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Tissue homeostasis and regeneration involve complex cellular changes. The role of rRNA modification-dependent translational regulation in these processes remains largely unknown. Planarians, renowned for their ability to undergo remarkable tissue regeneration, provide an ideal model for the analysis of differential rRNA regulation in diverse cell types during tissue homeostasis and regeneration. We investigated the role of RNA 2'-O-methyltransferase, Fibrillarin (FBL), in the planarian Schmidtea mediterranea and identified two FBL homologs: Smed-fbl-1 (fbl-1) and Smed-fbl-2 (fbl-2). Both are essential for planarian regeneration, but play distinct roles: fbl-1 is crucial for progenitor cell differentiation, while fbl-2 is important for late-stage epidermal lineage specification. Different 2'-O-methylation patterns were observed upon fbl-1 and fbl-2 knockdown, suggesting their roles in translation of specific mRNA pools during regeneration. Ribo-seq analysis further revealed differing impacts of fbl-1 and fbl-2 knockdown on gene translation. These findings indicate divergent roles of the duplicate fbl genes in specific cell lineage development in planarians and suggest a role of rRNA modifications in translational regulation during tissue maintenance and regeneration., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer's disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Rib high -L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Rib high -L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Rib high -L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD., Competing Interests: Conflict of interest X.W., J.Y., E.J., W.L., G.S., Z.F., C.D., L.L., X.D., Z.Y., Z.L., C.G., and J.Z. are full-time employees of Shanghai Green Valley Pharmaceutical Co., Ltd. The other authors declare no competing interests., (© 2024. The Author(s).)

Colorectal cancer (CRC) development involves a series of molecular events that drive the progression from normal colorectal epithelium to adenoma and eventually to invasive carcinoma. While the involvement of extrachromosomal circular DNAs (ecDNAs) in cancer genome remodeling has been established, their specific roles in CRC formation remain unclear. Using Circle-Sequencing and whole transcriptomic sequencing, we comprehensively profile circular DNAs and transcriptomes in healthy individuals, colorectal adenoma, and CRC patients. Our delineate analyses characterize the key circular DNAs involved in oncogene expression through the normal-adenoma-carcinoma continuum and highlight that immune response-related pathways and cell cycle pathways, are the dominat events in CRC progression. Notably, chr8 ecDNA 64950741-114379093 exhibits robust up-regulation during CRC progression. Further validation in a new cohort of 50 CRC patients confirms the higher expression of chr8 ecDNA 64950741-114379093 and its strong correlation with poor prognosis. Thus, these findings provide unprecedented insights into the landscape of circular DNAs in CRC and highlights the potential of chr8 ecDNA 64950741-114379093 as a promising biomarker and therapeutic target for CRC management., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

With the progression of regional connectivity, attaining the 'dual-carbon target' is no longer the narrative of a single city. To achieve synergistic governance among cities in the basin economic zone, it is essential to establish a multidimensional ecological compensation mechanism. This research amended the conventional carbon accounting model by utilising carbon emissions and economic data from 59 cities in China's Yellow River Basin, covering the period from 2004 to 2021, after the timeframe of significant alterations in the administrative divisions of cities was removed. It additionally compares and analyses the clustering patterns and trajectories of centre-of-gravity shifts in regional ecocompensation credits while investigating the impact processes through geo-probes. The findings indicate that the amended carbon account has a more decentralised distribution when interregional disparities are considered. Second, ecocompensation credits are characterised mostly by low-high and low-low agglomeration; nevertheless, their regional distribution is uneven. Moreover, the rankings of the top five cities in terms of ecocompensation exhibited minimal variation each year. The degree of green technology is the primary determinant of the spatiotemporal evolution of ecological compensation. The conclusions of this study can serve as a valuable reference for the execution of medium- and long-term ecocompensation policies and aid in attaining the 'dual-carbon' aim., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown potential as a therapeutic option for lupus nephritis (LN), particularly in patients refractory to conventional treatments. Despite extensive translational research on MSCs, the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood. Here, we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment. This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10, predominantly produced by glomerular vascular endothelial cells through the IFN-γ/IRF1-KPNA4 pathway. Interestingly, the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes. Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment. Furthermore, hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1 (IL4I1) in response to the microenvironment of LN kidney, thereby suppressing Th1 cells. Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3 + Th1 cell infiltration into LN kidneys. This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment. Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Process mining holds promise for analysing longitudinal data in clinical epidemiology, yet its application remains limited. The objective of this study was to propose and evaluate a methodology for applying process mining techniques in observational clinical epidemiology. We propose a methodology that integrates a cohort study design with data-driven process mining, with an eight-step approach, including data collection, data extraction and curation, event-log generation, process discovery, process abstraction, hypothesis generation, statistical testing, and prediction. These steps facilitate the discovery of disease progression patterns. We implemented our proposed methodology in a cohort study comparing new users of proton pump inhibitors (PPI) and H2 blockers (H2B). PPI usage was associated with a higher risk of disease progression compared to H2B usage, including a greater than 30% decline in estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio [HR] 1.6, 95% Confidence Interval [CI] 1.4-1.8), as well as increased all-cause mortality (HR 3.0, 95% CI 2.1-4.4). Furthermore, we investigated the associations between each transition and covariates such as age, gender, and comorbidities, offering deeper insights into disease progression dynamics. Additionally, a risk prediction tool was developed to estimate the transition probability for an individual at a future time. The proposed methodology bridges the gap between process mining and epidemiological studies, providing a useful approach to investigating disease progression and risk factors. The synergy between these fields enhances the depth of study findings and fosters the discovery of new insights and ideas., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Migraine is a common neurological disorder observed after coronavirus disease 2019 (COVID 19) infection. However, the intricate relationship between COVID 19 and migraine, particularly the potential mediating role of brain imaging-derived phenotypes (BIPs), remains unclear. This study used linkage disequilibrium score regression (LDSC), a bidirectional two-sample Mendelian randomization (MR) approach, and two-step MR analysis to investigate potential causal links. The robustness of the MR findings was corroborated through generalized summary-data-based Mendelian randomization (GSMR) and MR-Steiger methods. The results of the LDSC analysis revealed that the genetic correlation coefficient between COVID 19 traits and migraine was 0.0277 for infection (P = 0.0051), 0.1690 for hospitalization (P = 0.0016), and 0.1147 for severity (P = 0.0330). The genetic correlation coefficients between COVID 19 infection, hospitalization, severity and migraine and migraine with aura (MA) were 0.2654 (P = 0.0012), 0.2065 (P = 0.0043), and 0.1537 (P = 0.0230), respectively. Two-sample MR analysis revealed a significant causal association of COVID 19 infection (odds ratio [OR] 1.2502, P = 0.0083; OR 1.4956, P = 0.0084), hospitalization (OR 1.0689, P = 0.0138; OR 1.0919, P = 0.0208), and severity (OR 1.0644, P = 0.0072; OR 1.0844, P = 0.0098) with increased risk of migraine and migraine with aura (MA). Cortical thickness (CT), total surface area (TSA), and fractional anisotropy (FA) were identified as BIP intermediaries in the risk trajectory from COVID 19 to migraine. The TSA exhibited a more pronounced mediating effect than did CT. This study revealed that genetically predicted COVID 19 is associated with an increased risk of migraine and MA, and BIPs act as potential mediators of these causal relationships, offering insights into the neurobiological underpinnings of migraine in the context of COVID 19., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

