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Abstract Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis. Graphical abstract

Objective: The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. Methods: PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Results: Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR) 10 mg = 0.390 (95% confidence interval {CI}, 0.201–0.756), P = 0.005; HR 12 mg = 0.397 (0.208–0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR 10 mg = 0.445 (0.210–0.939), P = 0.034; HR 12 mg = 0.369 (0.174–0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR 10 mg = 0.340 (0.156–0.742), P = 0.007; HR 12 mg = 0.340 (0.159–0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Conclusions: Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Abstract Proteasome inhibition emerges as a promising strategy for cancer prevention. PNO1, pivotal for colorectal cancer (CRC) progression, is involved in proteasome assembly in Saccharomyces cerevisiae. Hence, we aimed to explore the role of PNO1 in proteasome assembly and its up- and down-streams in CRC. Here, we demonstrated that PNO1 knockdown suppressed CRC cells growth, proteasome activities and assembly, as well as CDKN1B/p27Kip1 (p27) degradation. Moreover, p27 knockdown partially attenuated the inhibition of HCT116 cells growth by PNO1 knockdown. The up-stream studies of PNO1 identified miR-326 as a candidate miRNA directly targeting to CDS-region of PNO1 and its overexpression significantly down-regulated PNO1 protein expression, resulting in suppression of cell growth, decrease of proteasome activities and assembly, as well as increasing the stability of p27 in CRC cells. These findings indicated that miR-326 overexpression can suppress CRC cell growth, acting as an endogenous proteasome inhibitor by targeting PNO1.

Objective To explore the expression and significance of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway in vascular tissue of intimal hyperplasia after arteriovenous fistula (AVF) and explore the effect of suppressing MAPK/ERK pathway on autophagy and proliferation of myofibroblasts. Methods From January 2023 to March 2023, 6 patients undergoing reconstruction of AVF were selected. Vascular tissues of patients with severe intimal hyperplasia were collected in observation group while normal collateral venous tissues requiring ligation in control group. General data were collected before operation and inner diameter and intima thickness of vessels were measured by ultrasound. The vascular expression levels of phosphorylation-extracellular regulated protein kinase 1/2 (p-ERK1/2), myosin-like B cell lymphoma/leukemia-2 interacting protein 1 (Beclin-1) and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot (WB) and correlation with venous intimal thickness was examined. Myofibroblast was cultured in uremic sera and exposed to ERK1/2 inhibitor corynoxeine. Total protein and RNA of cells were extracted and the expression changes of Beclin-1 and PCNA detected by WB and real-time polymerase chain reaction (PCR). Results Insufficient blood flow appeared during dialysis. Gray scale ultrasound indicated that venous intima thickened obviously [(0.143±0.014) cm vs (0.097±0.016) cm] at the stenosis of AVF and average diameter of vascular lumen was (0.166±0.028) cm. As compared with normal collateral vascular tissues, the expressions of p-ERK1/2, Beclin-1 and PCNA proteins were markedly up-regulated in vascular tissues of severe intimal hyperplasia and the differences were statistically significant (P

Abstract Similar to optical spin-orbit interactions (SOIs), acoustic SOIs are anticipated to offer fresh perspectives and capabilities for acoustic manipulation beyond conventional scalar degrees of freedom. However, the acoustic extrinsic SOIs caused by particular properties of the medium were seldom explored. Here, the acoustic extrinsic SOI is observed in a double spiral acoustic beam (DSAB), as evidenced by the rotation of the spatial intensity pattern along the propagation axis. The interaction of the acoustic plane wave with the well-designed artificial flat structure generates two non-paraxial focused acoustic vortices (NFAVs) with different spin angular momentums. The coaxial coupling between them leads to acoustic spin-controlled orbital rotation (SOR). Theoretical formulations, supported by numerical simulations and experimental results, are provided to demonstrate the validity of acoustic SOR. Our work provides new perspectives and capabilities for understanding sound processing, and may open an avenue for the development of spin-orbit acoustics.

Abstract Background Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. Results In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137 –/– ) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137 –/– miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137 –/– miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. Conclusions Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137 –/– miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.

Abstract Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

The wolf spider Pardosa astrigera L. Koch, 1878, an important biological control agent for pests in agriculture, is widely distributed in various ecosystems across East Asia. This study used mitochondrial DNA and aimed to provide an in-depth understanding of population genetic structure and evolutionary history throughout the species. Mitochondrial gene sequences from 107 samples of P. astrigera from 25 East Asian populations were used for genetic analyses. Our data revealed an asymmetric phylogeographic distribution in two sympatric lineages (1–2) of P. astrigera in continental East Asia. The spatio-temporal pattern of two mitotypes of P. astrigera in this region gives strong support for a Northeast Asian origin during the late Pleistocene (~1.69 million years ago) and the population expansion time of ~74,340 (58,832–104,236) years ago (during the last glacial period) and dual colonization around East Asia from two directions: from North to South and from East to West. Our phylogeographic results suggested that Pleistocene climate oscillations with subsequent fragmentation events and secondary contacts were the major impact factors of the diversification, geographic distribution, and expansion patterns of P. astrigera, and human activities and ballooning probably accelerated its recent dispersal.

Programmed cell death contributes to neurological damage in ischemic stroke, especially during the reperfusion stage. Several cell death pathways have been tested preclinically and clinically, including ferroptosis, necroptosis, and apoptosis. However, the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation. Here, we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion, followed by apoptosis. Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion, while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation. Protein–protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice. Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis. Collectively, these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.

