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Abstract Background The surgical treatment and management of postoperative soft tissue complications in diabetic patients with displaced calcaneal fractures are still controversial. We aimed to evaluate the short-term efficacy of percutaneous minimally invasive screw fixation in treatment of diabetic patients with Sanders II and III calcaneal fractures under subtalar arthroscopy assisted by preoperative musculoskeletal ultrasonic locating lateral calcaneal branch (LCB) of the sural nerve and calcaneal-talar joint distraction device. Methods The clinical data of 52 diabetic patients diagnosed with Sanders II or III calcaneal fractures from March 2016 to August 2020 were followed up and analyzed. There were 23 patients of type II and 29 patients of type III, 34 males and 18 females, with a mean age of 61.7 ± 14.5 years (range: 45–72 years). Preoperative musculoskeletal ultrasonography was routinely examined to locate LCB of the sural nerve. During surgery, we performed arthroscopic percutaneous prying reduction screw fixation assisted by medial calcaneal-talar joint distraction. Incision healing, local skin paraesthesia and other conditions were observed regularly at 3 days, 6, 12 months, and the last follow-up after surgery. Also, we measured the length, width, height, Böhler angle, and Gissane angle of the calcaneus on lateral and axial x-rays. Visual analogue pain scale (VAS), American Orthopedic Foot and Ankle Society (AOFAS) score and Maryland score were used to evaluate the efficacy. Results 52 patients were followed up for 23.7 ± 3.2 months (range: 20–28 months) without incision-related complications. Calcaneal radiographic parameters (length, width, height, Böhler/Gissane angle) were improved after surgery, and the differences were all statistically significant (P0.05). Postoperative VAS, AOFAS scores, and Maryland scores were significantly improved compared with those before surgery (P

IntroductionAt the crucial stage of China’s transition from extensive expansion driven by external factors to intensive, connotation-focused development, scientifically optimizing the spatial form of new urban districts, promoting dynamic and adaptive spaces, and enhancing the quality and diversity of urban environments are issues of substantial importance.MethodsBased on urban morphology, this study proposes that high street accessibility, appropriate building density and typology, and a sufficient degree of functional mixing are the foundations of spatial morphology for promoting sustainable urban development. Using spatial syntax, a spatial matrix, and mixed-function indices, this study measures urban spatial morphology elements and explores differences and rhythms in sustainable spatial morphology in new urban districts with varying development functions and cycles.ResultsThe results of the study show that: 1) the overall synergy of the accessibility spatial network in the new urban districts of Yinzhou and Xianlin is high. The building typology was dominated by mid-rise slab and enclosed types, low-rise enclosed types, and high-rise slab types, while the multistory high-coverage forms were interspersed with intervals. 2) Development in new urban districts primarily adopted a large land plot development mode with a single function. The degree of multifunctional mixing was observed to be relatively low. The dual-functional mixing degree in the Yinzhou New Urban District is higher than that in the New Xianlin urban district. 3) A significant level of overlap was observed among functional mixing, accessibility, building density, and typology. Of the functional mixing units, 42.41% of the dual-function and 78.57% of multi-function types were clustered in high-value areas of urban vitality. Additionally, 50.25% of dual-function and 85.71% of multi-function units were aggregated in high-accessibility areas.DiscussionThe mixed-use of sites contributes to the creation of urban vitality and sustainability, and the effect of the correlation between mixed-functionality and accessibility is more pronounced when mixed units involve utility land. The research results provide a reference for evaluating the current sustainable challenges of spatial patterns and offer specific tools for optimizing new urban districts.

