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Spermiation is the process that releases mature spermatids from Sertoli cells into the lumen of the seminiferous tubule. Tubulobulbar complexes (TBCs) are elaborate cytoskeleton-related structures that are indispensable for spermiation. Despite well-defined ultrastructural events, the molecular regulation of TBCs during spermiation remains largely unknown. Here, we show that autophagy is active in TBC regions, and impaired autophagy in Sertoli cells affects spermiation. Further studies demonstrated that many TBC components bound to LC3 and could be selectively degraded through the autophagy-lysosome pathway. Perturbed autophagy impaired the degradation of some TBC components in Sertoli cells, such as VCL and CTTN, and led to the accumulation of TBC components surrounding the spermatid head, which may be associated with the sperm-releasing defect. Together, our results reveal that autophagy is essential for the TBC components degradation in mouse Sertoli cells and define a functional role of autophagy during spermiation.

Abstract Background There is no regulation in the current guidelines on the sequence of ligation of the inferior mesenteric artery and vein during rectal cancer surgery owing to a lack of sufficient evidence. Circulating tumor cells (CTCs) in peripheral blood can be used as potential indicators for predicting prognosis in colorectal cancer patients. This study aims to explore the feasibility of different ligation sequences for the inferior mesenteric vessels and their potential influence on CTCs. Methods This pilot study involved 29 stage I-III rectal adenocarcinoma patients undergoing laparoscopic surgery. Patients were allocated into two groups based on the sequence of vascular ligation: vein-first (V-first) and artery-first (A-first). The primary objective was to assess the impact of the ligation sequence on peripheral blood CTC levels pre- and post-operatively. Secondary outcomes included intraoperative complications, surgical duration, blood loss, and number of lymph nodes harvested, and postoperative complications. The study was approved by the ethics committee of our hospital (SCCHEC-02-2024-102), and all patients provided informed consent. Results No significant differences were found between the two groups regarding surgical duration, blood loss, lymph nodes harvested, or postoperative complications. A reduction in CTCs postoperatively was observed in 36% of patients in the V-first group, in comparison to 20% in the A-first group. Conclusion Both A-first and V-first ligation sequences are viable and safe options in laparoscopic rectal cancer surgery. The V-first approach may be more effective in reducing levels of CTCs in peripheral blood. Further randomized studies are warranted to explore these findings comprehensively.

Abstract Comprehensive characterizations of genetic diversity and demographic models of ethnolinguistically diverse Chinese populations are essential for elucidating their forensic characteristics and evolutionary past. We developed a 114-plex NGS InDel panel to genotype 114 genome-wide markers and investigated the genetic structures of Zhuang, Hui, Miao, Li, Tibetan, Yi, and Mongolian populations, encompassing five language families. This panel demonstrated robust performance, with exceptional potential for forensic individual identification and paternity testing, evidenced by the combined power of discrimination for 77 autosomal InDels (ranged from 1-3.6400 × 10–30 to 1-3.5713 × 10–32) and the combined power of exclusion (ranged from 1-2.1863 × 10–6 to 1-2.1261 × 10–7). The cumulative mean exclusion chance for 32 X-chromosomal InDels varied between 0.99996 and 0.99999 for trios and 0.99760 to 0.99898 for duos. We also analyzed genetic similarities and differences between these populations and 27 global populations, revealing distinct clusters among African, South Asian, East Asian, and European groups, with a close genetic affinity to East Asians. Notably, we identified geography-related genetic substructures: Inner Mongolia Mongolians and Gansu Huis formed a northern branch, Tibetans and Yis from Sichuan constituted a highland branch, and Guangxi Zhuangs exhibited close ties with Hainan Lis and Guangxi Miaos in the southern branch. Additionally, many InDels proved to be ancestry-informative markers for biogeographic ancestry inference. Collectively, these findings underscore the utility of the 114-plex NGS InDel panel as a complementary tool for forensic investigations and as a source of insights into the genetic architecture of ethnolinguistically distinct Chinese populations.

Abstract The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells. Here, we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment. Our study reveals that intratumor injection of E. coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5, together facilitating tumor infiltration of adoptively transferred T cells. The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy. This combinatorial therapy, consisting of E. coli adjuvant and adoptive T-cell therapy, effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors. Notably, this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination. This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors, including melanoma and hepatocellular carcinoma, by converging attacks from both inside and outside the tumor tissues.

Abstract Accurate treatment response assessment using serial CT scans is essential in oncological clinical trials. However, oncologists’ assessment following the Response Evaluation Criteria in Solid Tumors (RECIST) guideline is subjective, time-consuming, and sometimes fallible. Advanced liver cancer often presents multifocal hepatic lesions on CT imaging, making accurate characterization more challenging than with other malignancies. In this work, we developed a tumor volume guided comprehensive objective response evaluation based on deep learning (RECORD) for liver cancer. RECORD performs liver tumor segmentation, followed by sum of the volume (SOV)-based treatment response classification and new lesion assessment. Then, it can provide treatment evaluations of response, stability, and progression, and calculates progression-free survival (PFS) and response time. The RECORD pipeline was developed with both CNN and ViT backbones. Its performance was evaluated in three longitudinal cohorts involving 60 multi-national centers, 206 patients, 891 CT scans, using internal five-fold cross-validation and external validations. RECORD with the most effective backbone achieved an average AUC-response of 0.981, AUC-stable of 0.929, and AUC-progression of 0.969 for SOV-based disease status classification, F1-score of 0.887 for new lesion identification, and accuracy of 0.889 for final treatment outcome assessments across all cohorts. RECORD’s PFS and response time predictions strongly correlated with clinician’s assessments (P

Abstract Background Although mesenchymal stem cells (MSCs) have been proven to be appropriate candidates for the treatment of AKI-CKD, their efficacy is limited and variable. Astilbin (AST) had a protective effect on MSCs from oxidative stress via ROS-scavenging, however, whether it can improve MSCs’ renoprotection and the underlying mechanism need to be elucidated. Methods AST-pretreated MSCs were administered intravenously into the ischemia–reperfusion injury mice models and the renal function, pathological changes and inflammation. Were evaluated. In addition, DARTS, molecular docking, surface plasma resonance(SPR), dual-luciferase reporter gene assay and the ChIP-PCR were utilized to explore the potential signaling pathways through which AST exert renal protective effects on MSCs. Results AST-pretreated MSCs markedly improved kidney function, reduced kidney pathological injury and inflammation in AKI and AKI-CKD mice. RNA-seq results showed that PTGS2 related pathway was significantly up-regulated in MSCs after AST pretreatment. DARTS assay, molecular docking and SPR assay revealed that AST could bind with the transcriptional factor of Kruppel-Like Factor 4(KLF4) protein. The promoter of PTGS2 had the binding and transcriptional activation by KLF4. Furthermore, AST pretreatment promoted the secretion of PGE2 in MSCs. And then the westren blot results showed that the protein levels of CD163 and CD206 were upregulated after coculture in AST-pretreated MSCs, indicating that the polarization of RAW264.7 cells towards M2-like macrophages was induced. Knockdown of PTGS2 reversed the ability of AST-pretreated MSCs in converting macrophages to M2 phenotype and reducing their therapeutic effects on AKI-CKD mice. Conclusion AST pretreatment enhances the efficacy of MSCs on AKI and AKI-CKD mice by inducing of M2-like phenotype polarization in macrophages through the PTGS2-mediated pathway. This approach not only provides a novel strategy to strengthen the capability of MSCs but also helps elucidate the beneficial effects of the Chinese herbal medicine AST.