As a typical sedimentary rock, coal seams are usually rich in bedding planes, which significantly affect the propagation process of hydraulic fracture (HF) network and reservoir permeability. In this study, the profile characteristics and the bedding roughness of the coal seam at depth of 2800 m from Daniudi Gas Field in China is investigated. The failure mechanism of shear-expansion effect under low pressure and dynamic shear under high pressure of coal beddings induced by the dissolution-corrosion effect of fracturing liquid is analyzed. The development process of HF network under different bedding angles, joint roughness coefficients (JRCs), stress differences, and confining pressures is numerically simulated by cohesive element method. Results show that the JRC of coal beddings has significant effects on the morphology of HF networks. When the JRC exceeds 15, a HF network structure with tensile main fractures and shear secondary cracks is developed. The shear fractures account for a considerable proportion (33-66%) multi-layer layered coal seams and should be taken seriously during reservoir reconstruction. As confining pressure increases, the total length of tensile HFs sharply decreases, while the change in the total length of shear HFs is not significant. When the confining pressure increases from 5 to 15 MPa, the length ratio of shear HFs to tensile hydraulic fractures increases from 0.36 to about 1, confirming that increasing confining pressure can promote the transformation of HF failure types from tension to shear. The ratio of secondary crack to main crack length is between 6.31 and 9.78, indicating the secondary fractures occupy an absolute proportion in the hydraulic fracture network. This study is of significance for understanding the hydraulic fracture network development in coal reservoirs., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Environmental osmolarity plays a crucial role in regulating the functions and behaviors of both host cells and pathogens. However, it remains unclear whether and how environmental osmotic stimuli modulate bacterial‒host interfacial adhesion. Using single-cell force spectroscopy, we revealed that the interfacial adhesion force depended nonlinearly on the osmotic prestimulation of host cells but not bacteria. Quantitatively, the adhesion force increased dramatically from 25.98 nN under isotonic conditions to 112.45 or 93.10 nN after the host cells were treated with the hypotonic or hypertonic solution. There was a strong correlation between the adhesion force and the number of host cells harboring adherent/internalized bacteria. We further revealed that enhanced overexpression levels of collagen XV and II were responsible for the increases in interfacial adhesion under hypotonic and hypertonic conditions, respectively. This work provides new opportunities for developing host-directed antibacterial strategies related to interfacial adhesion from a mechanobiological perspective., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: This study aimed to identify large duplications (>5 Mb) that are harmless through long-term clinical follow-ups of fetuses and phenotype analyses of carrier family members., Methods: We retrospectively analyzed fetuses undergoing prenatal diagnosis and who had >5 Mb chromosomal duplications. Routine karyotyping and single-nucleotide polymorphism array analysis were performed to identify the source and location information of the duplicated segments. Genotype-phenotype analyses were conducted based on genetic information and phenotypes during postnatal follow-up., Results: Eight eligible cases were included. All fetuses carried maternal or paternal duplications ranging in length from 5.3 to 12.2 Mb. The locations were as follows: 2q32.3q33.1 (Chr2:192322509-199548704), 4q22.1 (Chr4: 88347368-93602855), 4q34.2q35.2 (Chr4:176956406-189189971), 4q34.3q35.2 (Chr4:180613345-189353740), 5p14.3p14.1 (Chr5:19093749-28557664), 10q22.2q23.2 (Chr10:77448435-88786593), 12q21.31q21.32 (Chr12:81983257-87322734), and 13q14.11q14.2 (Chr13: 40825382-47633710). Karyotyping revealed that these duplications occurred within their respective chromosomal regions, except in pedigrees 6 and 7. In the eight pedigrees, the coordinates and lengths of duplicated segments in family members were matched with those in fetuses. Neither the fetuses nor other carriers were clinically symptomatic., Conclusion: Our findings revealed that the eight pedigrees carrying duplications >5 Mb were asymptomatic, providing new data to inform genetic counseling for the observed segments., Impact: We focused on unrelated fetuses among eight pedigrees who carried duplications of different chromosomal segments. These duplications had been stably transmitted through 2 or 3 generations of normal individuals. Importantly, phenotypic abnormalities were lacking, which was unexpected given that the maximum segment size was approximately 12.2 Mb. We found that duplications in these regions were benign in the context of prenatal genetic counseling. These results provide a foundation for addressing genotype-phenotype correlations. To our knowledge, this is the first description of normal phenotypes in individuals with duplications in these regions., Competing Interests: Competing interests The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article. Consent to participate Written informed consent was obtained from the patients. Ethical approval This study was approved by the Ethics Committee of Southwest Hospital, Third Military Medical University (Army Medical University). The approval number is (B)KY2021023., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Understanding the properties of explosives is the basis for investigating and analyzing explosion cases. To date, due to the strict legal control of standard explosives and initiators, homemade pyrotechnics composed of oxidizers and fuels have become popular explosive sources of improvised explosive devices (IEDs) threatening greatly social stability and personal safety. The reactivity of pyrotechnics strongly depends on their intrinsic characteristics and operating conditions, which determine the efficiencies of heat and mass transfer between the reaction zone and the unreacted zone. Herein, the tests of thermodynamics, pressurization characteristics, and combustion propagation behaviors are conducted to explore the effects of oxidizer species, particle size, and loading density on the reactivity of homemade binary aluminum-based pyrotechnics. The results show that the pyrotechnics with potassium chlorate (KClO 3 ) have the strongest reactivity with the highest pressurization rate (dp/dt) and the shortest combustion duration. Compared with their counterparts based on aluminum microparticles(mAl), pyrotechnics consisting of Al nanoparticles (nAl) possess superior reactivity as expected, which results from the relatively short heat and mass transfer distances. The nAl-based pyrotechnics have a low reaction exothermic peak temperature, great heat release, great aluminothermic reaction completeness, and high produced peak pressure with several orders of magnitude higher pressurization rate. Increasing the loading density of the pyrotechnics over a certain value can change the dominant mode of heat transfer from convective to conduction, sharply decreasing the pressurization characteristics and combustion front propagation velocities (v p ). The results of theoretical calculations using the NASA-CEA codes show that loading density can alter the reaction process of the pyrotechnics, leading to a decrease in the predicted pressure per unit mass for Al/KNO 3 or Al/AP, and an increase for Al/KClO 3 . For nAl/potassium nitrate (KNO 3 ), the density is between 1.0 and 1.25 g cm -3 , across which dp/dt decreases by one order of magnitude from 0.148 to 0.014 MPa ms -1 . In addition, v p decreases by three orders of magnitude from 0.040 to 0.078 m s -1 . Distinct pressurization behaviors of nAl/AP are observed at a density of 1.5 g cm -3 , while the variation in nAl/KClO 3 reactivity fluctuates. These results are beneficial for the damage assessment of scenes caused by an explosion and for inversely calculating charge parameters., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

