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Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

ObjectivesDeep Brain Stimulation (DBS) effectively treats Parkinson’s motor symptoms, but its effects on the urogenital system are debated.MethodsA research was conducted in PubMed, Embase, Cochrane Library, Web of Science, and Scopus until February 27, 2024. We primarily focused on DBS’s impact on Parkinson’s patients’ Urine storage function, voiding function, sexual function, and quality of life.ResultsOur meta-analysis included 14 studies. The main results showed that DBS resulted in fewer instances of urinary urgency (OR = 1.85, 95% CI: 1.26 to 2.70, p = 0.002) and increased maximum bladder capacity (MD = −66.10, 95% CI: −119.37 to −12.82, p = 0.02) in terms of urinary storage function. However, there were no significant differences in first desire to void and strong desire to void. In terms of voiding function, DBS showed significant improvements in maximum flow rate (MD = −0.64, 95% CI: −1.23 to −0.05, p = 0.03), post-void residual (MD = −6.79, 95% CI: 4.54 to 9.05, P

Abstract Background Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. Methods Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. Results UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. Conclusions These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.

Glucocorticoids and glucocorticoid receptor (GR) signalling can suppress anti-tumour immunity. Here the authors show that GR activates PD-L1 expression and represses MHC-I expression in pancreatic cancer cells, while GR inhibition enhances anti-tumour immunity and sensitises the cancer cells to immunotherapy.

Abstract Background The human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms. Methods Comparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts. Results In vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group. Conclusion hEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.

Abstract Mobile colistin resistance enzyme MCR‐3 is a phosphoethanolamine transferase modifying lipid A in Gram‐negative bacteria. MCR‐3 generally mediates low‐level (≤8 mg L−1) colistin resistance among Enterobacteriaceae, but occasionally confers high‐level (>128 mg L−1) resistance in aeromonads. Herein, it is determined that MCR‐3, together with another lipid A modification mediated by the arnBCADTEF operon, may be responsible for high‐level colistin resistance in aeromonads. Lipid A is the critical site of pathogens for Toll‐like receptor 4 recognizing. However, it is unknown whether or how MCR‐3‐mediated lipid A modification affects the host immune response. Compared with the wild‐type strains, increased mortality is observed in mice intraperitoneally‐infected with mcr‐3‐positive Aeromonas salmonicida and Escherichia coli strains, along with sepsis symptoms. Further, mcr‐3‐positive strains show decreased clearance rates than wild‐type strains, leading to bacterial accumulation in organs. The increased mortality is tightly associated with the increased tissue hypoxia, injury, and post‐inflammation. MCR‐3 expression also impairs phagocytosis efficiency both in vivo and in vitro, contributing to the increased persistence of mcr‐3‐positive bacteria in tissues compared with parental strains. This study, for the first time, reveals a dual function of MCR‐3 in bacterial resistance and pathogenicity, which calls for caution in treating the infections caused by mcr‐positive pathogens.

The utilization of environmentally friendly hydrogen energy requires proton exchange membrane fuel cell devices that offer high power output while remaining affordable. However, the current optimization of their key component, i.e., the membrane electrode assembly, is still based on intuition-guided, inefficient trial-and-error cycles due to its complexity. Hence, we introduce an innovative, explainable artificial intelligence (AI) tool trained as a reliable assistant for a variable analysis and optimum-value prediction. Among the 8 algorithms considered, the surrogate model built with an artificial neural network achieves high replaceability in the experimentally validated multiphysics simulation (R2= 0.99845) and a much lower computational cost. For interpretation, partial dependence plots and the Shapley value method are applied to black-box models to intelligently simulate the impact of each parameter on performance. These methods show that a tradeoff existed in the catalyst layer thickness. The AI-guided optimization suggestions regarding catalyst loading and the ionomer content are fully supported by the experimental results, and the final product achieves 3.2 times the Pt utilization of commercial products with a time cost orders of magnitude smaller.