Abstract Chronic infection with the bacterial pathogen Pseudomonas aeruginosa often leads to coexistence of heterogeneous populations carrying diverse mutations. In particular, loss-of-function mutations affecting the quorum-sensing regulator LasR are often found in bacteria isolated from patients with lung chronic infection and cystic fibrosis. Here, we study the evolutionary dynamics of polymorphic P. aeruginosa populations using isolates longitudinally collected from patients with chronic obstructive pulmonary disease (COPD). We find that isolates deficient in production of different sharable extracellular products are sequentially selected in COPD airways, and lasR mutants appear to be selected first due to their quorum-sensing defects. Polymorphic populations including lasR mutants display survival advantages in animal models of infection and modulate immune responses. Our study sheds light on the multistage evolution of P. aeruginosa populations during their adaptation to host lungs.

Abstract Stimulus-responsive ionic liquids have gained significant attention for their applications in various areas. Herein, three kinds of azobenzimidazole ionic liquids with reversible photo-induced conductivity regulation were designed and synthesized. The change of electrical conductivity under UV/visible light irradiation in aqueous solution was studied, and the effect of chemical structure and concentration of ionic liquids containing azobenzene to the regulation of photoresponse conductivity were discussed. The results showed that exposing the ionic liquid aqueous solution to ultraviolet light significantly increased its conductivity. Ionic liquids with longer alkyl chains exhibited an even greater increase in conductivity, up to 75.5%. Then under the irradiation of visible light, the electrical conductivity of the solution returned to its initial value. Further exploration of the mechanism of the reversible photo-induced conductivity regulation of azobenzene ionic liquids aqueous solution indicated that this may attributed to the formation/dissociation of ionic liquids aggregates in aqueous solution induced by the isomerization of azobenzene under UV/visible light irradiation and resulted the reversible conductivity regulation. This work provides a way for the molecular designing and performance regulation of photo-responsive ionic liquid and were expected to be applied in devices with photoconductive switching and micro photocontrol properties.

Abstract Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCIIhi neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCIIhi neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCIIhi neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCIIhi neutrophils as the principal mediator between chronic infection and tumor metastasis.

ObjectiveTo explore the bidirectional causal relationship between Ankylosing Spondylitis (AS) and Osteoarthritis (OA) at the genetic level within the European ancestry.MethodsWe implemented a series of quality control steps to select instrumental variables (IVs) related to the exposure. We conducted two-sample Mendelian randomization (MR) using the inverse-variance weighted method as the primary approach. We adjusted significance levels using Bonferroni correction, assessed heterogeneity using Cochrane’s Q test. Sensitivity analysis was conducted through leave-one-out method. Additionally, external datasets and relaxed IV selection criteria were employed, and multivariate MR analyses were performed for validation purposes. Finally, Bayesian colocalization (COLOC) analysis identified common genes, validating the MR results.ResultsThe investigation focused on the correlation between OA and AS in knee, hip, and hand joints. MR results revealed that individuals with AS exhibit a decreased risk of knee OA (OR = 0.9882, 95% CI: 0.9804-0.9962) but no significant increase in the risk of hip OA (OR = 0.9901, 95% CI: 0.9786-1.0018). Conversely, AS emerged as a risk factor for hand OA (OR = 1.0026, 95% CI: 1.0015-1.0036). In reverse-direction MR analysis, OA did not significantly influence the occurrence of AS. Importantly, minimal heterogeneity was observed in our MR analysis results (p > 0.05), and the robustness of these findings was confirmed through sensitivity analysis and multivariate MR analysis. COLOC analysis identified four colocalized variants for AS and hand OA (rs74707996, rs75240935, rs181468789, and rs748670681).ConclusionIn European population, individuals with AS have a relatively lower risk of knee OA, whereas AS serves as a risk factor for hand OA. However, no significant causal relationship was found between AS and hip OA. Additionally, it offers novel insights into genetic research on AS and OA.