A rise in blood glucose is an early warning sign of underlying pancreatic cancer (PC) and may be an indicator of genetic events in PC progression. However, there is still a lack of mechanistic research on pancreatic cancer-associated new-onset diabetes (PCAND). In the present study, we identified a gene SRI, which possesses a SNP with the potential to distinguish PCAND and Type 2 diabetes mellitus (T2DM), by machine learning on the basis of the UK Biobank database. In vitro and in vivo, sorcin overexpression induced pancreatic β-cell dysfunction. Sorcin can form a positive feedback loop with STAT3 to increase the transcription of serpin E1 and CCL5, which may directly induce β-cell dysfunction. In 88 biopsies, the expression of sorcin was elevated in PC tissues, especially in PCAND samples. Furthermore, plasma serpin E1 levels are higher in peripheral blood samples from PCAND patients than in those from T2DM patients. In conclusion, sorcin may be the key driver in PCAND, and further study on the sorcin-STAT3-serpin E1/CCL5 signaling axis may help us better understand the pathogenesis of PCAND and identify potential biomarkers., (© 2024. The Author(s).)

The increasing prevalence of carbapenem-resistant Enterobacter cloacae complex (CREC) poses great challenges to infection treatment in the clinical setting. In this study, we reported the emergence of carbapenemase in a rare species, Enterobacter chuandaensis, belonging to the Enterobacter cloacae complex (ECC). We elucidated the genetic characteristics of carbapenem-resistant isolate FAHZZU5885, co-harboring bla NDM-1 and bla KPC-2 . Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and average nucleotide identity (ANI) analysis were used to identify E. chuandaensis. S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting were used to clarify the number and size of the plasmids in FAHZZU5885. Antimicrobial phenotypes were identified by antimicrobial susceptibility testing (AST), and the characteristics of the strain were examined with whole-genome sequencing (WGS). The conjugation experiment and stability assay were conducted to verify the transferability and stability of the plasmid carrying carbapenemase-encoding genes. E. chuandaensis FAHZZU5885 was isolated from a perianal swab of a patient admitted to the ICU. This strain simultaneously carried bla NDM-1 and two bla KPC-2 genes. FAHZZU5885 was resistant to most of the tested antibiotics except for amikacin, tigecycline, and colistin. Two bla KPC-2 were located separately on two different plasmids, the ~ 120 kb IncFIA-IncFII plasmid and the ~ 80 kb IncR plasmid. Both plasmids shared the conserved sequence klcA-korC-ISkpn6-bla KPC-2 -ISkpn27-tnpR-tnpA. The bla NDM-1 -bearing plasmid had the potential to transfer and can remain stable after successive passages. In addition, the bla NDM-1 was carried on a ~ 80 kb IncFII plasmid with the conserved sequence ISAba125-bla NDM-1 -ble-trpF-dsbD-cutA-groS-groL. In summary, this study marks the first report of the multidrug-resistant E. chuandaensis strain FAHZZU5885 harboring two bla KPC-2 -bearing plasmids, indicating the potential for the further dissemination of carbapenemase-encoding genes in novel species. The findings contribute to enhancing our understanding of CREC strains, emphasizing the need for continued and comprehensive surveillance of this species., (© 2024. The Author(s).)

To investigate the dynamic mechanical behavior and energy dissipation characteristics of low-temperature rock samples under cyclic impact loading, a temperature-controlled impact system that combines Hopkins bars with a low-temperature compensation device was used. Five temperature gradients were confirmed via a trial impact test, and impact tests were conducted under two kinds of impact air pressures. The macroscopic damage characteristics of rock samples under cyclic impact at different temperatures, dynamic stress-strain curves, changes in peak stress and strain, energy dissipation, and cumulative damage at different temperatures, and the macroscopic and microscopic structural characteristics of low-temperature rock samples after cyclic impact were analyzed in combination with damage. The findings indicated that low-temperature saturated granite primarily experienced tensile damage under cyclic impact loading, with the required number of impacts increasing with decreasing temperature, and rock samples exhibited freeze-induced brittleness and significantly increased fragmentation. The dynamic stress-strain curve generally exhibited rebound characteristics in the post-peak stage. With an increasing number of cycles, an overall decrease in peak stress was observed, whereas the peak strain and cumulative specific dissipated energy exhibited opposite trends. This trend was more pronounced at lower temperatures, with a significant increase in peak strain and specific energy amplitude. In addition, the cumulative damage factor of the rock samples increased at lower temperatures, consistent with macroscopic damage characteristics, and exhibited a negative correlation with peak stress. The degree of crack extension in the macroscopic samples corresponded with the observed fracture changes. Microanalysis (SEM) indicated that decreasing temperature resulted in freeze brittleness of the fracture surfaces, characterized by reduced flatness and an expansion of brittle cracks across the damage surface. The slip separation phenomenon became increasingly pronounced, and these observations were positively correlated with the cumulative damage value., (© 2024. The Author(s).)