Abstract Background Ischemic stroke (IS) is a commonly seen cerebrovascular disease which seriously endangers the health of middle age and old people. However, its etiology and pathogenesis have not yet fully comprehended. miR-30 gene is a novel gene which may be involved in IS. However, no studies have investigated the relationship between IS and the single-nucleotide polymorphisms (SNPs) of miR-30. Therefore, this study examined the relationship between miR-30 polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) and the risk of IS. Methods Totally 248 IS patients and 230 age-, sex- and race-matched controls were involved in this study. Based on SNPscan technique, four polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) were genotyped. Results There exists a significant association between rs2222722 polymorphism and the risk of IS according to analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 1.616, 95% CI: 0.943–2.768, P = 0. 081); (AA vs. GG: adjusted OR = 2.447, 95% CI: 1.233–4.858, P = 0.011); dominant model: adjusted (OR = 1.806, 95% CI, 1.082–3.016, P = 0.024); (G vs. A: adjusted OR = 1.492, 95% CI: 1.148–1.939, P = 0.003). Besides, miR-30a expression was significantly higher in patients undergoing IS relative to that in controls (P

Abstract Age-related macular degeneration (AMD) is the leading cause of blindness in older people in developed countries. It has been suggested that heavy metal exposure may be associated with the development of AMD, but most studies have focused on the effects of a single metal with traditional methods. In this study, we analyzed the relationship between 13 urinary heavy metal concentrations and AMD using NHANES data between 2005 and 2008. We constructed and compared 11 machine learning models to identify the best model for predicting AMD risk. We further interpreted the models by Permutation Feature Importance (PFI), Partial Dependence Plot (PDP) analysis, and SHapley Additive exPlanations (SHAP) analysis. 216 AMD patients out of 2380 participants. The random forest (RF) model performed optimally in predicting the risk of AMD, with an AUC value of 0.970. PFI analyses revealed that age and urinary cadmium (Cd) were the main factors influencing the risk of AMD. SHAP analyses further confirmed the significance of Cd concentration in predicting the risk of AMD, and we revealed a significant interaction with significant interaction of race. Our study firstly explored the relationship between heavy metal exposure levels and AMD based on machine learning techniques, found that urinary Cd concentration had the greatest impact on AMD, and revealed the superior predictive performance of machine learning methods. Furthermore, our study provided a new perspective for early screening and intervention of AMD.

Central Asia, a crucible of prehistoric and historical Trans-Eurasian interactions, has been pivotal in shaping cultural exchanges, population dynamics, and genetic admixture. Recent insights from ancient DNA studies have shed light on the extensive population turnover within this region, encompassing a spectrum of groups from Paleolithic hunter-gatherers to Holocene herders and the nomadic pastoralist empires of historical times. The genomic analysis of ancient pathogens across the Eurasian steppe has further deepened our understanding of pathogen origins, clonal expansions, and the intricate processes of host-pathogen coevolution in relation to varying pathogen exposures and their spread. We consolidate the latest findings pertaining to the ancient human and pathogen genomes of Central Asia, elucidating their profound influence on the genomic tapestry of contemporary Central Asians. A notable gap in the current genomic databases for Central Asia is underscored, particularly within the scope of genomics-driven precision medicine. We stress the urgent need for the development of extensive, region-specific genomic resources that hold promise for revealing the genetic blueprints underlying human traits and diseases, refining polygenic scoring models for predictive medicine, and bolstering genomic research endeavors across Central Asia.

This study established a circulating system to control the concentration of substances and temperature in the aqueous solution. Simultaneously, sensors were used to continuously monitor the corrosion of three pipe materials: ductile iron (DI), surface-treated ductile iron (SDI), and carbon steel (CS). A corrosion decision model based on a machine learning framework was developed for data mining. The results show that the developed model provides accurate corrosion prediction strategies. Analysis revealed that high temperature is the primary factor accelerating corrosion in water systems. SDI accelerates at 60 °C, reaching its peak at 90 °C, while DI and CS peak at 80 °C. The superior corrosion resistance of SDI is attributed to its ability to withstand accelerated corrosion under high temperatures and environmental coupling, making it more stable when immersed in water.

The excellent energy storage performances of dielectric materials, a high energy density and efficiency, the stability in a wide range of temperature, frequency and cycling time, are surely desirable for the energy storage devices. A trade-off relationship between polarization and breakdown strength, however, limits the enhancement of energy storage properties of dielectric materials. To effectively boost the energy density and efficiency of dielectric capacitors, by inserting a BiFeO3 layer into the BaTiO3 film in present case, the symmetric BaTiO3/BiFeO3/BaTiO3 tri-layer film heterostructure with antiferroelectric-like characteristics was constructed based on the dual-interlayer coupling effect, what's more, its antiferroelectric-like characteristics will evolve with electric field. Such the tunable polarization behavior endows it with an enhanced maximum polarization but a reduced remnant one, a delayed saturation of polarization and a high breakdown strength, which are synergistically accountable for a large energy density (Wrec∼109 J/cm3) and a high efficiency (η∼82.6%), together with the good thermal (TR∼200 °C, ΔWrec

This paper presents a memory-efficient approach to the combinatorial challenges associated with the process in search of conservative cuts for degeneracy removal in disjoint bilinear programming. Drawing inspiration from Pascal’s Triangle, the new randomized approach surpasses its predecessor from the perspective of memory, and thereby enables the possibility of its application to disjoint bilinear models with high degrees of degeneracy in imprecise decision analysis on a PC. Numerical reports are provided to validate its computational performance.

BackgroundDibutyl phthalate (DBP) is one of the most commonly used plasticizers, and has been found to relate to allergic asthma. However, mechanisms behind the phenomenon linking DBP and allergic asthma are still not well comprehended. ObjectiveTo investigate the role of endoplasmic reticulum stress in DBP-exacerbated allergic asthma. MethodsThirty-two male mice were divided into four groups at random, eight mice in each group: control group, allergic asthma model group (ovalbumin, OVA), OVA+40 mg·kg−1 DBP exposure group (OVA+DBP), and OVA+40 mg·kg−1 DBP+50 mg·kg−1 4-phenyl butyric acid (4-PBA) group (OVA+DBP+4-PBA). The control group mice were treated with saline via intraperitoneal injection on day 21, 35, 42, and 49, and atomized saline for 30 min per day from day 54 to 60. The OVA group mice were injected with 0.3 mL OVA sensitizing solution via intraperitoneal injection on day 21, 35, 42, and 49, and atomized with 1% OVA solution from day 54 to 60. The OVA+DBP group was treated in the same way as the OVA group to build an allergic asthma model, and was orally exposed to 40 mg·kg−1 DBP from day 1 to 53, plus atomized with 1% OVA solution from day 54 to 60. In order to verify the role of endoplasmic reticulum stress in DBP-exacerbated allergic asthma, 4-PBA was injected intraperitoneally every 2 d from day 1 to 53 in the OVA+DBP+4-PBA group mice. The pathological changes such as airway remodeling, inflammatory cell infiltration, and airway mucous hyperplasia in lung tissues were observed after hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. The contents of total immunoglobulin E (T-IgE) and ovalbumin immunoglobulin E (OVA-IgE) levels in serum, and interleukin (IL)-4, IL-5, IL-13, and IL-17A in alveolar lavage fluid (BALF) were detected by Enzyme-Linked ImmunoSorbent Assay(ELISA). The expression levels of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1α (IRE1α), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were detected by immunohistochemistry. ResultsCompared to the control mice, the OVA mice showed significant asthma-like symptoms, including inflammatory cell infiltration, increased inflammatory cytokines, airway remodeling, and mucous hyperplasia. Compared to the OVA group, long-term exposure to DBP aggravated airway pathological changes in the OVA+DBP mice, and increased the serum T-IgE and OVA-IgE levels (P