Background In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens.Methods In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes.Results Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of −5.2% and −3.3%; both were >−10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1–3 severity.Conclusions Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL.Trial registration number Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

ObjectiveThis study explores the effectiveness of new media in enhancing public enthusiasm for voluntary blood donation in the post-pandemic era and proposes effective publicity strategies to promote the sustainability and healthy development of blood donation activities.MethodsA questionnaire survey was widely used to collect public opinions and attitudes toward voluntary blood donation. The sample data underwent rigorous reliability and validity analysis to ensure authenticity and reliability. Statistical methods such as correlation analysis and regression analysis were employed to deeply investigate the underlying relationships between factors like new media publicity, emotional value, social recognition, convenience, information reliability, and willingness to donate blood voluntarily. Based on these analyses, a research model was constructed, and relevant hypotheses were verified through empirical methods.ResultsThe study found that new media publicity may be associated with increasing the willingness of the public to voluntarily donate blood. Survey participants indicated that they were more likely to consider donating blood after exposure to new media publicity. Among these factors, the emotional value and content conveyed by the publicity appeared to be particularly important. Additionally, our research revealed that social recognition, the convenience of blood donation, and the reliability of promotional information seemed to have a direct impact on the public’s willingness to donate blood. At the same time, these factors may indirectly promote actual blood donation behavior by enhancing the public’s emotional resonance and acceptance of blood donation.ConclusionThis study suggests that new media may play multiple positive roles in promoting voluntary blood donation. Based on these findings, we propose a series of strategic recommendations, including further optimizing publicity content, striving to enhance the public’s emotional resonance, improving the reliability of promotional information, and enhancing service convenience. These suggestions aim to potentially raise public awareness and willingness to participate in voluntary blood donation, providing a scientific basis and strong support for the promotion of voluntary blood donation in the post-epidemic era.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Beijing, with the highest number of motor vehicles in China, significantly contributes to O3 pollution through substantial NOx and VOC emissions in the on-road transportation sector. Understanding the unique impact of emissions from different vehicle types on O3 levels is crucial for developing targeted strategies for O3 pollution. This study applied the Community Multiscale Air Quality Modeling System (CMAQ) to comprehensively investigate the impacts of emissions from different vehicle types on O3 levels in various regions of Beijing and to provide valuable insights into source contributions and formation processes. The results revealed that various vehicle types exhibited different spatial-temporal emission patterns, with medium-heavy duty trucks (HDT) and mini-light passenger vehicles (LDPV) identified as the primary contributors to NOx (36.1 %) and VOC (57.6 %) emissions. Using the Integrated Source Apportionment Method (ISAM) coupled in CMAQ, we found the total vehicle emissions contributed to over 20 % of daily maximum 8–h average O3 (MDA8 O3) concentration, ranked as the second largest contributor after regional transport. Contributions to O3 formation from LDPV and medium-large passenger vehicles (MDPV) were 2.6–4.0 and 4.2–6.8 ppb and mainly concentrated in urban areas, while the contributions from mini-light duty trucks (LDT) and HDT were 3.5–4.8 and 3.7–6.2 ppb and mainly concentrated in suburban areas. Through scenario analysis that removed emissions from specific types of vehicles, we found removing LDPV emissions led to decreases in daytime O3 concentration by 0.3–3.8 ppb. In contrast, removing MDPV emissions led to notable O3 increases by 4.0–11.8 ppb at rush hours. Removing LDT and HDT emissions resulted in 0.6–8.0 ppb increases in nocturnal O3 concentrations while 0.8–2.0 ppb decreases during the afternoon. This research highlights the necessity of tailoring control strategies for different vehicle types to effectively reduce O3 levels in Beijing and provides useful information for decision-makers to formulate effective measures of vehicle management in the future.

AbstractThe pond wolf spider Pardosa pseudoannulata Bösenberg & Strand, 1906 (Araneae: Lycosidae) is an important predator of agricultural pests in southern, eastern and southeastern Asia. Here, we report the complete mitogenome of this spider reconstructed from Illumina sequencing data. The circular mitogenome length is 14,533 bp with the nucleotide composition A (33.3%), C (8.2%), G (15.2%), and T (43.3%). The P. pseudoannulata mitogenome comprises 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and a control region. Phylogenetic analyses of Lycosidae mitogenomes supported the monophyly of the subfamily Pardosinae and the two genera Pardosa and Alopecosa, and indicated the polyphyly of the subfamily Lycosinae and the paraphyly of its type genus Lycosa. In this study, P. pseudoannulata is the closest relative to P. pusiola. These results provide useful genetic information for future studies on the diversity, phylogeny, and evolution for wolf spiders.

Abstract Ultrasonic imaging is crucial in the fields of biomedical engineering for its deep penetration capabilities and non-ionizing nature. However, traditional techniques heavily rely on impedance differences within objects, resulting in poor contrast when imaging acoustically transparent targets. Here, we propose a compact spatial differentiator for underwater isotropic edge-enhanced imaging, which enhances the imaging contrast without the need for contrast agents or external physical fields. This design incorporates an amplitude meta-grating for linear transmission along the radial direction, combined with a phase meta-grating that utilizes focus and spiral phases with a first-order topological charge. Through theoretical analysis, numerical simulations, and experimental validation, we substantiate the effectiveness of our technique in distinguishing amplitude objects with isotropic edge enhancements. Importantly, this method also enables the accurate detection of both phase objects and artificial biological models. This breakthrough creates new opportunities for applications in medical diagnosis and nondestructive testing.

Abstract Glioma is easy to develop resistance to temozolomide (TMZ). TMZ-resistant glioma secretes interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), recruiting regulatory T cell (Treg) and inhibiting the activity of T cells and natural killer cell (NK cell), subsequently forming an immunosuppressive microenvironment. Oxaliplatin (OXA) greatly inhibits the proliferation of TMZ-resistant glioma cells, but the ability of OXA to cross blood–brain barrier (BBB) is weak. Thus, the therapeutic effect of OXA on glioma is not satisfactory. Transferrin receptor 1 (TfR1) is highly expressed in brain capillary endothelial cells and TMZ-resistant glioma cells. In this study, OXA was loaded into ferritin (Fn) to prepare glioma-targeted oxaliplatin/ferritin clathrate OXA@Fn. OXA@Fn efficiently crossed BBB and was actively taken up by TMZ-resistant glioma cells via TfR1. Then, OXA increased the intracellular H2O2 level and induced the apoptosis of TMZ-resistant glioma cells. Meanwhile, Fn increased Fe2+ level in TMZ-resistant glioma cells. In addition, the expression of ferroportin 1 was significantly reduced, resulting in Fe2+ to be locked up inside the TMZ-resistant glioma cells. This subsequently enhanced the Fenton reaction and boosted the ferroptosis of TMZ-resistant glioma cells. Consequently, T cell mediated anti-tumor immune response was strongly induced, and the immunosuppressive microenvironment was significantly reversed in TMZ-resistant glioma tissue. Ultimately, the growth and invasion of TMZ-resistant glioma was inhibited by OXA@Fn. OXA@Fn shows great potential in the treatment of TMZ-resistant glioma and prospect in clinical transformation. Graphical Abstract

Chronic myeloid leukemia (CML) is a common adult leukemia. Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis. The N6-methyladenine (m6A) modification plays an important regulatory role in various physiological and pathological processes. KIAA1429 is a known m6A regulator, but the biological role of KIAA1429 in CML is unclear. In this study, we observed that the m6A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML. Notably, KIAA1429 regulated the total level of RNA m6A modification in the CML cells and promoted the malignant biological behaviors of CML cells, including proliferation, migration, and imatinib resistance. Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m6A/YTHDF1 axis, consequently inhibiting CML proliferation and drug efflux, ultimately increasing the sensitivity of CML cells to imatinib. Moreover, the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis. Rucaparib, a recently developed anti-cancer agent, suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis. Rucaparib also inhibited the tumorigenesis of CML cells in vivo. The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib. Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m6A/YTHDF1 axis to up-regulate RAB27B expression, thereby promoting CML progression. Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.