Endometriosis, an estrogen-dependent chronic inflammatory condition, afflicts reproductive-aged women. However, the underlying pathological mechanisms remain to be elucidated. Nicotinamide N-methyltransferase (NNMT) is a critical enzyme involved in cellular metabolism and methylation regulation. This study investigated the role of NNMT in endometriosis. By analyzing datasets GSE5108, GSE7305, GSE141549, GSE23339, and GSE25628, we identified a significant overexpression of NNMT in the eutopic endometrium and ectopic lesions of endometriosis patients compared to normal endometrium. Furthermore, NNMT was upregulated in collected endometrioma specimens and isolated primary endometrial stromal cells (ESCs) compared to their respective controls. Inhibition of NNMT using JBSNF-000088 attenuated the proliferation, migration, and invasion of ESCs. In vivo, treatment of mouse models of endometriosis with JBSNF-000088 resulted in a marked reduction in lesion weight and quantity. NNMT expression in ESCs was dose-dependently upregulated by 17β-estradiol at concentrations of 1 nM, 10 nM, and 100 nM, an effect that was attenuated by 10 nM progesterone. Additionally, treating HESCs with macrophage-conditioned medium elevated NNMT expression at both mRNA and protein levels. Knockdown of NNMT impeded the proliferation, migration, and invasion of ESCs, which was paralleled by decreased phosphorylation levels of Erb-b2 receptor tyrosine kinase 4 (ERBB4), PI3K, and AKT. Conversely, overexpressing ERBB4 mitigated the NNMT knockdown-induced decline in phosphorylated PI3K and AKT and rescued the proliferation of ESCs. Altogether, these results indicate that the overexpression of NNMT induced by estrogen and macrophage interaction modulates ESC proliferation via the NNMT-ERBB4-PI3K/AKT signaling pathway, as well as promotes cellular migration and invasion, contributing to the development of endometriosis., (© 2024. The Author(s).)

This study aimed to construct a high-performance prediction and diagnosis model for type 2 diabetic retinopathy (DR) and identify key correlates of DR. This study utilized a cross-sectional dataset of 3,000 patients from the People's Liberation Army General Hospital in 2021. Logistic regression was used as the baseline model to compare the prediction performance of the machine learning model and the related factors. The recursive feature elimination cross-validation (RFECV) algorithm was used to select features. Four machine learning models, support vector machine (SVM), decision tree (DT), random forest (RF), and gradient boost decision tree (GBDT), were developed to predict DR. The models were optimized using grid search to determine hyperparameters, and the model with superior performance was selected. Shapley-additive explanations (SHAP) were used to analyze the important correlation factors of DR. Among the four machine learning models, the optimal model was GBDT, with predicted accuracy, precision, recall, F1-measure, and AUC values of 0.7883, 0.8299, 0.7539, 0.7901, and 0.8672, respectively. Six key correlates of DR were identified, including rapid micronutrient protein/creatinine measurement, 24-h micronutrient protein, fasting C-peptide, glycosylated hemoglobin, blood urea, and creatinine. The logistic model had 27 risk factors, with an AUC value of 0.8341. A superior prediction model was constructed that identified easily explainable key factors. The number of correlation factors was significantly lower compared to traditional statistical methods, leading to a more accurate prediction performance than the latter., (© 2024. The Author(s).)

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate We obtained written informed consent from the patients and permission from Institutional Research Ethics Committee to collect and use these clinical data, and were carried out in accordance with International Ethical Guidelines for Health-related Research Involving Humans. All experimental animal procedures were performed according to guidelines approved by the Institutional Animal Care and Use Committees (IACUCs) and were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality globally and p53, a widely recognized tumor suppressor, contributes to the development of CRC. Ubiquitin-specific protease 36 (USP36), belonging to the deubiquitinating enzyme family, is involved in tumor progression across multiple cancers. However, the underlying molecular mechanism in which USP36 regulates p53 signaling pathway in CRC is unclear. Here, our study revealed that USP36 was increased in CRC tissues and associated with unfavorable prognosis. Functionally, elevated USP36 could promote proliferation, migration, and invasion of CRC cells in vitro and in vivo. Mechanistically, USP36 could interact with and stabilize RBM28 via deubiquitination at K162 residue. Further, upregulated RBM28 could bind with p53 to suppress its transcriptional activity and therefore inactivate p53 signaling pathway. Collectively, our investigation identified the novel USP36/RBM28/p53 axis and its involvement in promoting cell proliferation and metastasis in CRC, which presents a promising therapeutic strategy for CRC treatment., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval Approval from the ethics committee of The First School of Clinical Medicine, Nanjing Medical University was obtained for the human tissue study, and informed consent was provided by all patients involved. All animal experiments are conducted with the approval of the Committee on the Ethics of Animal Experiments of Nanjing Medical University. The ethical number of the animal experiment is IACUC-2310047. All methods were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s).)

Par6α encoded by PARD6A is a member of the PAR6 family and is reported to promote cancer initiation and progression. PARD6A is frequently upregulated in different types of cancers, but its regulatory role in lung cancer progression is yet to be established. In this study, we analyzed the PARD6A expression in biopsies from lung adenocarcinoma (LUAD) patients, and the survival probability using LUAD tissue microarray (TMA) and online datasets from TCGA and GEO. We conducted in vitro and in vivo assays to assess the role of PARD6A in regulating lung cancer progression, including proliferation, wound healing, transwell, RNA-seq, and subcutaneous tumor mice models. Our findings revealed that PARD6A is highly expressed in cancer tissues from LUAD patients and is associated with poor prognosis in LUAD patients. In vitro assays showed that PARD6A promoted cell proliferation, migration, and invasion. The transcriptome sequencing identified Serpina3 as one of the key downstream molecules of PARD6A. Ectopic expression of Serpina3 rescued impaired proliferation, migration, and invasion in PARD6A-knocking down H1299 cells, whereas silencing Serpina3 impeded enhanced proliferation, migration, and invasion in PARD6A-overexpressing H1975 cells. Our findings suggest that PARD6A promotes lung cancer progression by inducing Serpina3, which may be a promising therapeutic target., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The tumor tissue microarray (TMA) was purchased from Outdo Biotech Co., Ltd. (China). The study using the TMA was approved by the Life Sciences Ethics Committee of Outdo Biotech Co., Ltd., under the reference number: YB M-05-02. All patients and healthy donors provided informed consent to participate., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Resident microbiota produces small molecules that influence the chemical microenvironments on leaves, but its signalling roles in pathogen defence are not yet well understood. Here we show that Aspergillus cvjetkovicii, enriched in rice leaf microbiota, subverts Rhizoctonia solani infections via small-molecule-mediated interspecies signalling. 2,4-Di-tert-butylphenol (2,4-DTBP), identified as a key signalling molecule within the Aspergillus-enriched microbiota, effectively neutralizes reactive oxygen species-dependent pathogenicity by switching off bZIP-activated AMT1 transcription in R. solani. Exogenous application of A. cvjetkovicii and 2,4-DTBP demonstrated varying degrees of protective effects against R. solani infection in diverse crops, including cucumber, maize, soybean and tomato. In rice field experiments, they reduced the R. solani-caused disease index to 19.7-32.2%, compared with 67.2-82.6% in the control group. Moreover, 2,4-DTBP showed activity against other rice phytopathogens, such as Fusarium fujikuroi. These findings reveal a defensive strategy against phytopathogens in the phyllosphere, highlighting the potential of symbiotic microbiota-driven neutralization of pathogenicity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6 -/- ) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