Abstract Pantropical climate interactions across ocean basins operate on a wide range of timescales and can improve the accuracy of climate predictions. Here, we show in observations that Central Pacific (CP) El Niño-like sea surface temperature (SST) anomalies have coevolved with tropical South Atlantic SST anomalies on a quasi-decadal (~10-year) timescale over the past seven decades. During the austral autumn–winter season, decadal warm SSTs in the tropical CP effectively induce tropical SST cooling in the South Atlantic, mainly by strengthening the South Atlantic subtropical anticyclone via an extratropical atmospheric wave teleconnection in the southern hemisphere. Partially coupled pacemaker simulations corroborate the observational findings, indicating that tropical CP decadal SSTs play a primary pacing role, while Atlantic feedback is of secondary importance throughout the study period. Our results suggest that the tropical CP could be an important source of decadal predictability for tropical South Atlantic SST and the surrounding climate.

Abstract Achieving green development in Old Revolutionary Base Areas (ORBAs) is an urgent task to narrow the regional gap and promote high-quality development. Starting from the dual perspective of development and environment, this paper used the Multi-period DID model to assess the impacts of the National Revitalization Plan (NRP) for ORBAs on economic growth and environmental quality, as well as its transmission mechanism, and to explore whether the implementation of the plan can promote the covered areas to achieve green development. The results find that the implementation of NRP boosts the ORBAs to achieve green development. The NRP realize green development through industrial restructuring, technological progress, ecological space governance, and public service provision. The ORBAs of Jiangxi-Fujian- Guangdong, Left-Right River, and Sichuan-Shaanxi, counties situated in mountainous terrain and with higher quartile of economy and environment play a more prominent role in promoting green development. This study provides practical inspiration and theoretical reference for ORBAs to realize green development.

Abstract Aims The present study aims to develop a nano-delivery system that encapsulates berberine (BBR) into PLGA-based nanoparticles (BPL-NPs), to treat ulcerative colitis (UC). Furthermore, the therapeutic efficacy and molecular targeting mechanisms of BPL-NPs in the management of UC are thoroughly examined. Methods Emulsion solvent-driven methods were used to self-assemble BBR and PLGA into nanoparticles, resulting in the development of the nano-delivery system (BPL-NPs). The therapeutic effectiveness of BPL-NPs was evaluated using a dextran sulfate sodium (DSS)-induced model of ulcerative colitis in mice and a lipopolysaccharide (LPS)-induced model of inflammation in THP-1 macrophages. The interaction between Mφs and NCM-460 cells was investigated using a co-culture system. The molecular targeting ability of BPL-NPs in the treatment of UC was validated through in vitro as well as in vivo experiments. Results The BPL-NPs demonstrated a particle size of 184 ± 22.4 nm, enhanced dispersibility in deionized water, and a notable encapsulation efficiency of 31.1 ± 0.2%. The use of BPL-NPs clearly improved the clinical symptoms and pathological changes associated with UC in mice while also ensuring minimal toxicity. In addition, BPL-NPs improved intestinal epithelial cell apoptosis and enhanced the function of the intestinal barrier by inhibiting M1 Mφs infiltration and IL-6 signaling pathway in mice with UC. Furthermore, the BPL-NPs were found to selectively target the IL-6/IL-6R axis during the M1 Mφs-induced apoptosis of NCM460 cells. Conclusion The BPL-NPs were confirmed to harbor anti-inflammatory effects both in vitro and in vivo, along with enhanced water solubility and bioactivity. In addition, the precise targeting of the IL-6/IL-6R axis was confirmed as the mechanism by which the BPL-NPs exerted therapeutic effects in UC, as demonstrated in both in vitro as well as in vivo studies. Graphical Abstract

Abstract Background The family Lauraceae is subdivided into six main lineages: Caryodaphnopsideae, Cassytheae, Cryptocaryeae, Hypodaphnideae, Laureae, and Neocinnamomeae. However, phylogenetic relationships among these lineages have been debatable due to incongruence between trees constructed using nuclear ribosomal DNA (nrDNA) sequences and chloroplast (cp) genomes. As with cp DNA, the mitochondrial (mt) DNA of most flowering plants is maternally inherited, so the phylogenetic relationships recovered with mt genomes are expected to be consistent with that from cp genomes, rather than nrDNA sequences. Results The mitogenome of Machilus yunnanensis, with a length of 735,392 bp, has a very different genome size and gene linear order from previously published magnoliid mitogenomes. Phylogenomic reconstructions based on 41 mt genes from 92 Lauraceae mitogenomes resulted in highly supported relationships: sisterhood of the Laureae and a group containing Neocinnamomeae and Caryodaphnopsideae, with Cassytheae being the next sister group, followed by Cryptocaryeae. However, we found significant incongruence among the mitochondrial, chloroplast, and nuclear phylogenies, especially for the species within the Caryodaphnopsideae and Neocinnamomeae lineages. Time-calibrated phylogenetic analyses showed that the split between Caryodaphnopsideae and Neocinnamomeae dated to the later Eocene, around 38.5 Ma, Laureae originated in the Late Cretaceous, around 84.9 Ma, Cassytheae originated in the mid-Cretaceous around 102 Ma, and Cryptocaryeae originated in the Early Cretaceous around 116 Ma. From the Late Cretaceous to the Paleocene, net diversification rates significantly increased across extant clades of major lineages, and both speciation rates and net diversification rates continued steady growth towards the present. Conclusions The topology obtained here for the first time shows that mt genes can be used to support relationships among lineages of Lauraceae. Our results highlight that both Caryodaphnopsideae and Neocinnamomeae lineages are younger than previously thought, likely first diversifying in the Eocene, and species in the other extant lineages of Lauraceae dates in a long-time span from the Early Cretaceous to the Eocene, and the climate of a period of about 90 million years was relatively warm, while the extant species of Lauraceae then continuously diversified with global cooling from the Eocene to the present day.

