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Managing chronic non-healing wounds presents a significant clinical challenge due to their frequent bacterial infections. Mesoporous silica-based materials possess robust wound-healing capabilities attributed to their renowned antimicrobial properties. The current study details the advancement of mesoporous silicon-loaded MnO and CaO molecules (HMn-Ca) against bacterial infections and chronic non-healing wounds. HMn-Ca was synthesized by reducing manganese chloride and calcium chloride by urotropine solution with mesoporous silicon as the template, thereby transforming the manganese and calcium ions on the framework of mesoporous silicon. The developed HMn-Ca was investigated using scanning electron microscopy (SEM), transmission electron microscope (TEM), ultraviolet-visible (UV-visible), and visible spectrophotometry, followed by the determination of Zeta potential. The production of reactive oxygen species (ROS) was determined by using the 3,3,5,5-tetramethylbenzidine (TMB) oxidation reaction. The wound healing effectiveness of the synthesized HMn-Ca is evaluated in a bacterial-infected mouse model. The loading of MnO and CaO inside mesoporous silicon enhanced the generation of ROS and the capacity of bacterial capture, subsequently decomposing the bacterial membrane, leading to the puncturing of the bacterial membrane, followed by cellular demise. As a result, treatment with HMn-Ca could improve the healing of the bacterial-infected wound, illustrating a straightforward yet potent method for engineering nanozymes tailored for antibacterial therapy.

Composite aquiclude rock is an important part of the water barrier layer of coal seam floor, and its mechanical properties and failure characteristics have an important impact on the safety of coal seam mining. In order to explore the uniaxial compression failure characteristics and mechanical properties of composite aquiclude rocks, the mineral composition and microstructure of the composite cement rock were measured by XRD and SEM. Using a WAW-1000D electrohydraulic servo universal test system, uniaxial compression tests were carried out on samples of four structural types, namely, mudstone/siltstone, mudstone/fine sandstone, fine sandstone/siltstone, and siltstone/mudstone/fine sandstone composites soaked in saline water with various immersion periods and pH values. The experimental results show that the failure of composite rock samples was mainly concentrated in the mudstone part. With the increased proportion of soft rock in the structure, the rock samples exhibited changes in tensile, X-shaped conjugate inclined plane shear, and single inclined plane shear failure modes. The overall compressive strength of composite rock samples decreased with immersion time, and their failure mode shifted from shear to tensile with increasing immersion time. The strength-weakening effect of high-salinity water with different acidity and alkalinity on composite rock samples was significant. The increased pH promoted the tensile failure-shear failure-tensile failure evolution. The results of this study can provide important experimental data and theoretical basis for the stability control of composite aquiclude rock in coal mining.

BackgroundThe etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions.MethodsA retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies.ResultsThe prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ± 2.98 vs 1.89 ± 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.

Mesenchymal stem cells (MSCs) are highly effective in the treatment of acute liver failure (ALF). The efficacy of MSCs is closely related to the inflammatory environment. Therefore, we investigated the functional changes of MSCs in response to interleukin-33 (IL-33) stimulation. The results showed that bone marrow mesenchymal stem cells (BMSCs) pretreated with IL-33 had increased CCR2 expression, targeted CCL2 in the injured liver tissue, and improved the migration ability. Under LPS stimulation, the NF-κB pathway of BMDM was activated, and its phenotype polarized to the M1-type, while BMSCs pretreated with IL-33 inhibited the NF-κB pathway and enhanced M2 macrophage polarization. The M2-type macrophages could further inhibit hepatocytes inflammation, reduce hepatocytes apoptosis, and promote hepatocytes repair. These results suggest that IL-33 can enhance the efficacy of BMSCs in ALF and provide a new strategy for cell therapy of liver diseases.

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the μ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.