The discovery of natural products derived from marine sources has demonstrated a consistent upward trajectory for the decade of 2011-2020, holding significant promise for the development of novel drugs and many other marine bioproducts. In recent years, the spotlight has shifted away from marine sponges (Porifera) towards marine microorganisms as the primary source of discovery. Despite reports of marine sponges spanning 20 different orders and being the subject of 769 papers between 2011 and 2020, they only contributed to 19.29% of all new compounds discovered, in contrast to 51.94% by marine microorganisms and phytoplankton. 563 new compounds were reported from marine sponge-associated microbes, more than doubling the number for the previous decade (2001-2010). It heralds a positive outlook for a sustainable resource strategy as the extraction of bioactive compounds produced by pure cultures of sponge-associated microbes could overcome supply challenges that arise with isolation from host sponges for the same compound. However, the application of novel marine natural products (MNPs) remains challenging due to the limited yield of compounds from large amounts of sponges. This review covers the literature published between 2011 and 2020, focusing on MNPs isolated from marine sponges. A total of 2603 new compounds are documented, detailing their chemical classification, biological activities, source country or geographic locations, and the taxonomic information of the source organisms, including order, family, genus, and species.

Background Colorectal cancer (CRC) remains a global health concern with persistently high incidence and mortality rates. However, the specific pathogenesis of CRC remains poorly understood. This study aims to investigate the role and pathogenesis of serine and arginine rich splicing factor 10 (SRSF10) in colorectal cancer. Methods Bioinformatics analysis was employed to predict SRSF10 gene expression in CRC patients. Functional experiments involving SRSF10 knockdown and overexpression were conducted using CCK8, transwell, scratch assay, and flow cytometry. Additionally, the PRIdictor website was utilized to predict the SRSF10 interaction site with RFC5. The identification of different transcripts of SRSF10-acting RFC5 pre-mRNA was achieved through agarose gel electrophoresis. Result The knockdown of SRSF10 inhibited the proliferation and migration ability of CRC cells, while promoting apoptosis and altering the DNA replication of CRC cells. Conversely, when SRSF10 was highly expressed, it enhanced the proliferation and migration ability of CRC cells and caused changes in the cell cycle of colorectal cancer cells. This study revealed a change in the replicating factor C subunit 5 (RFC5) gene in colorectal cancer cells following SRSF10 knockdown. Furthermore, it was confirmed that SRSF10 increased RFC5 exon2-AS1(S) transcription variants, thereby promoting the development of colorectal cancer through AS1 exclusion to exon 2 of RFC5. Conclusion In summary, this study demonstrates that SRSF10 promotes the progression of colorectal cancer by generating an aberrantly spliced exclusion isoform of AS1 within RFC5 exon 2. These findings suggest that SRSF10 could serve as a crucial target for the clinical diagnosis and treatment of CRC.

Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are associated with drug resistance and prognosis in lung cancer; however, the consistency and clinical value of PIK3CA mutations between tissue and liquid samples are unknown. Methods: Circulating tumor DNA (ctDNA) and matched tumor tissue samples from 405 advanced lung cancer patients were collected at Jilin Cancer Hospital between 2018 and 2022, and the PIK3CA mutation status was sequenced using next-generation sequencing based on a 520 gene panel. The viability of different mutant lung cancer cells was detected using MTT assay. Results: PIK3CA mutations were detected in 46 (5.68 %) of 810 lung cancer samples, with 21 (5.19 %) of 405 plasma samples and 25 (6.17 %) of 405 matched tissues. p.Glu542Lys, p.Glu545Lys, and p.His1047Arg were the most common mutation types of PIK3CA in both the ctDNA and tissue samples. The concordance of PIK3CA mutations was 97.53 % between ctDNA and matched tissues (kappa: 0.770, P = 0.000), with sensitivity/true positive rate of 72.0 %, specificity/true negative rate of 99.2 %, and negative predictive value and positive predictive value of 0.982 and 0.857, respectively (AUC = 0.856, P = 0.000). Furthermore, the concordance of PIK3CA mutations was 98.26 % in lung adenocarcinoma and 96.43 % in lung squamous cell carcinoma. TP53 and EGFR were the most common concomitant mutations in ctDNA and tissues. Patients with PIK3CA mutations showed a high tumor mutational burden (TMB) (P

ObjectiveSelecting between programmed cell death ligand 1 (PD-L1) inhibitor or programmed cell death 1 (PD-1) inhibitor plus chemotherapy as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) patients urgently needs to be answered.MethodsEligible phase 3 randomized clinical trials evaluating regimens based on PD-1/PD-L1 inhibitors as first-line treatment in ES-SCLC patients were systematically searched on the PubMed and Cochrane Library databases and major international conferences from 01/01/2018 to 18/09/2023. The individual patient data (IPD) were recuperated from the Kaplan–Meier curves of the overall survival (OS) and progression-free survival (PFS) of the included studies using the IPDfromKM method. The reconstructed data were pooled into unified arms, including the PD-L1 inhibitor plus chemotherapy group (PD-L1 group), PD-1 inhibitor plus chemotherapy group (PD-1 group), and PD-1 (L1) inhibitor and chemotherapy plus other (anlotinib group, tiragolumab group, and tremelimumab group). Subsequently, the PD-L1 group was indirectly compared with the other groups. A standard statistical analysis was conducted using the “survival” package for the time-to-event endpoint. The primary outcomes were the OS and PFS of the PD-L1 group and the PD-1 inhibitor group. The secondary outcomes included safety and the 12- and 24-month restricted mean survival time (RMST) of the PD-L1 group and PD-1 group.ResultsA total of 9 studies including 11 immunotherapy cohorts were included. No significant difference in PFS (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.86–1.06), OS (HR: 0.94, 95% CI: 0.84–1.05), and 12-month and 24-month RMST for OS (P = 0.198 and P = 0.216, respectively) was observed between the PD-L1 group and the PD-1 group. In contrast, the anlotinib group showed significantly better OS (HR: 0.70, 95% CI: 0.55–0.89), PFS (HR: 0.69, 95% CI: 0.58–0.83), and RMST for OS compared to the PD-L1 group. The tiragolumab group showed similar efficacy to the PD-L1 group. However, the tremelimumab group exhibited inferior efficacy than the PD-L1 group. The incidence of ≥grade 3 treatment-emergent adverse events (TEAEs) was significantly higher in the PD-1 group compared to the PD-L1 group (85.4% vs. 69.6%, P