Abstract Background Short-term exposure to ozone (O3) has been associated with higher stroke mortality, but it is unclear whether this association differs between urban and rural areas. The study aimed to compare the association between short-term exposure to O3 and ischaemic and haemorrhagic stroke mortality across rural and urban areas and further investigate the potential impacts of modifiers, such as greenness, on this association. Methods A multi-county time-series analysis was carried out in 19 counties of Shandong Province from 2013 to 2019. First, we employed generalized additive models (GAMs) to assess the effects of O3 on stroke mortality in each county. We performed random-effects meta-analyses to pool estimates to counties and compare differences in rural and urban areas. Furthermore, a meta-regression model was utilized to assess the moderating effects of county-level features. Results Short-term O3 exposure was found to be associated with increased mortality for both stroke subtypes. For each 10-µg/m3 (lag0-3) rise in O3, ischaemic stroke mortality rose by 1.472% in rural areas and 1.279% in urban areas. For each 0.1-unit increase in the Enhanced Vegetation Index (EVI) per county, the ischaemic stroke mortality caused by a 10-µg/m3 rise in O3 decreased by 0.60% overall and 1.50% in urban areas. Conclusions Our findings add to the evidence that short-term O3 exposure increases ischaemic and haemorrhagic stroke mortality and has adverse effects in urban and rural areas. However, improving greenness levels may contribute to mitigating the detrimental effects of O3 on ischaemic stroke mortality.

Abstract Myeloid cells are pivotal in the inflammatory and remodeling phases of fracture repair. Here, we investigate the effect of periostin expressed by myeloid cells on bone regeneration in a monocortical tibial defect (MTD) model. In this study, we show that periostin is expressed by periosteal myeloid cells, primarily the M2 macrophages during bone regeneration. Knockout of periostin in myeloid cells reduces cortical bone thickness, disrupts trabecular bone connectivity, impairs repair impairment, and hinders M2 macrophage polarization. Mechanical stimulation is a regulator of periostin in macrophages. By activating transforming growth factor-β (TGF-β), it increases periostin expression in macrophages and induces M2 polarization. This mechanosensitive effect also reverses the delayed bone repair induced by periostin deficiency in myeloid cells by strengthening the angiogenesis-osteogenesis coupling. In addition, transplantation of mechanically conditioned macrophages into the periosteum over a bone defect results in substantially enhanced repair, confirming the critical role of macrophage-secreted periostin in bone repair. In summary, our findings suggest that mechanical stimulation regulates periostin expression and promotes M2 macrophage polarization, highlighting the potential of mechanically conditioned macrophages as a therapeutic strategy for enhancing bone repair.

Abstract The Atlantic Niño, a primary climatic variability mode in the equatorial Atlantic Ocean, exhibits pronounced variability not only in boreal summer but also in winter. However, the role of the winter Atlantic Niño in trans-basin interactions remains underexplored compared to its summer counterpart. Through analysis of observational reanalysis data since the mid-twentieth century, here we found that the winter Atlantic Niño significantly influences the development of El Niño–Southern Oscillation (ENSO), surpassing the impact of summer Atlantic Niño, with a longer lead time. This effect is reasonably captured in the CMIP6 Historical simulations from a multi-model ensemble perspective. Further analysis of the global warming scenario projects that the influence of winter Atlantic Niño on ENSO will persist into the future, in contrast to the reduced impact of summer Atlantic Niño. Therefore, these findings underscore the importance of further investigating the winter Atlantic Niño to gain a comprehensive understanding of trans-basin interactions and their future changes.

Abstract Purpose Despite the efforts of countless researchers to develop glioma treatment strategies, the current therapeutic effect of glioma is still not ideal, and it is necessary to further explore the mechanism to guide treatment. Thus, this study aims to introduce a novel approach for predicting patient prognosis and guiding further treatment interventions. Methods Initially, we conducted a differential gene expression analysis to identify Hippo pathway-associated genes overexpressed in tumors and determined genes correlated with prognosis. Subsequently, employing cluster analysis, we categorized samples into two groups and performed further analyses including prediction, immune cell infiltration abundance, and drug response rates. We utilized weighted gene co-expression analysis to reveal gene sets with high co-variation, delineate inter-sample gene correlation patterns, and conduct enrichment analysis. Prognostic models were built using ten machine learning algorithms combined in 101 different combinations, followed by evaluation and validation. Immune infiltration analysis, differential expression analysis of depleted T cell-related markers, drug sensitivity analysis, and exploration of pathway dysregulation were performed for different risk groups. Quality control and batch integration were performed, and single-cell data were analyzed using dimensionality reduction clustering algorithms and annotation tools to evaluate the activity of the prognostic model in malignant cells. Results We conducted data filtering to identify genes overexpressed in tumors, intersecting these genes with Hippo pathway-related genes, identifying 62 genes correlated with prognosis, and performing cluster analysis to divide tumor tissues into two groups. Cluster 2 exhibited a poorer prognosis and demonstrated differences in immune cell infiltration. Utilizing weighted gene co-expression analysis on Cluster 2, we identified gene modules, conducted functional enrichment analysis, and delineated pathways. Employing a combined model based on ten machine learning algorithm combinations, we selected the optimal prognostic model system and validated the model’s predictive ability within the dataset. Through immune-related analysis and drug sensitivity analysis, we uncovered differences in immune infiltration and varying sensitivities to chemotherapy drugs. Additionally, the enrichment analysis of gene set revealed discrepancies in upregulation within relevant pathways between the high and low-risk groups. Finally, annotation and evaluation of malignant cells via single-cell analysis showed increased activity of the prognostic model and variations in distribution across different prognostic levels in malignant cells. Conclusion This study introduces a novel approach utilizing the Hippo pathway and associated genes for glioma prognosis research, demonstrating the potential and significance of this method in evaluating the outcome for patients with glioma. These findings hold substantial clinical significance in guiding therapy and predicting outcomes for individuals diagnosed with glioma, offering significant clinical utility.

Abstract Subsea manifold system is a complex system that occupies a pivotal role in contemporary ocean engineering and has a significant impact on the safety of marine resource exploitation. Reliability technology plays a significant role in ensuring the safe operation of the subsea manifold system. To perform a comprehensive analysis of the reliability of complex systems, a combination method of FMECA-FFTA (Failure Modes, Effects and Criticality Analysis - Fuzzy Fault Tree Analysis) is introduced in this study. Firstly, FMECA is used to accomplish a qualitative analysis of system reliability considering multifactorial failure modes, which included analyzing potential failure modes, causes of system failure, and evaluating the degree of hazard to the system through a risk matrix diagram. Then, FFTA is applied to build a fault tree model to divide the system into “system-subsystem-component” and determine the minimal cut sets for quantitative analysis of system reliability. In addition, fuzzy set theory is incorporated to improve the accuracy of handling uncertainty in quantitative reliability analysis. Finally, a qualitative and quantitative reliability analysis is conducted by using FMECA-FFTA method for subsea manifold system. The failure modes of the subsea manifold system are clearly identified, including high-risk modes such as external leakage, medium-high-risk modes such as fail to close/lock on demand, and medium-risk modes such as leakage of critical location, plugged, and effective measures should be taken to focus on preventive protection and regular testing for the high risk, medium-high risk and medium risk modes.