ObjectivePaleopathological evidence of cancer from past populations is rare, especially outside of Europe and North Africa. This study expands upon the current temporal and spatial distribution of cancer by presenting a probable case of multiple myeloma from Bronze Age China.MaterialThe human skeletal remains of an adult male from the Qijia culture horizon (1750-1400 BCE) of the Bronze Age cemetery of Mogou (), located in Gansu Province, Northwest China.MethodsThe human skeletal remains were assessed macroscopically and radiographically using plain x-rays.ResultsMultiple ovoid-shaped osteolytic lesions with sharply demarcated margins were observed. The axial skeletal had the greatest involvement, specifically the vertebrae, ribs, and sternum. Radiographic imaging revealed more extensive destruction of cancellous than cortical bone, indicating that the marrow was the focal point of the disease.ConclusionBased on the nature, distribution, and radiographic appearance of the lesions, the most likely diagnosis is multiple myeloma.SignificanceThis is one of the only cases of cancer identified in archaeological human skeletal remains from East Asia and is the first published case of a hematopoietic malignancy from mainland China. The analysis and publication of examples of neoplasia from areas that expand upon the current known temporal and spatial distribution is necessary in order to better reconstruct the history and evolution of cancer.LimitationsPoor skeletal preservation prevented the full extent of osteolytic lesions to be observed.Suggestions for future researchBy placing case studies such as this into a temporal and spatial framework, it is possible for future research to begin to interrogate possible underlying causes of cancer in ancient populations within the context of changing environmental conditions and subsistence strategies.

Abstract Background The prognostic value of in-hospital hemoglobin drop in non-overt bleeding patients with acute myocardial infarction (AMI) admitted to the intensive care unit (ICU) remains insufficiently investigated. Methods A retrospective analysis was performed based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. 2,334 ICU-admitted non-overt bleeders diagnosed with AMI were included. In-hospital hemoglobin values (baseline value on admission and nadir value during hospitalization) were available. Hemoglobin drop was defined as a positive difference between admission and in-hospital nadir hemoglobin. The primary endpoint was 180-day all-cause mortality. The time-dependent Cox proportional hazard models were structured to analyze the connection between hemoglobin drop and mortality. Results 2,063 patients (88.39%) experienced hemoglobin drop during hospitalization. We categorized patients based on the degree of hemoglobin drop: no hemoglobin drop (n = 271), minimal hemoglobin drop (

Abstract Lead halide perovskites have recently emerged as promising X/γ-ray scintillators. However, the small Stokes shift of exciton luminescence in perovskite scintillators creates problems for the light extraction efficiency and severely impedes their applications in hard X/γ-ray detection. Dopants have been used to shift the emission wavelength, but the radioluminescence lifetime has also been unwantedly extended. Herein, we demonstrate the intrinsic strain in 2D perovskite crystals as a general phenomenon, which could be utilized as self-wavelength shifting to reduce the self-absorption effect without sacrificing the radiation response speed. Furthermore, we successfully demonstrated the first imaging reconstruction by perovskites for application of positron emission tomography. The coincidence time resolution for the optimized perovskite single crystals (4 × 4 × 0.8 mm3) reached 119 ± 3 ps. This work provides a new paradigm for suppressing the self-absorption effect in scintillators and may facilitate the application of perovskite scintillators in practical hard X/γ-ray detections.

Twin boundaries (TBs) are effective sinks for solutes to segregate, as they may drive the structural transformation and therefore tailor the properties of magnesium alloys. In this study, a systematic investigation on the TB segregation energy (Eseg) has been performed for the {101¯2} and {101¯1} TBs by first-principles calculations. The segregation of 19 solute atoms (X: Be, Si, Ge, Zn, Ga, Al, Ag, Sb, Ti, Cd, Sn, Li, Bi, Zr, In, Pb, Na, Ca, and Sr) has been considered at the TBs. The solute atoms smaller than Pb are prone to occupying the compression sites of TBs (exception: Ti and Zr for the {101¯1} twin), while the ones larger than Pb prefer to locate at the extension sites. Further inspections suggest that the segregation of solute atoms into preferable sites can be attributed to the combined effect of bond strengthening and alleviated lattice distortion in the vicinity of TBs. For both of the TBs, the Eseg decreases approximately linearly with an increase in the size deviations (equilibrium volume and atomic radius) between Mg and solute atoms, implying the increased propensity for segregation and the enhanced stability of twins. Considering the segregation potency and solubility, the strengthening effects of the 19 solute atoms on TBs are evaluated. Our calculated results may provide guidance for future design of novel Mg alloys based on TB strengthening.