Facial recognition technology (FRT) has emerged as a powerful tool for public governance and security, but its rapid adoption has also raised significant concerns about privacy, civil liberties, and ethical implications. This paper critically examines the current rules and policies governing FRT, highlighting the tensions between state and corporate interests on one hand, and individual rights and ethical considerations on the other. The study also investigates international legal frameworks aimed at protecting individual rights and privacy, arguing that current legislative measures often fall short of robust scholarly standards and international human rights norms. The paper concludes with recommendations for developing principled and adaptable governance frameworks that harness the benefits of FRT while mitigating its risks and negative impacts, underscoring the importance of placing human rights and ethics at the center of regulating this transformative technology.

Summary: Background: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). Methods: In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80 mg once daily or gefitinib 250 mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Findings: Three hundred and fifty-seven patients (furmonertinib group, n = 178; gefitinib group, n = 179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25–4.04], p = 0.027), nausea/vomiting (−1.56 [95% CI −2.62 to −0.49], p = 0.004), appetite loss (−2.24 [95% CI −4.26 to −0.23], p = 0.029), diarrhoea (−3.36 [95% CI −5.19 to −1.54], p < 0.001), alopecia (−2.62 [95% CI −4.54 to −0.71], p = 0.007), and pain in other parts (−4.55 [95% CI −7.37 to −1.74], p = 0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42–0.94], p = 0.021), cognitive functioning (0.73 [95% CI 0.54–0.98], p = 0.034), nausea/vomiting (0.64 [95% CI 0.41–0.99], p = 0.042), appetite loss (0.63 [95% CI 0.43–0.92], p = 0.016), diarrhoea (0.63 [95% CI 0.46–0.85], p = 0.002), dyspnoea (0.72 [95% CI 0.53–0.98], p = 0.034), cough (0.67 [95% CI 0.44–1.00], p = 0.049), dysphagia (0.54 [95% CI 0.35–0.83], p = 0.004), and alopecia (0.62 [95% CI 0.42–0.90], p = 0.012) was longer with furmonertinib versus gefitinib. Interpretation: In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Funding: Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

The pathogenesis of schizophrenia (SCZ) is heavily influenced by genetic factors. Ring finger protein 4 (RNF4) and squamous cell carcinoma antigen recognized by T cells 3 (SART3) are thought to be involved in nervous system growth and development via oxidative stress pathways. Moreover, they have previously been linked to SCZ. Yet the role of RNF4 and SART3 in SCZ remains unclear. Here, we investigated how these two genes are involved in SCZ by studying their variants observed in patients. We first observed significantly elevated mRNA levels of RNF4 and SART3 in the peripheral blood in both first-episode (n = 30) and chronic (n = 30) SCZ patients compared to controls (n = 60). Next, we targeted-sequenced three single nucleotide polymorphisms (SNPs) in SART3 and six SNPs in RNF4 for association with SCZ using the genomic DNA extracted from peripheral blood leukocytes from SCZ participants (n = 392) and controls (n = 572). We observed a combination of SNPs that included rs1203860, rs2282765 (both in RNF4), and rs2287550 (in SART3) was associated with increased risk of SCZ, suggesting common pathogenic mechanisms between these two genes. We then conducted experiments in HEK293T cells to better understand the interaction between RNF4 and SART3. We observed that SART3 lowered the expression of RNF4 through ubiquitination and downregulated the expression of nuclear factor E2-related factor 2 (NRF2), a downstream factor of RNF4, implicating the existence of a possible shared regulatory mechanism for RNF4 and SART3. In conclusion, our study provides evidence that the interaction between RNF4 and SART3 contributes to the risk of SCZ. The findings shed light on the underlying molecular mechanisms of SCZ and may lead to the development of new therapies and interventions for this disorder.

ABSTRACT: The aim of this research was to explore the effects of ellagic acid (EA) on growth performance, meat quality, and metabolomics profile of broiler chickens. 240 healthy yellow-feathered broilers were randomly divided into 4 groups (6 replicates/group and 10 broilers /replicate): 1) a standard diet (CON); 2) CON+0.01% EA; 3) CON+0.02% EA; 4) CON+0.04% EA. Compared with the CON group, dietary 0.02% EA increased linearly and quadratically the ADG and lowered F/G ratio from 29 to 56 d and from 1 to 56 d of age (P < 0.05). The EA groups had higher spleen index and showed linear and quadratic improve thymus index (P < 0.05). A total of 0.02% EA linearly and quadratically increased the leg muscle percentage and quadratically increased the breast muscle percentage (P < 0.05). Compared to the control diet, 0.02% EA decreased quadratically the L* and increased a* of breast muscle at 45 min postslaughter (P < 0.05), and quadratically decreased (P < 0.05) the b* and increased linearly and quadratically (P < 0.05) drip loss. Additionally, EA improved linearly and quadratically (P < 0.05) serum total protein concentration and reduced linearly and quadratically (P < 0.05) serum blood urea nitrogen concentration. A total of 0.02% EA quadratically increased catalase activity and decreased malondialdehyde concentration in breast muscle compared with the control diet (P < 0.05). 0.02% and 0.04% EA could linearly and quadratically increase (P < 0.05) the concentrations of histidine, leucine and essential amino acids (EAA), 0.02% EA could linearly and quadratically increase (P < 0.05) the concentrations of threonine, glutamate, and flavored amino acids in breast muscle. 0.02% EA linearly and quadratically improved the C20:3n6, C22:6n3, polyunsaturated fatty acid (PUFA) concentrations, and the ratio of PUFA to saturated fatty acids (SFA), but reduced the C16:0 and the SFA concentrations in breast muscle than the CON group (P < 0.05). The EA diet linearly increased (P = 0.035) and quadratically tended (P = 0.068) to regulate the C18:2n6c concentration of breast muscle. Metabolomics showed that alanine metabolism, aspartate and glutamate metabolism, arginine and proline metabolism, taurine and hypotaurine metabolism, and glycerophospholipid metabolism were the most differentially abundant. These results showed that EA supported moderate positive effects on growth performance, meat quality, and metabolomics profile of broilers.