Abstract Background The surgical clinical practice skill training is an important part of medical undergraduate education. Surgical skills are complex and difficult to master. However, the traditional teaching method has some disadvantages, for example, low student participation, weak learning atmosphere, inadequate mastery of the subject matter. We innovatively put forward the segmented teaching method in the field of clinical practice skills training. The segmented teaching method refers to dividing a specific teaching content into several relatively independent parts and providing segmented practice for each part. This approach enhances students’ learning outcomes.The aim of this controlled study is to investigate the effects of the segmented teaching methods on clinical practice skills training in medical students. Methods 31 medical students participating in clinical practice skill training at The First Affiliated Hospital of University of South China from March to April 2024 were randomly assigned to either the experimental group (n = 16) receiving segmented teaching method or the control group (n = 15) receiving traditional teaching method. After completion of practical exercises, both groups underwent operational assessments, theoretical assessments, Mini-Clinical Evaluation Exercise (Mini-CEX), and Student Evaluation of Educational Quality (SEEQ) for teaching quality evaluation. A comparative analysis of the results between the two groups was conducted. Results After implementing the program, there were no statistically significant differences (P > 0.05) between the experimental and control groups in theoretical assessment scores, Mini-CEX clinical judgment scores, and SEEQ teaching quality evaluation scores. However, compared to the control group, the experimental group demonstrated better operational assessment scores, higher Mini-CEX scores in history taking, physical examination, professionalism, doctor-patient communication, organizational efficiency, and comprehensive abilities, with statistically significant differences (P

Outdoor thermal comfort is crucial for creating sustainable and livable urban spaces. Studying the distribution and impact factors of the thermal environment can provide theoretical support for improving the thermal environment and spatial planning. This study investigates the influence of well-defined boundary spaces on outdoor thermal comfort and proposes design measures to improve spatial thermal comfort. High-resolution data obtained from unmanned aerial vehicles (UAVs) is integrated into outdoor microclimate simulations to enhance the accuracy and precision of the models. The Physiological Equivalent Temperature (PET) index is employed as an evaluation indicator, considering the categorization of PET values into different comfort levels. Additionally, the axial evaluation method is introduced to assess thermal comfort more accurately, reflecting the perceived thermal comfort by individuals. Through a case study in a mixed-use and clear boundary area, the research identifies the variables that influence outdoor thermal comfort and provides design guidelines to enhance spatial thermal comfort. The correlations between the spatial morphology index and PET were analyzed by multiple regression. The findings contribute to the understanding of outdoor thermal comfort in complex urban environments and offer valuable insights for the design and planning of comfortable and sustainable outdoor spaces.

Abstract Background Anaplastic lymphoma kinase (ALK) test in advanced non‐small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real‐world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC. Methods In this real‐world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)‐VENTANA‐D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well. Results The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC‐VENTANA‐D5F3 revealed an intra‐hospital consistency rate of 98.2% (879/895) and an inter‐hospital consistency rate of 99.2% (646/651). IHC‐VENTANA‐D5F3 was used in 53.6%, real‐time polymerase chain reaction (RT‐PCR) in 25.4%, next‐generation sequencing (NGS) in 18.3%, and fluorescence in‐situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC‐VENTANA‐D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT‐PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05). Conclusions This study highlights the real‐world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC‐VENTANA‐D5F3 with high consistency and distinct clinicopathological features in ALK‐positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision‐making in NSCLC.

Abstract Background Studies have found dysbiosis of the gut microbiota in individuals infected with the hepatitis B virus (HBV). Tenofovir dipivoxil (TDF) is one of the preferred oral antiviral drugs used for the treatment of chronic hepatitis B (CHB), but the extent to which TDF is able to affect the gut microbiota and inflammatory factors of a patient remains largely unexplored. In this study, we collected stool samples from HBV patients prior to medication and from CHB patients treated with TDF. Results The gut microbiota and inflammatory factors were assessed in 42 healthy subjects (HC group), 109 HBV-infected subjects, including 48 CHB patients who were not medicated with nucleoside analogue drugs (No-NAs group), and 61 CHB patients who were medicated with TDF (TDF group). 16 S rRNA sequencing revealed that TDF treatment caused significant changes in the gut microbiota of HBV-infected individuals; however, the gut microbiota of HBV-infected individuals did not fully recover to a pre-dysbiosis state. The relative abundance of Bacteroidota gradually decreased from the HC group to the No-NAs and TDF groups. The relative abundance of Fusobacteriota was significantly higher in the No-NAs group than in the HC group. At the genus level, Dialister, Eubacterium_hallii_group, Halomonas, Collinsella, Sphingomonas, Xanthomonadaceae_unclassified, and Rhizobiaceae_unclassified were overrepresented; while the abundance of Bacteroides and Fusobacterium decreased significantly in the No-NAs and TDF groups. Conclusions This study showed that TDF treatment significantly improved the regulation of the gut microbiota and aided in dysbiosis recovery. We did not observe significant improvement in serum inflammatory factor concentrations, which may be related to the relatively short duration of TDF administration in this study.

Abstract Background Children and adolescents diagnosed with major depressive disorder (MDD) often grapple with significant non-suicidal self-injury (NSSI), linked to interpersonal challenges, insecure attachment, and internet addiction. This study explores these relationships in children and adolescents using network analysis, drawing data from seven hospitals in China. Results The study included 162 youths with depressive disorder and 102 healthy controls from seven hospitals. The MDD + NSSI group exhibited severe internet addiction, heightened depressive symptoms, and insecure attachment. Network analysis identified central symptoms (compulsive use) and key bridge symptoms (tolerance symptoms) in the networks related to depressive symptoms, internet addiction, and attachments. These findings suggest potential targets for intervention among children and adolescents at risk for or suffering from depression. Conclusions This study sheds light on the intricate relationship between NSSI, attachment issues, and internet addiction in Chinese adolescents with MDD. The network analysis pinpointed central and key bridge symptoms, offering valuable insights for targeted interventions in children and adolescents at risk for or experiencing depression and associated challenges.

Abstract Background Although electronic alerts are being increasingly implemented in patients with acute kidney injury (AKI), their effect remains unclear. Therefore, we conducted this meta-analysis aiming at investigating their impact on the care and outcomes of AKI patients. Methods PubMed, Embase, Cochrane Library, and Clinical Trial Registries databases were systematically searched for relevant studies from inception to March 2024. Randomized controlled trials comparing electronic alerts with usual care in patients with AKI were selected. Results Six studies including 40,146 patients met the inclusion criteria. The pooled results showed that electronic alerts did not improve mortality rates (relative risk (RR) = 1.02, 95% confidence interval (CI) = 0.97–1.08, P = 0.44) or reduce creatinine levels (mean difference (MD) = − 0.21, 95% CI = − 1.60–1.18, P = 0.77) and AKI progression (RR = 0.97, 95% CI = 0.90–1.04, P = 0.40). Instead, electronic alerts increased the odds of dialysis and AKI documentation (RR = 1.14, 95% CI = 1.05–1.25, P = 0.002; RR = 1.21, 95% CI = 1.01–1.44, P = 0.04, respectively), but the trial sequential analysis (TSA) could not confirm these results. No differences were observed in other care-centered outcomes including renal consults and investigations between the alert and usual care groups. Conclusions Electronic alerts increased the incidence of AKI and dialysis in AKI patients, which likely reflected improved recognition and early intervention. However, these changes did not improve the survival or kidney function of AKI patients. The findings warrant further research to comprehensively evaluate the impact of electronic alerts.