This study aimed to explore the association between inflammation-based prognostic markers and outcomes in non-small cell lung cancer (NSCLC) patients undergoing therapy with immune checkpoint inhibitors (ICIs). We conducted a comprehensive search of the Embase, PubMed, and Cochrane databases for studies that reported on the impact of inflammation-based prognostic factors, such as C-reactive protein (CRP), on the prognosis of NSCLC patients treated with ICIs. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). Statistical analyses were performed using Stata 14 software, with assessments of publication bias and heterogeneity conducted as necessary. Our meta-analysis included 27 studies encompassing 5,174 patients, evaluating factors such as CRP, the modified Glasgow Prognostic Score (mGPS), and the CRP-albumin ratio (CAR). The analysis revealed that elevated levels of CRP were significantly correlated with both reduced PFS (I 2  = 0%, P = 0.72; HR = 1.50, 95%CI: 1.33-1.67, P < 0.01) and shorter OS (I 2  = 0%, P = 0.55; HR = 1.90, 95%CI: 1.50-2.30, P < 0.01). Similarly, elevated levels of mGPS values were associated with worse PFS (I 2  = 0%, P = 0.75; HR = 1.28, 95%CI: 1.10-1.46, P < 0.05) and OS (I 2  = 0%, P = 0.94; HR = 1.56, 95%CI: 1.31-1.81, P < 0.05). However, the relationship between elevated levels of CAR and worse outcomes for PFS (I 2  = 59.6%, P = 0.94; HR = 1.42, 95%CI: 0.74-2.11, P > 0.05) and OS (I 2  = 45.3%, P = 0.16; HR = 1.41, 95%CI: 0.70-2.13, P > 0.05) was not statistically significant. Our findings suggest that CRP and mGPS may serve as potential prognostic markers in NSCLC patients receiving immunotherapy. Nonetheless, further research with more homogeneous study populations is necessary to valid these observations., (© 2024. The Author(s).)

Breast cancer is a common malignant tumor, which mostly occurs in female population and is caused by excessive proliferation of breast epithelial cells. Breast cancer can cause nipple discharge, breast lumps and other symptoms, but these symptoms lack certain specificity and are easily confused with other diseases, thus affecting the early treatment of the disease. Once the tumor progresses to the advanced stage, distant metastasis can occur, leading to dysfunction of the affected organs, and even threatening the patients' lives. In this study, we synthesized high drug-loading gel particles and applied them to control the release of insoluble drugs. This method is simple to prepare, cost-effective, and validates their potential in breast cancer therapy. We first characterized the morphology and physicochemical properties of gel loaded with newly synthesized compound 1 by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA). Using newly synthesized insoluble compound 1 as a model drug, its efficacy in treating breast cancer was investigated. The results showed that hydrogel@compound 1 was able to significantly inhibit the proliferation, migration and invasion of breast cancer cells. Additionally, we utilized machine learning to screen three structurally similar compounds, which showed promising therapeutic effects, providing a new approach for the development of novel small-molecule drugs., (© 2024. The Author(s).)

This study examined the associations between tobacco smoking and serum cotinine levels, an objective biochemical measure of tobacco smoke exposure, with markers of inflammation, i.e., interferon-gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2) and tumour necrosis factor-alpha (TNF-α) in people living with HIV (PLWH).These specific markers were selected because of their hypothesised associations with smoking, PLWH and their outcomes. In a random sample of ≥ 18-year-old PLWH receiving care at 17 public healthcare facilities across the Western Cape Province in South Africa, data collection included self-reported smoking history, and serum levels of cotinine and selected inflammatory markers. The inflammatory marker data were log transformed because of the skewedness of their distribution. Linear regression models (1) adjusted for age and gender, and (2) fully adjusted for age, gender, current alcohol use, body mass index and CD4 counts were used to examine the associations between smoking tobacco or serum cotinine and inflammatory markers. Level of significance was p < 0.05. Among 749 PLWH who were mainly women (79%), the mean age was 38.5 (8.9) years and similar when stratified by smoking status. Serum cotinine levels exhibited a striking discrepancy, with a median of 154 ng/mL among current smokers, in stark contrast to the consistent median values of 10 ng/mL observed among past and never smokers. In regression models adjusted for age and gender, current smoking and frequent smoking were associated with lower IL-2 but higher TNF-α. Log-cotinine exhibited associations with IFN-γ, IL-10, and TNF-α, while cotinine levels ≥ 10 ng/mL compared to < 10 ng/mL were associated with higher IFN-γ and TNF-α. In fully adjusted models, log-cotinine and cotinine levels ≥ 10 ng/mL displayed significant associations with higher IFN-γ and lower IL-2. This study underscores the importance of investigating the interplay between smoking tobacco or serum cotinine levels with pro-inflammatory cytokines in PLWH. It signals the need for comprehensive research to unravel the potential synergistic impacts of smoking tobacco and HIV infection on chronic inflammation and immune dysregulation, shedding light on critical avenues for intervention and management strategies., (© 2024. The Author(s).)

The aim of this study was to investigate the prevalence of diastasis recti abdominis (DRA) and to find the possible risk factors for DRA based on two diagnostic criteria among women in long-term postpartum period. A cross-sectional study was conducted on 1000 postpartum women at five different time points (3, 5, 10, 20, and 30 years after partum, respectively). Inter-recti distance (IRD) was assessed using ultrasound imaging, while basic data were collected through self-reported questionnaires. Two diagnostic criteria, IRD > 2 cm and IRD > 3 cm, were used to present the prevalence of DRA. Univariate and multivariate analyses were employed to explore the risk factors for DRA. When using the diagnostic criterion of IRD > 2 cm for DRA, the prevalence was 36%, 31%, 22%, 26%, and 30% at 3, 5, 10, 20, and 30 years postpartum, respectively. When using the diagnostic criterion of IRD > 3 cm for DRA, the prevalence was 13%, 8%, 6%, 8%, and 10%, respectively. The results revealed that higher body mass index (BMI) was a risk factor for DRA at 10 years postpartum (p = 0.000), bigger number of parturitions was a risk factor at 3, 5, and 10 years postpartum (p = 0.000, 0.004 and 0.000), twins was a risk factor at 3 years postpartum (p = 0.001), and diabetes was a risk factor at 20 and 30 years postpartum (P = 0.000 and 0.004). (1) The prevalence of DRA in the long-term postpartum period was high, especially when IRD > 2 cm was used as the diagnostic criterion. (2) Higher BMI, bigger number of parturitions, twins and diabetes were independently associated with higher odds of DRA at different long-term postpartum time points. (3) The diagnostic criterion for DRA should be further improved to avoid excessive clinical diagnosis and treatment. (1) This study elucidated the prevalence and risk factors associated with long-term postpartum DRA, thereby enhancing clinical awareness and advocating for early intervention and prevention measures to mitigate serious adverse outcomes. (2) This study presented the research results using two diagnostic criteria, increasing comparability with existing studies. In addition, discussions on reasonable diagnostic criterion for DRA were also conducted to avoid excessive clinical diagnosis and treatment., (© 2024. The Author(s).)