Abstract This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0–11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9–65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy. Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.

Abstract Small cell lung cancer (SCLC) is heterogenous in phenotype and microenvironment. Dynamic phenotypic reprogramming, leading to heterogeneity, is prevalent in SCLC, while the mechanisms remain incompletely understood. Cancer-associated fibroblasts (CAFs) possess comprehensive roles in cancer progression, while their function in phenotypic reprogramming of SCLC remain elusive. Here, we obtained transcriptome data of SCLC tissues from publicly available databases, subsequently estimated abundance of CAFs. We found CAF-abundant SCLC exhibited non-neuroendocrine (Non-NE) characteristics. Supporting this, the positive correlation of expression level of α-SMA, the CAF marker, and expression level of REST, protein typically expressed in Non-NE type SCLC, was identified in SCLC tissue arrays. Moreover, we revealed that fibroblasts inhibited NE markers expression and cell proliferation of SCLC cells in the co-culture system comprising lung fibroblasts and SCLC cells, indicating a phenotypic reprogramming from NE to Non-NE. During this process, fibroblast-derived IL-6 activated the JAK2/STAT3 signaling, upregulated c-MYC expression, and subsequently activated the NOTCH pathway, driving phenotypic reprogramming. Moreover, CAF-enriched SCLC exhibited increased immune cell infiltration, elevated expression of immune activation-related signatures, and checkpoint molecules. Our data also highlighted the chemoresistance induced by fibroblasts in SCLC cells, which was effectively reversed by JAK inhibitor. In conclusion, fibroblasts induced phenotypic reprogramming of SCLC cells from NE to Non-NE, likely contributes to inflamed immune microenvironment and chemoresistance. These findings provide novel insights into the clinical implications of CAFs in SCLC.

In the digital age, the rapid growth of web information has made it increasingly challenging for individuals and organizations to effectively explore and extract valuable insights from the vast amount of information available. This paper presents a novel approach to automated web text summarization that combines advanced natural language processing techniques with recent breakthroughs in deep learning. we propose a dual-faceted technique that leverages extensive pre-training on a broad dataset outside the domain, followed by a unique refined tuning process. We introduce a carefully curated dataset that captures the heterogeneous nature of web articles and propose an innovative pre-training and tuning approach that establishes a new state-of-the-art in news summarization. Through extensive experiments and rigorous comparisons against existing models, we demonstrate the superiority of our method, particularly highlighting the crucial role of the refined tuning process in achieving these results. Through rigorous experimentation against state-of-the-art models, we demonstrate the superior performance of our approach, highlighting the significance of their refined tuning process in achieving these results.

Abstract Active Learning has emerged as a viable solution for addressing the challenge of labeling extensive amounts of data in data-intensive applications such as computer vision and neural machine translation. The main objective of Active Learning is to automatically identify a subset of unlabeled data samples for annotation. This identification process is based on an acquisition function that assesses the value of each sample for model training. In the context of computer vision, image classification is a crucial task that typically requires a substantial training dataset. This research paper introduces innovative selection methods within the Active Learning framework, aiming to identify informative images from unlabeled datasets while minimizing the number of required training data. The proposed methods, namely Similari-ty-based Selection, Prediction Probability-based Selection, and Competence-based Active Learning, have been extensively evaluated through experiments conducted on popular datasets like Cifar10 and Cifar100. The experimental results demonstrate that the proposed methods outperform random selection and conventional selection techniques. The superior performance of the novel selection methods underscores their effectiveness in enhancing the Active Learning process for image classification tasks.

Abstract Background and objective Numerous previous studies have assessed the prognostic role of 18F-fluorodeoxyglucose positron-emission tomography (18F FDG PET) in patients with biliary tract cancer (BTC), but those results were inconsistent. The present study aims to determine the predictive value of 18F FDG PET in BTC patients via a meta-analysis. Methods The underlying studies related to 18F FDG PET and BTC patients` outcomes were searched and identified in the online databases. The interested parameters include total lesion glycolysis (TLG), metabolic tumor volume (MTV), primary tumor and metastatic lymph node (LN) maximum standardized uptake value (SUVmax), as well as change of SUVmax (ΔSUVmax) during treatment. Overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were considered as the primary endpoints. Hazard ratio (HR) and corresponding 95% confidence intervals (CIs) were defined as the effective measure and calculated by a pooled analysis. Publication bias was assessed by funnel plot, Bagg’s and Egger’s tests. Results Totally, 23 studies involving 1478 patients were included in the present meta-analysis. After a pooled analysis, it revealed that a high SUVmax was significantly associated with a poor OS (HR:2.07, 95%CI: 1.74–2.46, P = 0.000) and DFS (HR: 2.28, 95%CI: 1.53–3.41, P = 0.000). In addition, an increased TLG level contributed to a shorter OS (HR:1.91, 95%CI: 1.26–2.90, P = 0.002) and DFS (HR: 4.34, 95%CI: 1.42–13.27, P = 0.01). Moreover, we confirmed that an elevated MTV was significantly associated with increased mortality (HR:2.04, 95%CI:1.26–3.31, P = 0.004) and disease relapse (HR: 3.88, 95%CI:1.25–12.09, P = 0.019) risks. Besides, the present study uncovered that increased ΔSUVmax could predict poor OS (HR:1.26, 95%CI:1.06–1.50, P = 0.008) instead of PFS (HR: 1.96, 95%CI: 0.82–4.72, P = 0.280). Lastly, we found that LN SUVmax did not link to OS (HR: 1.49, 95%CI: 0.83–2.68, P = 0.178). No obvious publication bias was detected in the present study. Conclusion 18F FDG PET parameters, including SUVmax, TLG, MTV, and ΔSUVmax, could be applied as convenient and reliable factors for predicting BTC patients` outcomes.