Abstract Evidence shows that in the modern ocean, coral reefs are disappearing, and these losses are tied to climate change. However, research also shows that coral reefs can adapt rapidly to changing conditions leading some researchers to suggest that some reef systems will survive future climate change through adaptation. It is known that there were changes in the area covered by coral reefs in the past. Therefore, it is important to investigate the long-term response of coral reefs to environmental changes and high sea-surface temperatures (SSTs). However, because of diagenetic issues with SST proxies in neritic, metastable carbonate-rich environments, there is an incomplete and sometimes even incorrect understanding of how changes in SSTs affect carbonate reef systems. A good example is the Queensland Plateau offshore northeast Australia next to the threatened Great Barrier Reef. In the Late Miocene, between 11 and 7 Ma, a partial drowning caused the reef area on the Queensland Plateau to decline by ~ 50% leading to a Late Miocene change in platform geometry from a reef rimmed platform to a carbonate ramp. This reef decline was interpreted to be the result of SSTs at the lower limit of the modern reef growth window (20–18 °C). This article presents a new Late Miocene—ased SST record from the Coral Sea based on the TEX86 H molecular paleothermometer, challenging this long held view. Our new record indicates warm tropical SSTs (27–32 °C) at the upper end of the modern reef growth window. We suggest that the observed temperatures potentially exceeded the optimal calcification temperatures of corals. In combination with a low aragonite supersaturation in the ocean, this could have reduced coral growth rates and ultimately lowered the aggradation potential of the reef system. These sub-optimal growth rates could have made the coral reefs more susceptible to other stressors, such as relative sea-level rise and/or changes in currents leading to reef drowning. Given that these changes affected coral reefs that were likely adapted to high temperature/low aragonite saturation conditions suggests that reefs that have adapted to non-ideal conditions may still be susceptible to future climate changes due to the interaction of multiple stressors associated with climate change.

Abstract Acute ischemic stroke (AIS) induces high level of neutrophils, which correlates inversely with patient survival. Pyroptosis induced by gasdermin D (GSDMD) has been shown to have an important role in the pathophysiology of several inflammatory disorders. The role of GSDMD in the high level of neutrophils after AIS is unknown. Using a middle cerebral artery occlusion (MCAO) mouse model, we identified activation of pyroptosis signal, including expression of caspase-1/11, GSDMD, and interleukin-1β/18 (IL-1β/18), in the brain and spleen at early ischemic injury. Knockout of GSDMD in mice reduced infarct size, improved neurological function, and increased survival after MCAO. GSDMD deficiency decreased the overall degree of inflammation and the proportion of neutrophils in the brain after MCAO. Quantitative studies of neutrophils at several time intervals and organs demonstrated that early inflammatory leucocyte production and supplement (1 day after MCAO) was GSDMD-dependent. A series of bone marrow transplantation experiments, neutrophil depletion experiments, and RNA sequencing results demonstrated that neutrophil specific GSDMD is essential for the production and supply of neutrophil in bone marrow to blood. Moreover, pharmacological suppression of GSDMD decreased pathological abnormalities, infarct volume, and ameliorated neurological function. These results provided a new viewpoint on the immunological modulation of neutrophils after MCAO and suggest that suppression of GSDMD may relieve the neuroinflammatory load, thereby providing a potential treatment strategy for stroke. The absence of GSDMD reduces the high level of neutrophils in the brain, the production of neutrophils in bone marrow, and the supply of blood and spleen, while simultaneously the neutrophil-specific GSDMD signal deficiency restrains leukocytosis to improve the pathological outcome of AIS.

Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.

Aims: Our study focused on whether macrophages ferroptosis is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD) or not.Main methods: We first identified macrophage module genes by weighted gene co-expression network analysis (WGCNA) in RNA sequencing (RNA-seq) date from COPD, and then identified macrophage marker genes by comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data from COPD macrophages. There were 126 macrophage marker genes identified, and functional enrichment analyses indicated that ferroptosis pathway genes were significantly enriched. Secondly, we identified eight macrophage ferroptosis related genes and based on these eight genes, we performed co-expression analysis and drug prediction. Thirdly, two biomarkers (SOCS1 and HSPB1) were screened by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine-recursive feature elimination (SVM-RFE) and established an artificial neural network (ANN) for diagnosis. Subsequently, the biomarkers were validated in the dataset and validation set. These two biomarkers were then subjected to single gene-gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) analysis, and the ceRNA network was constructed. Finally, we carried out molecular validation with COPD models in vitro for cell counting kit-8 (CCK8) experiments, Western blot and quantitative real-time PCR (qRT-PCR) analysis and transmission electron microscopy (TEM).Key findings: This study revealed the vital role of macrophage ferroptosis in COPD, and novel biomarkers (SOCS1 and HSPB1) may be involved in the pathogenesis of COPD by regulating macrophage ferroptosis.Significance: Taken together, our results suggest that targeting SOCS1 and HSPB1 could treat COPD by inhibiting macrophage ferroptosis.