To determine the synergistic effect and mechanism of AO/854, a new Bloom syndrome protein (BLM) helicase inhibitor, and cisplatin (CDDP), a DNA-crosslinking agent, cell viability assays, neutral comet assays, and Western blotting (WB) were performed on prostate cancer (PCa) cells. According to our findings, combining AO/854 and CDDP enhanced the antiproliferative capabilities of PC3 cell lines. As evidenced by the upregulation of γH2AX, cleaved caspase-3/caspase-3, and BAX/Bcl-2, AO/854 dramatically increased PC3 apoptosis and DNA damage induced by CDDP. Furthermore, combining AO/854 and CDDP synergistically inhibited PC3 cell migration and invasion. In addition, AO/854 inhibited CDDP-induced S-phase cell-cycle arrest in PC3 cells while enhancing G2/M-phase cell-cycle arrest. In vivo, the antitumor efficacy of the combination therapy group was greater than that of the groups treated with AO/854 or CDDP alone. Our findings indicate that synergistic chemotherapy with AO/854 and CDDP may be a novel anticancer strategy for PCa., (© 2024. The Author(s).)

Extraction of gas from low-permeability thick coal seams poses challenges globally, attributed to low extraction efficiency, limited enrichment content, and extraction complexities. Investigating static fracturing in low-permeability thick coal seams holds substantial engineering significance and practical utility. This research delves into the current conditions in the Western region, characterized by low gas permeability and challenging extraction in thick coal seams. Through the utilization of FLAC 3D and COMSOL, simulation schemes are devised to analyze the influence of borehole parameters on fracture efficacy, elucidating the mechanisms by which external loads and internal gas pressure impact coal seam permeability. Field monitoring tests are employed to evaluate and model gas extraction enhancement via borehole positioning. The results suggest that the application of a static fracturing agent inducing 40 MPa expansion stress, along with a 75 mm borehole diameter and 0.5 m spacing, effectively fractures low-permeability thick coal seams. The spacing between extraction and fracturing holes adversely affects gas extraction efficiency due to the limited range of static fracturing. Field experiments demonstrate that static fracturing significantly improves gas extraction from low-permeability thick coal seams, resulting in a twofold increase in average gas extraction purity post-fracturing. This study establishes a robust theoretical foundation for optimizing gas extraction and mining activities in challenging low-permeability thick coal seam environments., (© 2024. The Author(s).)

To analyze the prevalence and influencing factors of myopia among children and adolescents in Hangzhou city, and provide ideas for the formulation of myopia prevention and control measures. A cross-sectional school-based study using stratified cluster random sampling method was used to select 31,880 students from 113 schools in Hangzhou city. Myopia screening and questionnaires on the influencing factors of poor visual acuity were carried out. Univariate and multivariate logistic regression were used to screen possible risk factors of myopia. The overall prevalence of myopia was found to be 55.3% (17,630/31,880), with the myopia rates observed among students in kindergarten, primary school, junior high school, and senior high school, at 5.8%, 34.9%, 74.2%, and 85.0%, respectively. As the academic year progresses, there has been an observable increase in the prevalence of myopia (χ 2  = 8676.748, P<0.001), low myopia (χ 2  = 5444.040, P<0.001) and high myopia (χ 2  = 2171.073, P<0.001) among students, with the difference between the three groups being statistically significant. The myopia prevalence in girls is higher than that in boys (χ 2  = 119.917, P<0.001); the prevalence of myopia in urban students is higher than that in suburban students (χ 2  = 4.603, P = 0.032). The time spent on homework after school, the correctness of reading and writing postures, the duration of exposure to electronic screens, and the use of lighting in an appropriate manner all have an impact on the development of myopia (all P<0.05). The overall prevalence of myopia and high myopia in schools in eastern China, is notably high. The prevalence of myopia and high myopia increases with grade or age. Myopia is associated with increased age, parental myopia, extended periods of homework after school, poor reading and writing posture, prolonged exposure to electronic screens and inappropriate lighting. In light of the findings of the present survey, it is recommended that a comprehensive prevention and control intervention model for myopia in children and adolescents based on society-hospital-school-family-individual students with a view to preventing and controlling myopia., (© 2024. The Author(s).)

This study aimed to identify predictive factors for the prognosis of acute-on-chronic liver disease (AoCLD) due to both hepatitis B virus (HBV) and alcohol and to develop prognostic models to improve treatment management. AoCLD patients with HBV and alcohol as etiological factors were selected from two multicenter prospective cohorts (NCT02457637,NCT03641872) and included in separate training and validation cohorts (n = 180 and n = 148). In the training cohort, the CATCH-LIFE A nomogram (based on age, bilirubin, international normalized ratio, serum sodium, and hepatic encephalopathy score) and CATCH-LIFE B nomogram (based on age, bilirubin, international normalized ratio, serum albumin, white blood cell, platelet count, and hepatic encephalopathy score) had discriminatory ability for predicting 28-day (c-indexes of 0.910 and 0.899) and 90-day mortality (c-indexes of 0.878 and 0.887, respectively). The area under the curve values for 28-day and 90-day mortality prediction by the CATCH-LIFE A nomogram were 0.922 (95% CI : 0.874, 0.971) and 0.905 (0.856, 0.956), respectively, while those for the CATCH-LIFE B nomogram were 0.916(0.861,0.972) and 0.915 (0.866,0.964), respectively. Similar performance results were observed in the validation cohort. Optimal cut-off scores for each nomogram could be used for patient stratification in high- and low-risk groups, and the high-risk groups showed shorter survival times than the low-risk groups in both the training and validation cohorts. Two nomograms constructed from the first short-term follow-up data from patients with AoCLD due to combined HBV infection and alcohol exposure showed good predictive performance for 28-day and 90-day mortality and might be used to guide clinical management., (© 2024. The Author(s).)