Soil moisture is not only an essential component of the water cycle in terrestrial ecosystems but also a major influencing factor of regional climate. In the soil hydrothermal process, soil moisture has a significant regulating effect on surface temperature; it can drive surface temperature change by influencing the soil’s physical properties and the partitioning of the available surface energy. However, limited soil temperature and moisture observations restrict the previous studies of soil hydrothermal processes, and few models focus on estimating the impact of soil moisture on soil temperature. Therefore, based on the experiments conducted in Wuchuan County in 2020, this study proposes a soil water and heat coupling model that includes radiation, evaporation, soil water transport, soil heat conduction and ground temperature coupling modules to simulate the soil temperature and moisture and subsequently estimate the effects of soil moisture. The results show that the model performs well. The Nash–Sutcliffe coefficient (NSE) and the concordance index (C) of the simulated and measured values under each treatment are higher than 0.26 and 0.7, respectively. The RMSE of the simulation results is between 0.0067–0.017 kg kg−1 (soil moisture) and 0.43–1.06 °C (soil temperature), respectively. The simulated values matched well with the actual values. The soil moisture had a noticeable regulatory effect on the soil temperature change, the soil surface temperature would increase by 0.08–0.43 °C for every 1% decrease in soil moisture, and with the increase in soil moisture, the variation of the soil temperature decreased. Due to the changes in the solar radiation, the sensitivity of the soil temperature to the decline in soil moisture was the greatest during June–July and the least in September. Moreover, the contributions of soil moisture changes to temperature increase under various initial conditions are inconsistent, the increase in sunshine hours, initial daily average temperature and decrease in leaf area index (LAI), soil density and soil heat capacity can increase the soil surface temperature. The results are expected to provide insights for exploring the impact mechanism of regional climate change and optimizing the structure of agricultural production.

Since the first report of the plasmid-mediated, colistin-resistant gene, mcr-1, nine mcr genes and their subvariants have been identified. The spreading scope of mcr-1~10 varies greatly, suggesting that mcr-1~10 may have different evolutionary advantages. Depending on MCR family phylogeny, mcr-6 is highly similar to mcr-1 and -2, and mcr-7~10 are highly similar to mcr-3 and -4. We compared the expression effects of MCR-1~5 on bacteria of common physiological background. The MCR-1-expressing strain showed better growth than did MCR-2~5-expressing strains in the presence of colistin. LIVE/DEAD staining analysis revealed that MCR-3~5 expression exerted more severe fitness burdens on bacteria than did MCR-1 and -2. Bacteria expressing MCRs except MCR-2 showed enhanced virulence with increased epithelial penetration ability determined by trans-well model (p < 0.05). Enhanced virulence was also observed in the Galleria mellonella model, which may have resulted from bacterial membrane damage and different levels of lipopolysaccharide (LPS) release due to MCR expression. Collectively, MCR-1-expressing strain showed the best survival advantage of MCR-1~5-expressing strains, which may partly explain the worldwide distribution of mcr-1. Our results suggested that MCR expression may cause increased bacterial virulence, which is alarming, and further attention will be needed to focus on the control of infectious diseases caused by mcr-carrying pathogens.

The aim of the study was to develop a multiplex assay for rapid detection of mcr-1, mcr-2, and mcr-3, a group of genes of conferring resistance to colistin mediated by plasmid in Enterobacteriaceae. A SYBR Green based real-time PCR assay has been designed to detect the mcr genes, and applied to cultured bacteria, feces and soil samples. All three mcr genes could be detected with a lower limit of 102 cultured bacteria. This test was highly specific and sensitive, and generated no false-positive results. The assay was also conclusive when applied to feces and soil samples containing mcr-1-positive Escherichia coli, which could facilitate the screening of mcr genes not only in the bacteria, but also directly from the environment. This simple, rapid, sensitive, and specific multiplex assay will be useful for rapid screening of the colistin resistance in both clinical medicine and animal husbandry.