Abstract Fueled by the rapid advancement of nanofabrication, metasurface has provided unprecedented opportunities for 3D holography. Large depth 3D meta-holography not only greatly increases information storage capacity, but also enables distinguishing of the relative spatial relationship of 3D objects, which has important applications in fields like optical information storage and medical diagnosis. Although the methods based on Fresnel diffraction theory can reconstruct the real depth information of 3D objects, the maximum depth is only 2 mm. Here, we develop a 3D meta-holography based on angular spectrum diffraction theory to break through the depth limit. By developing the angular spectrum diffraction theory into meta-holography, the metasurface structure with independent polarization control is used to create a polarization multiplexing 3D meta-hologram. The fabricated amorphous silicon metasurface increases the depth range by 47.5 times and realizes 0.95 dm depth reconstruction for polarization independent and different color 3D meta-hologram in visible. Such polarization controlled large-depth color meta-holography is expected to open avenue for data storage, display, information security and virtual reality.

Abstract Podocalyxin-like protein (PODXL) is known to originate from tumor cells in several cancers; however, which cell type it is expressed in, whether and how it may contribute to tumor progression after radiotherapy or chemoradiotherapy in cervical cancer (CC) remain unknown. In this study, we investigated these issues using a cohort of 180 immune stain data, single-cell RNA sequencing (scRNA-seq) data of 29,453 cells, and bulk RNA sequencing data from 187 cervical cancer samples treated with radiotherapy or chemoradiotherapy. ScRNA-seq analysis revealed that PODXL was predominantly expressed in tumor endothelial cells (TECs) of CC, which was corroborated by tumor section staining. Moreover, the PODXL expression level was negatively associated with progression-free survival and overall survival of 180 CC patients receiving radiotherapy or chemoradiotherapy (both p

Optical imaging in the second near-infrared (NIR-II; 900–1880 nm) window is currently a popular research topic in the field of biomedical imaging. This study aimed to explore the application value of NIR-II fluorescence imaging in foot and ankle surgeries. A lab-established NIR-II fluorescence surgical navigation system was developed and used to navigate foot and ankle surgeries which enabled obtaining more high-spatial-frequency information and a higher signal-to-background ratio (SBR) in NIR-II fluorescence images compared to NIR-I fluorescence images; our result demonstrates that NIR-II imaging could provide higher-contrast and larger-depth images to surgeons. Three types of clinical application scenarios (diabetic foot, calcaneal fracture, and lower extremity trauma) were included in this study. Using the NIR-II fluorescence imaging technique, we observed the ischemic region in the diabetic foot before morphological alterations, accurately determined the boundary of the ischemic region in the surgical incision, and fully assessed the blood supply condition of the flap. NIR-II fluorescence imaging can help surgeons precisely judge surgical margins, detect ischemic lesions early, and dynamically trace the perfusion process. We believe that portable and reliable NIR-II fluorescence imaging equipment and additional functional fluorescent probes can play crucial roles in precision surgery.

Abstract Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.

Abstract Background Colorectal cancer (CRC) is the third most prevalent cancer worldwide, with the tumor microenvironment (TME) playing a crucial role in its progression. Aggregated autophagy (AA) has been recognized as a factor that exacerbates CRC progression. This study aims to study the relationship between aggregated autophagy and CRC using single-cell sequencing techniques. Our goal is to explain the heterogeneity of the TME and to explore the potential for targeted personalized therapies. Objective To study the role of AA in CRC, we employed single-cell sequencing to discern distinct subpopulations within the TME. These subpopulations were characterized by their autophagy levels and further analyzed to identify specific biological processes and marker genes. Results Our study revealed significant correlations between immune factors and both clinical and biological characteristics of the tumor microenvironment (TME), particularly in cells expressing TUBA1B and HSP90AA1. These immune factors were associated with T cell depletion, a reduction in protective factors, diminished efficacy of immune checkpoint blockade (ICB), and enhanced migration of cancer-associated fibroblasts (CAFs), resulting in pronounced inflammation. In vitro experiments showd that silencing TUBA1B and HSP90AA1 using siRNA (Si-TUBA1B and Si-HSP90AA1) significantly reduced the expression of IL-6, IL-7, CXCL1, and CXCL2 and inhibition of tumor cell growth in Caco-2 and Colo-205 cell lines. This reduction led to a substantial alleviation of chronic inflammation and highlighted the heterogeneous nature of the TME. Conclusion This study marks an initial foray into understanding how AA-associated processes may potentiate the TME and weaken immune function. Our findings provide insights into the complex dynamics of the TME and highlight potential targets for therapeutic intervention, suggesting a key role for AA in the advancement of colorectal cancer.

Abstract Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer. Graphical abstract

Abstract Background With the advancement of world population aging, age-related sarcopenia (SP) imposes enormous clinical burden on hospital. Clinical research of SP in non-geriatric wards has not been appreciated, necessitating further investigation. However, observational studies are susceptible to confounders. Mendelian randomization (MR) can effectively mitigate bias to assess causality. Objective To investigate the correlation between SP and comorbidities in orthopedic wards, and subsequently infer the causality, providing a theoretical basis for developing strategies in SP prevention and treatment. Methods Logistic regression models were employed to assess the correlation between SP and comorbidities. The MR analysis was mainly conducted with inverse variance weighted, utilizing data extracted from the UK and FinnGen biobank (Round 9). Results In the cross-sectional analysis, SP exhibited significant associations with malnutrition (P = 0.013) and some comorbidities, including osteoporosis (P = 0.014), body mass index (BMI) (P = 0.021), Charlson Comorbidity Index (CCI) (P = 0.006). The MR result also provided supporting evidence for the causality between SP and hypertension, osteoporosis and BMI. These results also withstood multiple sensitivity analyses assessing the validity of MR assumptions. Conclusion The result indicated a significant association between SP and BMI, CCI, malnutrition, and osteoporosis. We highlighted that SP and comorbidities deserved more attention in non-geriatric wards, urging further comprehensive investigation.

Abstract Precision mapping of site-specific glycans using mass spectrometry is vital in glycoproteomics. However, the diversity of glycan compositions across species often exceeds database capacity, hindering the identification of rare glycans. Here, we introduce pGlycoNovo, a software within the pGlyco3 software environment, which employs a glycan first-based full-range Y-ion dynamic searching strategy. pGlycoNovo enables de novo identification of intact glycopeptides with rare glycans by considering all possible monosaccharide combinations, expanding the glycan search space to 16~1000 times compared to non-open search methods, while maintaining accuracy, sensitivity and speed. Reanalysis of SARS Covid-2 spike protein glycosylation data revealed 230 additional site-specific N-glycans and 30 previously unreported O-glycans. pGlycoNovo demonstrated high complementarity to six other tools and superior search speed. It enables characterization of site-specific N-glycosylation across five evolutionarily distant species, contributing to a dataset of 32,549 site-specific glycans on 4602 proteins, including 2409 site-specific rare glycans, and uncovering unexpected glycan fragments.