An effective health status assessment (HSA) for pump station units (PSUs) is crucial for accurately determining their real status and providing technical support for safe operational decisions. Due to the limitations of existing data-driven HSA methods, which primarily focus on the temporal dependencies of monitoring signals and fail to explore the complex interconnections among signals comprehensively. Moreover, when constructing performance degradation indices based on linear differences, these methods do not effectively integrate heterogeneous signals, resulting in an incomplete and inaccurate assessment of the overall system degradation. This paper proposes a real-time comprehensive HSA method for PSUs based on multi-source heterogeneous uncertainty information. Initially, a health benchmark model (HBM) is built using CrossGNN, which possesses cross-scale and cross-variable interaction capabilities, to precisely capture the temporal dependencies and dynamic relationships among variables in monitoring signals. Subsequently, key measurement points that reflect the operational status of the PSUs are identified through correlation analysis to establish multi-source evaluation indices. Then, considering the uncertainty in signal changes, a novel health degradation index (HDI) is developed using Mahalanobis distance (MD) and the Gaussian Cloud Model (GCM) to analyze changes in unit status. Furthermore, a weighting calculation method based on the non-dominated sorting genetic algorithm (NSGA-II) is proposed to establish a real-time comprehensive health index (RCHDI) for a thorough assessment of PSUs status. Finally, the effectiveness of the proposed method is validated through a case study using data from a pump station in the South-to-North Water Diversion Project in China. The results show that, compared to other studies, the proposed method significantly improves the stability and smoothness of the state assessment curve, with increases of 21.5% and 47.1% respectively, providing a new perspective for comprehensively assessing the health status of PSUs.V., (© 2024. The Author(s).)

COVID-19 survivors concerning about the rehabilitation and sustained sequelae of Coronavirus Disease 2019 (COVID-19) infection. We aimed to investigate the sequelae of patients' psychological and physical condition and its related factors in the early and late stages. This longitudinal study tracked 281 COVID-19 patients discharged from hospitals in Guangdong, China, for one year. Assessments occurred at 2,4,12,24 and 48 weeks post-discharge. We define 2 weeks, 4 weeks, and 12 weeks as early stage, and 24 weeks and 48 weeks as late stage. Psychological health was measured using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), and Pittsburgh Sleep Quality Index (PSQI) scales. Physical health was assessed through laboratory tests, chest computed tomography (CT) scans, and pulmonary function tests. Data were analyzed using multivariate regression models to evaluate the influence of demographic and clinical variables on health outcomes. COVID-19 survivors exhibited psychological and physical sequelae in both the early and late stages. Compared to the early stage, the proportions of patients with depression (early stage 14.6%, late stage 4.6%), anxiety (early stage 8.9%, late stage 5.3%), PTSD(early stage 3.6%, late stage 0.7%), abnormal liver function (early stage 24.6%, late stage 11.0%), abnormal cardiac function (early stage 10.0%, late stage 7.8%), abnormal renal function (early stage 20.6%, late stage 11.0%) and abnormal pulmonary function (early stage 40.9%, late stage 13.5%) were significantly reduced in the late stage. Factors such as gender, age, severity of COVID-19, hospitalization duration, and various comorbidities were significantly associated with these sequelae. We noticed that psychological and physical sequelae occurred to COVID-19 survivors in short and long stages, and these would gradually decrease as time went on. Male gender, age > 50 years old, severe clinical condition, longer hospitalization time and comorbidity history were related factors that significantly affected the rehabilitation of COVID-19 patients., (© 2024. The Author(s).)

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment., (© 2024. The Author(s).)

The cascade of metastasis in tumor cells, exhibiting organ-specific tendencies, may occur at numerous phases of the disease and progress under intense evolutionary pressures. Organ-specific metastasis relies on the formation of pre-metastatic niche (PMN), with diverse cell types and complex cell interactions contributing to this concept, adding a new dimension to the traditional metastasis cascade. Prior to metastatic dissemination, as orchestrators of PMN formation, primary tumor-derived extracellular vesicles prepare a fertile microenvironment for the settlement and colonization of circulating tumor cells at distant secondary sites, significantly impacting cancer progression and outcomes. Obviously, solely intervening in cancer metastatic sites passively after macrometastasis is often insufficient. Early prediction of metastasis and holistic, macro-level control represent the future directions in cancer therapy. This review emphasizes the dynamic and intricate systematic alterations that occur as cancer progresses, illustrates the immunological landscape of organ-specific PMN creation, and deepens understanding of treatment modalities pertinent to metastasis, thereby identifying some prognostic and predictive biomarkers favorable to early predict the occurrence of metastasis and design appropriate treatment combinations., (© 2024. The Author(s).)

Oncolytic virotherapy is emerging as a promising therapeutic avenue for cancer treatment, harnessing both innate and tumor-specific immune responses for targeted tumor elimination. In this study, we present a novel oncolytic virus (oHSV1-IL15B) derived from herpes simplex virus-1 (HSV-1), armed with IL-15/IL-15Rα complex, with a focus on treating colon cancer combined with oncolytic HSV-1 expressing anti-PD-1 antibody (oHSV1-aPD1). Results from our study reveal that recombinant oHSV-1 virus equipped with IL-15/IL-15Rα complex exhibited significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Notably, oHSV1-IL15B combined with oHSV-1-aPD1 demonstrates superior tumor inhibition and prolonged overall survival compared to oHSV1-mock and monotherapy groups. Further exploration highlights the impact of oHSV1-IL15B, oHSV-1-aPD1 and combined group on antitumor capacity, revealing a substantial increase in CD8 + T and CD4 + T cell proportions of CT26-bearing BALB/c mice and promoting apoptosis in tumor tissue. The study emphasizes the pivotal role of cytotoxic CD8 + T cells in oncolytic virotherapy, demonstrating that recombinant oHSV1-IL15B combined with oncolytic HSV-1-aPD1 induces a robust tumor-specific T cell response. RNA sequence analysis highlighted oHSV1-IL15B combined with oHSV1-aPD1 improved tumors immune microenvironment on immune response, antiviral response-related genes and apoptosis-related genes, which contributed to anti-tumor immunotherapy. The findings underscore the promising antitumor activity achieved through the combination of IL-15/IL-15Rα complex and anti-PD-1 antibody with oHSV-1. This research opens avenues for diverse therapeutic strategies, suggesting the potential of synergistically utilizing cytokines and anti-PD-1 antibody with oncolytic viruses to enhance immunotherapy for cancer management., (© 2024. The Author(s).)

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression., (© 2024. The Author(s).)

