 is involved in pseudo-anaphylaxis reactions. Silencing SPP1 affects the phosphorylation of AKT and P38. THF suppressed C48/80-induced paw edema, hypothermia and serum histamine, and chemokines release in vivo. Conclusions: Our results validated SPP1 is involved in IgE-independent MC activation anaphylactoid reactions. THF inhibited C48/80-mediated anaphylactoid reactions both in vivo and in vitro, suppressed calcium mobilization and inhibited SPP1-related pathways. [ABSTRACT FROM AUTHOR]