Abstract Knowledge of the changes in the immune microenvironment during pulmonary bacterial acute and chronic infections is limited. The dissection of immune system may provide a basis for effective therapeutic strategies against bacterial infection. Here, we describe a single immune cell atlas of mouse lungs after acute and chronic Pseudomonas aeruginosa infection using single‐cell transcriptomics, multiplex immunohistochemistry, and flow cytometry. Our single‐cell transcriptomic analysis revealed large‐scale comprehensive changes in immune cell composition and high variation in cell–cell interactions after acute and chronic P. aeruginosa infection. Bacterial infection reprograms the genetic architecture of immune cell populations. We identified specific immune cell types, including Cxcl2+ B cells and interstitial macrophages, in response to acute and chronic infection, such as their proportions, distribution, and functional status. Importantly, the patterns of immune cell response are drastically different between acute and chronic infection models. The distinct molecular signatures highlight the importance of the highly dynamic cell–cell interaction process in different pathological conditions, which has not been completely revealed previously. These findings provide a comprehensive and unbiased immune cellular landscape for respiratory pathogenesis in mice, enabling further understanding of immunologic mechanisms in infection and inflammatory diseases.

Extracellular vesicles (EVs) are nanosized lipid particles released by virtually every living cell. EVs carry bioactive molecules, shuttle from cells to cells and transduce signals, regulating cell growth and metabolism. Pathogenic bacteria can cause serious infections via a wide range of strategies, and host immune systems also develop extremely complex adaptations to counteract bacterial infections. As notable carriers, EVs take part in the interaction between the host and bacteria in several approaches. For host cells, several strategies have been developed to resist bacteria via EVs, including expelling damaged membranes and bacteria, neutralizing toxins, triggering innate immune responses and provoking adaptive immune responses in nearly the whole body. For bacteria, EVs function as vehicles to deliver toxins and contribute to immune escape. Due to their crucial functions, EVs have great application potential in vaccines, diagnosis and treatments. In the present review, we highlight the most recent advances, application potential and remaining challenges in understanding EVs in the interaction between the host and bacteria.

Abstract With the ageing of the world population, osteoporosis has become a problem affecting quality of life. According to the traditional view, the causes of osteoporosis mainly include endocrine disorders, metabolic disorders and mechanical factors. However, in recent years, the immune system and immune factors have been shown to play important roles in the occurrence and development of osteoporosis. Among these components, regulatory T (Treg) cells and T helper 17 (Th17) cells are crucial for maintaining bone homeostasis, especially osteoclast differentiation. Treg cells and Th17 cells originate from the same precursor cells, and their differentiation requires involvement of the TGF-β regulated signalling pathway. Treg cells and Th17 cells have opposite functions. Treg cells inhibit the differentiation of osteoclasts in vivo and in vitro, while Th17 cells promote the differentiation of osteoclasts. Therefore, understanding the balance between Treg cells and Th17 cells is anticipated to provide a new idea for the development of novel treatments for osteoporosis.