Xiong'an New Area was established as a state-level new area in 2017 and serves as a typical representative area for studying the ecological evolution of rural areas under rapid urbanization in China. Remote sensing-based ecological index (RSEI) is a regional eco-environmental quality (EEQ) assessment index. Many studies have employed RSEI to achieve rapid, objective, and effective quantitative assessment of the spatio-temporal changes of regional EEQ. However, research that combines RSEI with machine learning algorithms to conduct multi-scenario simulation of EEQ is still relatively scarce. Therefore, this study assessed and simulated EEQ changes in Xiong'an and revealed that: (1) The large-scale construction has led to an overall decline in EEQ, with the RSEI decreasing from 0.648 in 2014 to 0.599 in 2021. (2) Through the multi-scenario simulation, the non-unidirectional evolution of RSEI during the process of urban-rural construction has been revealed, specifically characterized by a significant decline followed by a slight recovery. (3) The marginal effects of urban-rural construction features for simulated RSEI demonstrate an inverted "U-shaped" curve in the relationship between urbanization and EEQ. This indicates that urbanization and EEQ may not be absolute zero-sum. These findings can provide scientific insights for maintaining and improving the regional EEQ in urban-rural construction., (© 2024. The Author(s).)

Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients' ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy.Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27., (© 2024. The Author(s).)

Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X., (© 2024. The Author(s).)

Natural gas hydrate is a promising unconventional natural gas source due to its high energy density and huge global reserves. During exploitation, the drilling fluid may invade the hydrate formation and induce hydrate decomposition, causing reservoir damage. Herein, a novel reservoir protectant made by bio-degradable temporary plugging material (BDTPM) was developed in the form of polymer-ceramic composite microcapsules. As an additive to the drilling fluid, the BDTPM can minimize drilling fluid intrusion by plugging the reservoir during drilling and afterwards maximize permeability recovery by degrading the material. The particle size distribution was in the range of 1-130 μm. The optimal mass ratio between modified ceramic particles, ethyl cellulose and epoxy resin was found to be 4:2:1. The plugging rate was 100% when ethyl cellulose and epoxy resin were mixed to coat the ceramic particles to form BDTPM, and the plugging performance was the best. At a temperature close to the typical hydrate reservoir environment (5 °C), 0.02 wt% low-temperature complex enzyme can degrade BDTPM, and the permeability recovery rate is 64.66%. The efficient reservoir protectant developed in this work could play an important role in the successful drilling of natural gas hydrate reservoirs., (© 2024. The Author(s).)

Stereotactic radiation therapy (SBRT) has emerged as a promising treatment modality for locally advanced pancreatic cancer. The aim of this study is to assess the dosimetric efficacy of online adaptive radiotherapy (ART) in comparison to image-guided radiation therapy (IGRT) for pancreatic cancer. We conducted a retrospective analysis involving 8 patients diagnosed with locally advanced pancreatic cancer. The gross tumor volume (GTV) delineates the visible extent of the tumor on imaging, while the planning tumor volume (PTV) was generated by expanding 5 mm from the GTV and ensuring a 3 mm distance from the small intestine, duodenum, and stomach simultaneously. Treatment planning was executed using the United Imaging Healthcare Treatment Planning System workstation. The control group underwent evaluation based on daily validated fan-beam CT (FBCT) scans, assessing both the dose delivered to actual organs at risk (OARs) and the target volume. Radiotherapy plans were developed utilizing simulation CT, and conventional radiotherapy with daily image-guided radiation therapy (IGRT) was administered using FBCT-Linac. Conversely, patients in the study group received daily validated FBCT-guided adaptive radiotherapy plans, with a focus on mean dose assessment of both the target volume and OARs. Subsequently, we compared the average outcomes of each treatment fraction between IGRT and online adaptive radiotherapy (ART). Comparison between ART and IGRT treatment plans revealed significant differences in various dosimetric parameters: For PTV: V98%: ART (96.28%) vs IGRT (89.73%), p = 0.000, V95%: ART (96.28%) vs IGRT (89.73%), p = 0.031, V90%: ART (98.58%) vs IGRT (93.65%), p = 0.000, Dmean: ART (4912.91) vs IGRT (4804.11), p = 0.000. For GTV: V100%: ART (97.96%) vs IGRT (94.85%), p = 0.314, V98%: ART (100.00%) vs IGRT (96.83%), p = 0.000, V90%: ART (100.00%) vs IGRT (97.75%), p = 0.000, Dmean: ART (4972.17) vs IGRT (4907.23), p = 0.000. For the duodenum: D0.5cc: ART (2883.92) vs IGRT (3359.35), p = 0.000, D1cc: ART (2726.32) vs IGRT (3128.66), p = 0.001, D5cc: ART (2051.96) vs IGRT (2273.93), p = 0.015, D10cc: ART (1650.73) vs IGRT (1731.74), p = 0.211. For the small bowel: D0.5cc: ART (3022.3) vs IGRT (3142.64), p = 0.037. D5cc: ART (2151.09) vs IGRT (2389.15), p = 0.043, D10cc: ART (1775.20) vs IGRT (1942.00), p = 0.079. For the stomach: D0.5cc: ART (3353.92) vs IGRT (4117.85), p = 0.000, D5cc: ART (2860.20) vs IGRT (3235.41), p = 0.000, D10cc: ART (2553.72) vs IGRT (2836.73), p = 0.000. For the Dmean of the left kidney and right kidney: Left kidney: ART (248.28) vs IGRT (239.65), p = 0.100. Right kidney: ART (314.55) vs IGRT (307.17), p = 0.345. These results suggest significant improvements in PTV coverage and sparing of OARs with ART compared to IGRT, indicating the potential of ART in optimizing treatment outcomes for pancreatic cancer patients. Compared to conventional IGRT-guided SBRT programs, ART-based SBRT for pancreatic cancer not only enhances the dose distribution to the target volume but also mitigates the radiation exposure to critical organs-at-risk (OARs) such as the duodenum, small intestine, and stomach. This approach may offer a more favorable safety profile while concurrently enhancing treatment efficacy., (© 2024. The Author(s).)

Most existing scene classification methods based on remote sensing images tend to ignore important interactive information at different levels in the image. We propose an effective remote sensing scene classification method named multi-scale dense residual correlation network. The method is divided into three parts. First, the multi-stream feature extraction module is introduced which effectively utilizes features at different scales to extract different levels of information. Secondly, the dense residual connected feature fusion technology is proposed, which allows for a wide range of feature fusion. The Correlation Attention Module learn feature representations at multiple levels. This improves classification performance. The method outperforms existing algorithms in terms of effectiveness and accuracy, achieving state-of-the-art results on widely used remote sensing scene classification benchmarks., (© 2024. The Author(s).)