This research addresses the critical challenge of classifying surface defects in lithium electronic components, crucial for ensuring the reliability and safety of lithium batteries. With a scarcity of specific defect data, we introduce an innovative Cross-Domain Generalization (CDG) approach, incorporating Cross-domain Augmentation, Multi-task Learning, and Iteration Learning. Leveraging a steel surface defect dataset as foundational knowledge, our approach compensates for the limited lithium-specific data and enhances model generalization. We also introduce the Lithium Electronic Surface Defect Classification (IESDC) dataset, demonstrating significant accuracy improvements over baseline methods. Our comprehensive evaluation covers model interpretability, robustness, and adaptability. Beyond battery technology, this methodology offers a framework for data scarcity challenges in various industries, emphasizing the importance of adaptable learning methods.

Abstract Glaucoma is a highly heritable disease, and myocilin was the first identified causal and most common pathogenic gene in glaucoma. Serine-to-proline mutation at position 341 of myocilin (MYOCS341P) is associated with severe glaucoma phenotypes in a five-generation primary open-angle glaucoma family. However, the underlying mechanisms are underexplored. Herein, we established the MYOCS341P transgenic mouse model and characterized the glaucoma phenotypes. Further, we systematically explored the functional differences between wild-type and MYOCS341P through immunoprecipitation, mass spectrometry, and RNA-seq analyses. We found that MYOCS341P transgenic mice exhibit glaucoma phenotypes, characterized by reduced aqueous humor outflow, elevated intraocular pressure, decreased trabecular meshwork (TM) cell number, narrowed Schlemm’s canal, retinal ganglion cell loss, and visual impairment. Mechanistically, the secretion of dysfunctional MYOCS341P accumulated in the endoplasmic reticulum (ER), inducing ER stress and dysregulation of autophagy, thereby promoting TM cell death. We describe an effective transgenic model for mechanistic studies and the screening of therapeutic targets. Our data generated from high-throughput analyses help elucidate the mechanism underlying mutant MYOC-related glaucoma.

Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

AbstractContext Gastrodin has been used as antihypertension therapy in China; however, the mechanisms underlying the effects of gastrodin have yet to be fully elucidated.Objective To explore the therapeutic efficiency of gastrodin as an antihypertensive and determine the mechanisms underlying this effect.Materials and methods C57BL/6 mice were continuously administered angiotensin II (Ang II) (500 ng/kg/min) to induce hypertension. Mice were randomly divided into control, Ang II and Ang II + gastrodin groups. Mice received intragastric administration of gastrodin (5 mg/kg) or double distilled water once a day for 4 weeks. Blood pressure, pulse wave velocity (PWV), thickness of the abdominal aorta, pathological morphology and differential expression transcripts (DETs) were assessed. Abdominal aorta rings and primary isolated vascular smooth muscle cells were subjected to Ang II stimulation to induce hypertension as ex vivo and in vitro models, respectively. Vascular ring tension, release of Ca2+ and levels of proteins involved in the myosin light chain kinase (MLCK)/phospho-myosin light chain 2 (p-MLC2) pathway were determined.Results Gastrodin treatment attenuated increases in blood pressure, PWV and thickness of the abdominal aorta. Treatment with gastrodin resulted in 2785 DETs and the enrichment of vascular contraction and calcium signalling pathways. Gastrodin treatment attenuated Ang II-induced vasoconstriction, produced a norepinephrine-precontracted vasodilation effect (attenuated by verapamil), and reduced intracellular Ca2+ release. Furthermore, gastrodin suppressed activation of the MLCK/p-MLC2 pathway in vivo and in vitro.Conclusions Gastrodin treatment lowers blood pressure, suppresses Ang II-induced vascular contraction and MLCK/p-MLC2 pathway activation, thereby demonstrating the mechanisms underlying the therapeutic efficacy of gastrodin as an antihypertensive.

Gastrodin, a highly potent compound found in the traditional Chinese medicine Gastrodia elata Blume, exhibits significant antihypertensive properties. However, its role and the mechanism behind its protective effects on hypertensive cardiac conditions are not well understood. This study aims to investigate the cardiac protective effects and underlying mechanisms of gastrodin in angiotensin II (Ang II)-induced hypertensive models, both in vivo and in vitro. Treatment with gastrodin significantly decreased blood pressure and the heart weight/tibial length (HW/TL) ratio and attenuated cardiac dysfunction and pathological damage in Ang II-infused C57BL/6 mice. RNA sequencing analysis (RNA-seq) revealed 697 up-regulated and 714 down-regulated transcripts, along with 1105 signaling pathways, in Ang II-infused C57BL/6 mice following gastrodin treatment, compared to Ang II-induced hypertensive mice. Furthermore, the analyses of the top 30 Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway indicated significant enrichment in apoptosis and the peroxiredoxin 2 (PRDX2)/p53 pathway. Consistently, gastrodin treatment significantly reduced myocardial apoptosis in both the cardiac tissues of Ang II-induced hypertensive mice and Ang II-stimulated H9c2 cells. Additionally, gastrodin treatment significantly decreased the protein levels of PRDX2, p53, cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2 ratio in the cardiac tissues of Ang II-infused mice and H9c2 cells stimulated with Ang II. In conclusion, gastrodin treatment can mitigate hypertension-induced myocardial apoptosis in hypertensive mice by inhibiting the PRDX2/p53 pathway.

IntroductionAlgorithmic decision-making systems are widely used in various sectors, including criminal justice, employment, and education. While these systems are celebrated for their potential to enhance efficiency and objectivity, they also pose risks of perpetuating and amplifying societal biases and discrimination. This paper aims to provide an indepth analysis of the types of algorithmic discrimination, exploring both the challenges and potential solutions.MethodsThe methodology includes a systematic literature review, analysis of legal documents, and comparative case studies across different geographic regions and sectors. This multifaceted approach allows for a thorough exploration of the complexity of algorithmic bias and its regulation.ResultsWe identify five primary types of algorithmic bias: bias by algorithmic agents, discrimination based on feature selection, proxy discrimination, disparate impact, and targeted advertising. The analysis of the U.S. legal and regulatory framework reveals a landscape of principled regulations, preventive controls, consequential liability, self-regulation, and heteronomy regulation. A comparative perspective is also provided by examining the status of algorithmic fairness in the EU, Canada, Australia, and Asia.ConclusionReal-world impacts are demonstrated through case studies focusing on criminal risk assessments and hiring algorithms, illustrating the tangible effects of algorithmic discrimination. The paper concludes with recommendations for interdisciplinary research, proactive policy development, public awareness, and ongoing monitoring to promote fairness and accountability in algorithmic decision-making. As the use of AI and automated systems expands globally, this work highlights the importance of developing comprehensive, adaptive approaches to combat algorithmic discrimination and ensure the socially responsible deployment of these powerful technologies.