ABSTRACT The mobile colistin resistance gene mcr-1 has attracted global attention, as it heralds the breach of polymyxins, one of the last-resort antibiotics for the treatment of severe clinical infections caused by multidrug-resistant Gram-negative bacteria. To date, six slightly different variants of mcr-1, and a second mobile colistin resistance gene, mcr-2, have been reported or annotated in the GenBank database. Here, we characterized a third mobile colistin resistance gene, mcr-3. The gene coexisted with 18 additional resistance determinants in the 261-kb IncHI2-type plasmid pWJ1 from porcine Escherichia coli. mcr-3 showed 45.0% and 47.0% nucleotide sequence identity to mcr-1 and mcr-2, respectively, while the deduced amino acid sequence of MCR-3 showed 99.8 to 100% and 75.6 to 94.8% identity to phosphoethanolamine transferases found in other Enterobacteriaceae species and in 10 Aeromonas species, respectively. pWJ1 was mobilized to an E. coli recipient by conjugation and contained a plasmid backbone similar to those of other mcr-1-carrying plasmids, such as pHNSHP45-2 from the original mcr-1-harboring E. coli strain. Moreover, a truncated transposon element, TnAs2, which was characterized only in Aeromonas salmonicida, was located upstream of mcr-3 in pWJ1. This ΔTnAs2-mcr-3 element was also identified in a shotgun genome sequence of a porcine E. coli isolate from Malaysia, a human Klebsiella pneumoniae isolate from Thailand, and a human Salmonella enterica serovar Typhimurium isolate from the United States. These results suggest the likelihood of a wide dissemination of the novel mobile colistin resistance gene mcr-3 among Enterobacteriaceae and aeromonads; the latter may act as a potential reservoir for mcr-3. IMPORTANCE The emergence of the plasmid-mediated colistin resistance gene mcr-1 has attracted substantial attention worldwide. Here, we examined a colistin-resistant Escherichia coli isolate that was negative for both mcr-1 and mcr-2 and discovered a novel mobile colistin resistance gene, mcr-3. The amino acid sequence of MCR-3 aligned closely with phosphoethanolamine transferases from Enterobacteriaceae and Aeromonas species originating from both clinical infections and environmental samples collected in 12 countries on four continents. Due to the ubiquitous profile of aeromonads in the environment and the potential transfer of mcr-3 between Enterobacteriaceae and Aeromonas species, the wide spread of mcr-3 may be largely underestimated. As colistin has been and still is widely used in veterinary medicine and used at increasing frequencies in human medicine, the continuous monitoring of mobile colistin resistance determinants in colistin-resistant Gram-negative bacteria is imperative for understanding and tackling the dissemination of mcr genes in both the agricultural and health care sectors.

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a growing concern due to its high mortality and limited treatment options. Although hypermucoviscosity is crucial for CR-hvKp infection, the role of changes in bacterial mucoviscosity in the host colonization and persistence of CR-hvKp is not clearly defined. Herein, we observed a phenotypic switch of CR-hvKp from a hypermucoviscous to a hypomucoviscous state in a patient with scrotal abscess and urinary tract infection (UTI). This switch was attributed to decreased expression of rmpADC, the regulator of mucoid phenotype, caused by deletion of the upstream insertion sequence ISKpn26. Postswitching, the hypomucoid variant showed a 9.0-fold decrease in mice sepsis mortality, a >170.0-fold reduction in the ability to evade macrophage phagocytosis in vitro, and an 11.2-to 40.9-fold drop in growth rate in normal mouse serum. Conversely, it exhibited an increased residence time in the mouse urinary tract (21 vs. 6 d), as well as a 216.4-fold boost in adhesion to bladder epithelial cells and a 48.7% enhancement in biofilm production. Notably, the CR-hvKp mucoid switch was reproduced in an antibiotic-free mouse UTI model. The in vivo generation of hypomucoid variants was primarily associated with defective or low expression of rmpADC or capsule synthesis gene wcaJ, mediated by ISKpn26 insertion/deletion or base-pair insertion. The spontaneous hypomucoid variants also outcompeted hypermucoid bacteria in the mouse urinary tract. Collectively, the ISKpn26-associated mucoid switch in CR-hvKp signifies the antibiotic-independent host adaptive evolution, providing insights into the role of mucoid switch in the persistence of CR-hvKp. [ABSTRACT FROM AUTHOR]