Abstract Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.

Abstract This paper aims to address the issue of environmental pollution resulting from marine oil spills by evaluating the oil adsorption performance of commonly used fence materials. Conventional oil adsorption materials exhibit limited rates and capacities for oil adsorption. Existing methods have proven insufficient in meeting the requirements for efficient and rapid oil–water separation. A new oil-absorbing barrier was developed by utilizing high oil adsorption resin as the primary material and hydroxypropyl methyl cellulose (HPMC) as the binder, leveraging the exceptional oil adsorption and hydrophobic properties of P(BMA-SMA-St)/MIL-101(Fe) resin. The oil-absorbing fence was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The oil adsorption rates of carbon tetrachloride, toluene, diesel and gasoline by the oil adsorption fence with 25 g/L resin content were 101.26 g/m2, 68.12 g/m2, 35.19 g/m2, and 46.69 g/m2, respectively. After 120 h of UV irradiation, the coating’s oil absorption capacity remained nearly unchanged, and it demonstrated outstanding mechanical, chemical, and wear resistance. As a result, the oil adsorption fence possesses the capability to rapidly absorb oil from the water’s surface during the process of containing oil pollution, leading to positive social and economic impacts.

Abstract Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9). Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. Trial registration ClinicalTrials.gov, NCT04228601.

Abstract Three-dimensional Spatial Transcriptomics has revolutionized our understanding of tissue regionalization, organogenesis, and development. However, existing approaches overlook either spatial information or experiment-induced distortions, leading to significant discrepancies between reconstruction results and in vivo cell locations, causing unreliable downstream analysis. To address these challenges, we propose ST-GEARS (Spatial Transcriptomics GEospatial profile recovery system through AnchoRS). By employing innovative Distributive Constraints into the Optimization scheme, ST-GEARS retrieves anchors with exceeding precision that connect closest spots across sections in vivo. Guided by the anchors, it first rigidly aligns sections, next solves and denoises Elastic Fields to counteract distortions. Through mathematically proved Bi-sectional Fields Application, it eventually recovers the original spatial profile. Studying ST-GEARS across number of sections, sectional distances and sequencing platforms, we observed its outstanding performance on tissue, cell, and gene levels. ST-GEARS provides precise and well-explainable ‘gears’ between in vivo situations and in vitro analysis, powerfully fueling potential of biological discoveries.

Background: Hyperbaric oxygen (HBO) therapy is widely used to treat bone defects, but the correlation of high oxygen concentration and pressure to osteogenesis is unclear. Methods: Bilateral monocortical tibial defect surgeries were performed on 12-week-old Prrx1-Cre; Rosa26-tdTomato and Prrx1-Cre; Piezo1fl/+ mice. Daily HBO treatment was applied on post-surgery day (PSD) 1–9; and daily mechanical loading on tibia was from PSD 5 to 8. The mice were euthanized on PSD 10, and bone defect repair in their tibias was evaluated using μCT, biomechanical testing, and immunofluorescence deep-tissue imaging. The degree of angiogenesis–osteogenesis coupling was determined through spatial correlation analysis. Bone marrow stromal cells from knockout mice were cultured in vitro, and their osteogenic capacities of the cells were assessed. The activation of genes in the Piezo1–YAP pathway was evaluated using RNA sequencing and quantitative real-time polymerase chain reaction. Results: Lineage tracing showed HBO therapy considerably altered the number of Prrx1+ cells and their progeny in a healing bone defect. Using conditional knockdown mice, we found that HBO stimulation activates the Piezo1–YAP axis in Prrx1+ cells and promotes osteogenesis–angiogenesis coupling during bone repair. The beneficial effect of HBO was similar to that of anabolic mechanical stimulation, which also acts through the Piezo1–YAP axis. Subsequent transcriptome sequencing results revealed that similar mechanosensitive pathways are activated by HBO therapy in a bone defect. Conclusion: HBO therapy promotes bone tissue regeneration through the mechanosensitive Piezo1–YAP pathway in a population of Prrx1+ osteogenic progenitors. Our results contribute to the understanding of the mechanism by which HBO therapy treats bone defects. The Translational Potential of this Article: Hyperbaric oxygen therapy is widely used in clinical settings. Our results show that osteogenesis was induced by the activation of the Piezo1–YAP pathway in osteoprogenitors after HBO stimulation, and the underlying mechanism was elucidated. These results may help improve current HBO methods and lead to the formulation of alternative treatments that achieve the same functional outcomes.

Converting carbohydrates into 5-hydroxymethylfurfural (5-HMF) is an attractive and promising route for value-added utilization of agricultural and forestry biomass resource. As an important platform compound, 5-HMF possesses high active furan structure with hydroxymethyl and aldehyde group for production of various bio-chemicals and materials, meanwhile, which suffer from low stability and poor yield during the industrial biorefinery process. Hence, selective production of 5-HMF with high-yield and low-cost has attracted extensive attention from scientific and industrial researchers. This review sorted and described the latest advanced research on solvent and catalyst system, as well as energy field effect for production of 5-HMF with different feedstock in detail, emphatically discussing the solvent effect and its synergistic effect with other aspects. Besides, the future prospects and challenges for production of 5-HMF from carbohydrates were also presented, which provide a profound insight into industrial 5-HMF process with economic and environmental feature.

Paper-based materials made from cellulose have been sought after as a sustainable and inexpensive packaging option. However, the porous structure and high hydrophilicity of paper-based materials result in inadequate water and oil repellency, as well as a limited water vapor barrier. In this work, lignin nanoparticles (LNPs) were prepared using a high-speed homogenizer, and subsequently coated on base paper along with cationic starch to enhance its multi-barrier performance to facilitate the packaging application. The LNPs obtained through such a facile process formed stable colloidal dispersion in water, which exhibited excellent interfacial compatibility with cationic starch. During the coating process, a highly adhesive emulsion consisting of cationic starch and LNPs were coated on the surface of base paper, imparting good hydrophobic properties to the paper. The resulting paper material exhibited good water resistance (Cobb value of 37.5 g m−2), high oil resistance (Kit rating 9) and tensile strength (48.93 MPa). The reduction in water vapor transmission rate (WVTR) exceeds sixfold. This study provides a new avenue for the application of lignin in high-barrier, fluorine-free, water-and oil-resistant packaging materials.

With the introduction of the “dual carbon” goal and the continuous promotion of low-carbon development, the integrated energy system (IES) has gradually become an effective way to save energy and reduce emissions. This study proposes a low-carbon economic optimization scheduling model for an IES that considers carbon trading costs. With the goal of minimizing the total operating cost of the IES and considering the transferable and curtailable characteristics of the electric and thermal flexible loads, an optimal scheduling model of the IES that considers the cost of carbon trading and flexible loads on the user side was established. The role of flexible loads in improving the economy of an energy system was investigated using examples, and the rationality and effectiveness of the study were verified through a comparative analysis of different scenarios. The results showed that the total cost of the system in different scenarios was reduced by 18.04%, 9.1%, 3.35%, and 7.03%, respectively, whereas the total carbon emissions of the system were reduced by 65.28%, 20.63%, 3.85%, and 18.03%, respectively, when the carbon trading cost and demand-side flexible electric and thermal load responses were considered simultaneously. Flexible electrical and thermal loads did not have the same impact on the system performance. In the analyzed case, the total cost and carbon emissions of the system when only the flexible electrical load response was considered were lower than those when only the flexible thermal load response was taken into account. Photovoltaics have an excess of carbon trading credits and can profit from selling them, whereas other devices have an excess of carbon trading and need to buy carbon credits.