Abstract Traumatic brain injury (TBI) leads to progressive neurodegeneration that may be caused by chronic traumatic encephalopathy (CTE). However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, axonemal dynein light intermediate polypeptide 1 (DNALI1), and elucidated its potential pathogenic role in post‐TBI neurodegeneration. The DNALI1 gene is systematically screened through analyses of Aging, Dementia, and TBI studies, confirming its elevated expression both in vitro and in vivo. Moreover, it is observed that altered DNALI1 expression under normal conditions has no discernible effect. However, upon overexpression, DNALI1 inhibits autophagosome‐lysosome fusion, reduces autophagic flux, and exacerbates cell death under pathological conditions. DNALI1 silencing significantly enhances autophagic flux and alleviates neurodegeneration in a CTE model. These findings highlight DNALI1 as a potential key target for preventing TBI‐related neurodegeneration.

This paper explores the evidentiary significance of blockchain records and the procedural implications of integrating this technology into the U.S. judicial system, as several states have undertaken legislative measures to facilitate the admissibility of blockchain evidence. We employ a comprehensive methodological approach, including legislative analysis, comparative case law analysis, technical examination of blockchain mechanics, and stakeholder engagement. Our study suggests that blockchain evidence may be categorized as hearsay exceptions or non-hearsay, depending on the specific characteristics of the records. The paper proposes a specialized consensus mechanism for standardizing blockchain evidence authentication and outlines strategies to enhance the technology’s trustworthiness. It also highlights the importance of expert testimony in clarifying blockchain’s technical aspects for legal contexts. This study contributes to understanding blockchain’s integration into judicial systems, emphasizing the need for a comprehensive approach to its admissibility and reliability as evidence. It bridges the gap between technology and law, offering a blueprint for standardizing legal approaches to blockchain and urging ethical and transparent technology use.

ObjectiveThis study aimed to analyze the population characteristics of apheresis platelet donors in Chongqing Province and provide a scientific basis for the development of precise and efficient recruitment strategies. The ultimate goal is to increase the number of regular platelet donors in preparation for public health emergencies.MethodsThis study involved 53,089 blood donors who donated apheresis platelets to the Chongqing Blood Center from 2020 to 2022. Data regarding age, sex, blood type, education level, occupation, and frequency of blood donation were collected and analyzed to identify factors influencing platelet donation.ResultsBetween 2020 and 2022, the majority of apheresis platelet donors in Chongqing were aged 25–35 years, with a male-to-female ratio of 2.6:1. The ABO blood group distribution was O > A > B > AB. The apheresis platelet donors mainly consisted of college students, and the donors who had donated only once accounted for the greatest proportion.ConclusionBased on the population characteristics of apheresis platelet donors in Chongqing, blood collection and supply organizations must refine emergency blood collection and supply plans during public health emergencies. This study underscores the importance of developing precise and efficient recruitment strategies for apheresis platelet donors and expanding the pool of regular apheresis platelet donors. These measures are essential to ensure the timely, safe, and effective use of clinical blood resources during public health emergencies.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

Diabetic retinopathy (DR) is the most common ocular fundus disease in diabetic patients. Chronic hyperglycemia not only promotes the development of diabetes and its complications, but also aggravates the occurrence of senescence. Previous studies have shown that DR is associated with senescence, but the specific mechanism has not been fully elucidated. Here, we first detected the differentially expressed genes (DEGs) and cellular senescence level of db/db mouse retinas by bulk RNA sequencing. Then, we used single-cell sequencing (scRNA-seq) to identify the main cell types in the retina and analyzed the DEGs in each cluster. We demonstrated that p53 expression was significantly increased in retinal endothelial cell cluster of db/db mice. Inhibition of p53 can reduce the expression of SA-β-Gal and the senescence-associated secretory phenotype (SASP) in HRMECs. Finally, we found that p53 can promote FoxO3a ubiquitination and degradation by increasing the expression of the ubiquitin-conjugating enzyme UBE2L6. Overall, our results demonstrate that p53 can accelerate the senescence process of endothelial cells and aggravate the development of DR. These data reveal new targets and insights that may be used to treat DR.

Baby chicks administered a fecal transplant from adult chickens are resistant to Salmonella colonization by competitive exclusion. A two-pronged approach was used to investigate the mechanism of this process. First, Salmonella response to an exclusive (Salmonella competitive exclusion product, Aviguard®) or permissive microbial community (chicken cecal contents from colonized birds containing 7.85 Log10Salmonella genomes/gram) was assessed ex vivo using a S. typhimurium reporter strain with fluorescent YFP and CFP gene fusions to rrn and hilA operon, respectively. Second, cecal transcriptome analysis was used to assess the cecal communities’ response to Salmonella in chickens with low (≤5.85 Log10 genomes/g) or high (≥6.00 Log10 genomes/g) Salmonella colonization. The ex vivo experiment revealed a reduction in Salmonella growth and hilA expression following co-culture with the exclusive community. The exclusive community also repressed Salmonella’s SPI-1 virulence genes and LPS modification, while the anti-virulence/inflammatory gene avrA was upregulated. Salmonella transcriptome analysis revealed significant metabolic disparities in Salmonella grown with the two different communities. Propanediol utilization and vitamin B12 synthesis were central to Salmonella metabolism co-cultured with either community, and mutations in propanediol and vitamin B12 metabolism altered Salmonella growth in the exclusive community. There were significant differences in the cecal community’s stress response to Salmonella colonization. Cecal community transcripts indicated that antimicrobials were central to the type of stress response detected in the low Salmonella abundance community, suggesting antagonism involved in Salmonella exclusion. This study indicates complex community interactions that modulate Salmonella metabolism and pathogenic behavior and reduce growth through antagonism may be key to exclusion.