BackgroundHome-based palliative care is an ideal model for providing continuous, effective, and timely care at the patient’s home. However, the timely recognition of palliative home care needs remains a clinical challenge, and few studies have described the characteristics of palliative care needs and quality of life at home.ObjectivesTo identify the palliative home care needs of patients with advanced cancer and explore the influencing factors in addressing these needs.MethodsIn this cross-sectional study, convenience samples were collected from four cities in mainland China between May 2020 and November 2021. The revised Problems and Needs in Palliative Care-short version was used to evaluate palliative home care needs. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 was used to evaluate the participants’ quality of life. We used SPSS version 23.0 for all statistical analyses. Descriptive statistics, Wilcoxon rank sum test, Spearman rho correlation independent t-test, and multiple linear regression were performed to analyze the data.ResultsCompleted the survey. The patients’ palliative home care needs were primarily related to physical symptoms, home health care services, and psychological issues. For items, the top three palliative home care needs were related to financial needs, “extra expenditures because of the disease” (75.9%), psychological issues, “fear of getting worse” (72.8%), and “fear of physical suffering” (67.9%). Multiple linear regression analysis revealed that 53.5% of palliative home care needs could be explained by the Karnofsky Performance Status and quality of life: physical, role, emotional, and financial difficulties dimensions.ConclusionThe palliative home care needs were associated with patients’ quality of life and financial difficulties. These findings may contribute to provide a framework for palliative home care service, and help to identify specific interventions.

BackgroundEsophageal cancer (EC) is a major global health issue characterized by high morbidity and mortality rates, with a notably low five-year survival rate. Comprehensive analyses of the global burden of EC remain limited and outdated, despite its global significance. This study aimed to systematically assess the global burden and trends of esophageal cancer across diverse populations.MethodsData on the burden of EC were collected from the Global Burden of Disease (GBD) 2021 study, including estimates of incidence, mortality, and disability-adjusted life years (DALYs), as well as risk factors, spanning 204 countries and territories. Age-standardized rates (ASRs) were calculated to allow comparisons across populations. The study further explored the relationship between EC burden and socioeconomic development by utilizing the Socio-demographic Index (SDI), aggregating data by regions. The Bayesian age-period-cohort model was applied to project future trends until 2050.ResultsIn 2021, there were 576,529 new esophageal cancer cases, with an age-standardized incidence rate (ASIR) of 6.65 per 100,000, reflecting a 24.87% decrease since 1990. The global number of deaths reached 538,602, with an age-standardized death rate (ASDR) of 6.25 per 100,000, representing a 30.67% decline. DALYs totaled 12,999,264, corresponding to an estimated annual percentage change (EAPC) of a 1.73% decrease in the age-standardized DALYs rate. East Asia accounted for nearly two-thirds of global EC cases and deaths, while Central Sub-Saharan Africa recorded the highest ASIR and ASDR. Central Asia experienced the largest reductions, whereas Western Sub-Saharan Africa showed increasing trends. Middle-SDI countries, such as Malawi and Lesotho, had disproportionately high burdens, while high-SDI countries, including Tunisia and Kuwait, had lower burdens. Males had higher incidence and mortality rates across all age groups. By 2050, the ASIR is projected to decrease to 6.17 per 100,000, and the ASDR to 5.23 per 100,000, though the absolute number of cases and deaths is expected to rise.ConclusionsThe global burden of EC remains significant, with ongoing challenges in regions such as Africa and East Asia. These findings highlight the need for sustained and targeted prevention efforts, particularly in high-risk populations, to address the increasing absolute number of cases and deaths.