Abstract This study aims to explore the efficacy of a hybrid deep learning and radiomics approach, supplemented with patient metadata, in the noninvasive dermoscopic imaging-based diagnosis of skin lesions. We analyzed dermoscopic images from the International Skin Imaging Collaboration (ISIC) dataset, spanning 2016–2020, encompassing a variety of skin lesions. Our approach integrates deep learning with a comprehensive radiomics analysis, utilizing a vast array of quantitative image features to precisely quantify skin lesion patterns. The dataset includes cases of three, four, and eight different skin lesion types. Our methodology was benchmarked against seven classification methods from the ISIC 2020 challenge and prior research using a binary decision framework. The proposed hybrid model demonstrated superior performance in distinguishing benign from malignant lesions, achieving area under the receiver operating characteristic curve (AUROC) scores of 99%, 95%, and 96%, and multiclass decoding AUROCs of 98.5%, 94.9%, and 96.4%, with sensitivities of 97.6%, 93.9%, and 96.0% and specificities of 98.4%, 96.7%, and 96.9% in the internal ISIC 2018 challenge, as well as in the external Jinan and Longhua datasets, respectively. Our findings suggest that the integration of radiomics and deep learning, utilizing dermoscopic images, effectively captures the heterogeneity and pattern expression of skin lesions.

Abstract Objectives To develop a deep learning model combining CT scans and clinical information to predict overall survival in advanced hepatocellular carcinoma (HCC). Methods This retrospective study included immunotherapy-treated advanced HCC patients from 52 multi-national in-house centers between 2018 and 2022. A multi-modal prognostic model using baseline and the first follow-up CT images and 7 clinical variables was proposed. A convolutional-recurrent neural network (CRNN) was developed to extract spatial-temporal information from automatically selected representative 2D CT slices to provide a radiological score, then fused with a Cox-based clinical score to provide the survival risk. The model’s effectiveness was assessed using a time-dependent area under the receiver operating curve (AUC), and risk group stratification using the log-rank test. Prognostic performances of multi-modal inputs were compared to models of missing modality, and the size-based RECIST criteria. Results Two-hundred seven patients (mean age, 61 years ± 12 [SD], 180 men) were included. The multi-modal CRNN model reached the AUC of 0.777 and 0.704 of 1-year overall survival predictions in the validation and test sets. The model achieved significant risk stratification in validation (hazard ratio [HR] = 3.330, p = 0.008), and test sets (HR = 2.024, p = 0.047) based on the median risk score of the training set. Models with missing modalities (the single-modal imaging-based model and the model incorporating only baseline scans) can still achieve favorable risk stratification performance (all p

Abstract RNase H1 has been acknowledged as an endoribonuclease specializing in the internal degradation of the RNA moiety within RNA–DNA hybrids, and its ribonuclease activity is indispensable in multifaceted aspects of nucleic acid metabolism. However, the molecular mechanism underlying RNase H1-mediated hybrid cleavage remains inadequately elucidated. Herein, using single-molecule approaches, we probe the dynamics of the hybrid cleavage by Saccharomyces cerevisiae RNase H1. Remarkably, a single RNase H1 enzyme displays 3′-to-5′ exoribonuclease activity. The directional RNA degradation proceeds processively and yet discretely, wherein unwinding approximately 6-bp hybrids as a prerequisite for two consecutive 3-nt RNA excisions limits the overall rate within each catalytic cycle. Moreover, Replication Protein A (RPA) reinforces RNase H1’s 3′-to-5′ nucleolytic rate and processivity and stimulates its 5′-to-3′ exoribonuclease activity. This stimulation is primarily realized through the pre-separation of the hybrids and consequently transfers RNase H1 to a bidirectional exoribonuclease, further potentiating its cleavage efficiency. These findings unveil unprecedented characteristics of an RNase and provide a dynamic view of RPA-enhanced processive hybrid cleavage by RNase H1.

Abstract. Background:. The potential impact of pre-existing coronary artery stenosis (CAS) on acute pulmonary embolism (PE) episodes remains underexplored. This study aimed to investigate the association between pre-existing CAS and the elevation of high-sensitivity cardiac troponin I (hs-cTnI) levels in patients with PE. Methods:. In this multicenter, prospective case-control study, 88 cases and 163 controls matched for age, sex, and study center were enrolled. Cases were patients with PE with elevated hs-cTnI. Controls were patients with PE with normal hs-cTnI. Coronary artery assessment utilized coronary computed tomographic angiography or invasive coronary angiography. CAS was defined as ≥50% stenosis of the lumen diameter in any coronary vessel >2.0 mm in diameter. Conditional logistic regression was used to evaluate the association between CAS and hs-cTnI elevation. Results:. The percentage of CAS was higher in the case group compared to the control group (44.3% [39/88] vs. 30.1% [49/163]; P = 0.024). In multivariable conditional logistic regression model 1, CAS (adjusted odds ratio [OR], 2.680; 95% confidence interval [CI], 1.243–5.779), heart rate >75 beats/min (OR, 2.306; 95% CI, 1.056–5.036) and N-terminal pro-B type natriuretic peptide (NT-proBNP) >420 pg/mL (OR, 12.169; 95% CI, 4.792–30.900) were independently associated with elevated hs-cTnI. In model 2, right CAS (OR, 3.615; 95% CI, 1.467–8.909) and NT-proBNP >420 pg/mL (OR, 13.890; 95% CI, 5.288–36.484) were independently associated with elevated hs-cTnI. Conclusions:. CAS was independently associated with myocardial injury in patients with PE. Vigilance towards CAS is warranted in patients with PE with elevated cardiac troponin levels.

Abstract Background Human adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro. Methods ADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs–SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then evaluated 12 and 20 weeks after surgery through gait analysis, von frey test, microcomputed tomography, MRI, and immunohistochemical and histological analyses. Finally, the mechanisms underlying these findings were investigated through the RNA sequencing of tissue samples in vivo and Western blot of the OA chondrocyte autophagy pathway. Results Among the MSCs treatment groups, 5A5S had the greatest synergistic effect that increased the chondrogenic potential of OA chondrocytes in vitro and inhibited early and advanced OA in vivo. The 5A5S group significantly reduced cartilage degeneration, synovial inflammation, pain sensation, and nerve invasion in subchondral nude rat OA, outperforming both single-cell treatments. The underlying mechanism was the activation of chondrocyte autophagy via the FoxO1 signaling pathway. Conclusion A combination of human ADSCs and SDSCs demonstrated higher potential than a single type of stem cell, demonstrating potential as a novel treatment for OA.