ObjectiveTo investigate the serum biomarkers in patients with drug-resistant epilepsy (DRE).MethodsA total of 9 DRE patients and 9 controls were enrolled. Serum from DRE patients was prospectively collected and analyzed for potential serum biomarkers using TMT18-labeled proteomics. After fine quality control, bioinformatics analysis was conducted to find differentially expressed proteins. Pathway enrichment analysis identified some biological features shared by differential proteins. Protein–protein interaction (PPI) network analysis was further performed to discover the core proteins.ResultsA total of 117 serum differential proteins were found in our study, of which 44 were revised upwards and 73 downwards. The up-regulated proteins mainly include UGGT2, PDIA4, SEMG1, KIAA1191, CCT7 etc. and the down-regulated proteins mainly include ROR1, NIF3L1, ITIH4, CFP, COL11A2 etc. Pathway enrichment analysis identified that the upregulated proteins were mainly enriched in processes such as immune response, extracellular exosome, serine-type endopeptidase activity and complement and coagulation cascades, and the down-regulated proteins were enriched in signal transduction, extracellular exosome, zinc/calcium ion binding and metabolic pathways. PPI network analysis revealed that the core proteins nodes include PRDX6, CAT, PRDX2, SOD1, PARK7, GSR, TXN, ANXA1, HINT1, and S100A8 etc.ConclusionThe discovery of these differential proteins enriched our understanding of serum biomarkers in patients with DRE and potentially provides guidance for future targeted therapy.

To study the alkaloids in the rhizomes of Stephania macrantha. The total alkaloids of S. macrantha were extracted by acid extraction and alkali precipitation method. Eleven alkaloids have been isolated and purified by silica gel column chromatography and preparative high performance liquid chromatography (HPLC). The structures of compounds were identified by spectroscopic methods (NMR and MS). The results were as follows: (1) Eleven compounds were designated as sinomenine (1), sinoactine (2), stepharine (3), reticuline (4), isocorydine (5), corydalmine (6), asimilobine (7), sukhodianine (8), dicentrine (9), 7-oxocrebanine (10) and palmatine (11). (2) The total alkaloids of S. macrantha and sinomenine had inhibitory activities on human lung cancer cells (A549), with IC50 values of 7.5×10-4 g·mL-1 and 6.59×10-9 g·mL-1, respectively. Compounds 2, 3, 4, 7, 8, 9 and 10 were isolated for the first time from S. macrantha. The chemical constituents from S. macrantha belong to five types of alkaloids such as morphanes, proaporphines, aporphines, benzyltetrahydroi soquinolines and protoberberines.

Abstract The oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core–shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS.

Abstract Background Dementia is characterized by progressive neurodegeneration and therefore early intervention could have the best chance of preserving brain health. There are significant differences in health awareness, living customs, and daily behaviors among Chinese older adults compared to Europeans and Americans. Because the synergistic benefits of multidomain non-pharmacological interventions are consistent with the multifactorial pathogenicity of MCI, such interventions are more appealing, easier to adhere to, and more relevant to daily life than single-mode interventions. One of the aims of this study is to verify the effect of multidomain intervention strategies for MCI patients based on Chinese population characteristics, and the other is to establish a biobank and image database to investigate the pathogenesis and pathways of cognitive impairment. Methods Our study was designed as a national multicenter, community-based randomized controlled trial (RCT). Twelve medical institutions in ten Chinese cities will participate in our study from 2020 to 2024, and 1080 community residents aged 50 and above will be enrolled as participants. Each sub-center will be responsible for 90 participants (30 people per community) across three communities (non-contact control group, health education group, and multidomain intervention group). The community will be the basic unit of the present study, and all participants in each community will receive the same intervention/control measure. Three working groups are set up in each sub-center to manage the three communities independently to minimize interference at the implementation level between the groups. The multidomain intervention group will receive integrated interventions including exercise, nutrition, sleep, health education and mindfulness meditation. All data generated by the research will be analyzed and processed by statistical software (such as SPSS 21.0, Python 3.0, etc.), and part of the research data will be displayed in the form of graphs and tables. Discussion In order to achieve a high-quality community intervention study, it is crucial to have a well-designed experimental protocol that follows rigorous scientific methodology. In addition, effective management of quality control measures and monitoring compliance throughout the study process are essential components. This study provides a detailed discussion of stakeholder compliance, research quality control, potential harm and mitigation, auditing, and future plans in order to better address research issues. Trial registration : ChiCTR2000035012 (July 27, 2020).

This study presents an innovative investigation into the wetting characteristic and flow behavior of sand particles, which have different shapes, sizes, and textures, when they bonded with silicate binder. The results revealed that the apparent contact angles of fine and angular particles with the binder are higher than those of coarse and circular particles. In addition, after modifying the four systems with anionic surfactants, the equilibrium contact angles decreased by 42.8%, 26.7%, 26.5%, and 7%. These findings suggest that coarse and circular particles demonstrate stronger wetting properties with the binder compared to fine and angled particles. Additionally, the cohesion and internal friction angle of the wet sand mixture can be measured through the ring shear test. Moreover, the unconfined yield strength and main consolidation stress can be calculated using the Mohr Coulomb model to obtain the yield locus and quantify the flowability of the wet sand mixture. The yield trajectory of sand mixtures at specific consolidation stresses suggests that the most important factor affecting the flowability of wet sand particles is particle size distribution. Wet mixtures of coarse and circular particles exhibit lower cohesive forces, indicating higher fluidity.

Microalloying is a cost-effective strategy to develop high performance nickel-based superalloys. Here, the mechanisms of rare earth Y in IN713C on purification, mechanical property improvement, and microstructure modification were systematically investigated. Via melt purification of Y, the O, N, and S elements are reduced to 5 ppm in the IN713C alloy. By adding Y to 74 ppm, the yield strength, tensile strength, and elongation of the IN713C alloy at 650 °C are increased by 12.2%, 14.5%, and 66%, respectively. Microstructure analysis indicated that the strength of the alloy is improved by refining the size and increasing the volume fraction of the γ’ phase. The plasticity of the alloy is improved by modifying the morphology and distribution of MC carbides. The modification of carbide morphology can be attributed to the enrichment of Y at the surface of carbides and the change of segregation of Nb, which is the main carbide-formation element.