Neonatal hypoxia–ischemia is a troublesome disease. Angelica polysaccharide (AP) is proved to have antioxidant effects. Our study was performed to confirm the effects of AP in hypoxia-exposed neural stem cells (NSCs). NSCs were pre-treated with AP and then stimulated with hypoxia. Viability of NSCs was examined by Cell Counting Kit-8 assay. Hypoxia-introduced apoptosis was observed by flow cytometry. Essential regulators of mTOR and Notch signalling pathways were examined by Western blot. mRNA expression was accessed using qRT-PCR. Bcl2/adenovirus EIB 19kD-interacting protein 3 (BNIP3) was altered by transfection. We noticed that NSCs were sensitive to hypoxia-induced apoptosis and showed decreased viability. Moreover, Beclin and light chain 3-II was upregulated while p62 was downregulated. However, AP reversed all these results. Similarly, hypoxia decreased the phosphorylation of mTOR and p70S6K and Notch1 expression while AP increased the phosphorylation of mTOR and p70S6K as well as the expression of Notch1. BNIP3 was upregulated by hypoxia while downregulated by AP. Further experiments demonstrated that overexpression of BNIP3 broken all the effects induced by AP shown in cell viability, apoptosis, autophagy and signalling pathways. Collectively, AP alleviated hypoxia-introduced NSCs damages by maintaining cell viability, blocking apoptosis and autophagy via downregulation of BNIP3 with the activation of mTOR and Notch signalling pathways.

Colchicine (Col) is considered a kind of highly effective alkaloid for preventing and treating acute gout attacks (flares). However, little is known about the underlying mechanism of Col in pain treatment. We have previously developed a customized virtual target identification method, termed IFPTarget, for small-molecule target identification. In this study, by using IFPTarget and ligand similarity ensemble approach (SEA), we show that the glycine receptor alpha 3 (GlyRα3), which play a key role in the processing of inflammatory pain, is a potential target of Col. Moreover, Col binds directly to the GlyRα3 as determined by the immunoprecipitation and bio-layer interferometry assays using the synthesized Col-biotin conjugate (linked Col and biotin with polyethylene glycol). These results suggest that GlyRα3 may mediate Col-induced suppression of inflammatory pain. However, whether GlyRα3 is the functional target of Col and serves as potential therapeutic target in gouty arthritis requires further investigations.

Listeria monocytogenes is an important food-borne pathogen that can persist in food processing environments and thus contaminate food products. Benzalkonium chloride (BC) is a common disinfectant widely used in food industry. Selective pressure associated with exposure to BC may result in adaptation to this agent in L. monocytogenes. In this study, the effect of BC adaptation on susceptibility to antimicrobial agents and tolerance to environmental stresses, as well as the role of efflux pumps in BC adaptation were investigated in Listeria monocytogenes. Exposure of L. monocytogenes to progressively increasing concentrations of BC led to adaptation not only to BC but also to several other antimicrobial agents with different modes of action, including cefotaxime, cephalothin, ciprofloxacin, and ethidium bromide (EtBr), indicating that the disinfectant BC has the ability to select for antibiotic resistance. Reserpine, an efflux pump inhibitor, reduced minimum inhibitory concentrations (MICs) of cephalosporins, ciprofloxacin, and EtBr in BC adapted strains, indicating that efflux pumps are involved in cross-adaptation to these antimicrobial agents. Our results showed that expression levels of the efflux pump MdrL in the BC adapted strains increased significantly relative to the corresponding wild-type strains (P < 0.05), with the highest increase in one BC adapted strain named HL06BCA. Moreover, the knockout mutant HL06BCAΔmdrL showed impaired growth compared to that of HL06BCA when exposed to 2 μg/ml of BC. It suggests that efflux pump MdrL is associated with BC adaptation in L. monocytogenes. However, we did not find mdrL to be associated with cross-adaptation to cephalosporins, ciprofloxacin, and EtBr in HL06BCA. Additionally, increased sensitivity to acid, alkali, osmotic, ethanol, and oxidative stresses was observed in most strains after repeated exposure to BC. These results suggest rotation of different disinfectant is helpful to maintain high effectiveness of BC toward L. monocytogenes and ethanol and hydrogen peroxide are at least the appropriate candidates.