Abstract Background Sarcopenia and osteoporosis are common diseases that predominantly affect older individuals. The interaction between muscle and skeleton exerts pivotal roles in bone remodeling. This study aimed to explore the function of myoblast-derived exosomal Prrx2 in osteogenic differentiation and its potential mechanisms. Methods Exosomes were isolated from myogenic differentiated C2C12 cells. qRT-PCR and Western blotting were used to determine target molecule expression. Osteogenic differentiation of BMSCs was evaluated by Alizarin red staining, ALP activity and levels of OCN, OPN, RUNX2, and BMP2. Dual-luciferase reporter assay, RIP, and ChIP assays were performed to verify the interaction between molecules. The nuclear translocation of YAP1 was observed by immunofluorescence staining. In vivo osteoporotic model was established by ovariectomy in mice. Bone loss was examined using HE staining. Results Prrx2 expression was elevated in myogenic differentiated C2C12 cells and their exosomes. Myoblast-derived exosomal Prrx2 enhanced osteogenic differentiation of BMSCs. Delivering exosomal Prrx2 directly bond to MIR22HG promoter and promoted its transcription and expression. MIR22HG enhanced expression and nuclear translocation of YAP via sponging miR-128, thus facilitating BMSC osteogenic differentiation. Knockdown of exosomal Prrx2 suppressed osteogenic differentiation, which could be abolished by MIR22HG overexpression. Similarly, miR-128 inhibitor or YAP overexpression reversed the inhibitory effect of MIR22HG depletion or miR-128 mimics on osteogenic differentiation. Finally, myoblast-derived exosomal Prrx2 alleviated osteoporosis in mice via up-regulating MIR22HG and activating the Hippo pathway. Conclusion Myoblast-derived exosomal Prrx2 contributes to transcriptional activation of MIR22HG to activate YAP pathway via sponging miR-128, thereby facilitating osteogenic differentiation of BMSCs.

By introducing heterogeneous lamella-structure, we obtained a superior strength-ductility synergy in Mg-alloy associated with excellent strain-hardening ability, i.e. yield strength of ∼251 MPa, tensile strength of ∼393 MPa and elongation of ∼23%. By using advanced characterization techniques, we showed that strengthening was mainly caused by the non-uniform distribution of hetero-deformation induced (HDI) stress associated with grain-boundary disclinations, which are mediated by heterogeneous multi-grain interactions. Induced by grain-boundary disclinations and intergranular slip transfers, a variety of abnormal deformation modes have been activated，which contributed significantly to enhanced ductility. This work suggests a new avenue to evade strength-ductility trade-off dilemma in Mg-alloys.

Vascular injury following traumatic knee injury quoted in the literature ranges from 3.3 to 65%, depending on the magnitude and pattern of the injury. Timely recognition is crucial to ensure the revascularization is done within 6 to 8 hours from the time of injury to avoid significant morbidity, amputation, and medicolegal ramifications. We present a case of an ischemic limb following delayed diagnosis of popliteal artery injury after knee dislocation. Even though we have successfully repaired the popliteal artery, the evolving ischemia over the distal limb poses a reconstruction challenge. Multiple surgical debridement procedures were performed to control the local tissue infection. Free tissue transfer with chimeric latissimus dorsi flap was done to resurface the defect. However, the forefoot became gangrenous despite a free muscle flap transfer. His limb appeared destined for amputation in the vicinity of tissue and recipient vessels, but we chose to use a cross-leg free flap as an option for limb salvage.

Abstract Background Serum lipids variations are closely related to the sepsis progression; however, their value for patients with pyogenic liver abscesses (PLA) has rarely been studied. We investigated the serum lipid level variations in patients with PLA and its predictive value to the disease. Methods The study included 328 patients with PLA hospitalized in the First Affiliated Hospital of Nanjing Medical University from January 2017 to December 2021; 35 (10.67%) in the severe group (SG) and 293 (89.33%) in the non-severe group (nSG). Their clinical records were analyzed retrospectively, and dynamic curves were drawn to clarify the changes in different indicators during the course of the disease. Results High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) (Lp(a)) in the SG were significantly lower than those in nSG (P

In order to explore the synergistic corrosion inhibition effect of spinach extract and KI on Q235 steel in 0.5 mol/L H2SO4 solution，the synergistic corrosion inhibition effect and mechanism of spinach extract chlorophyll (CHL) and KI on Q235 steel in 0.5 mol/L H2SO4 solution were studied by means of weight loss method，electrochemical impedance spectroscopy (EIS)，potentiodynamic polarization curve，scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS).Results showed that when CHL (100 mg/L) and KI (50～200 mg/L) were combined in 0.5 mol/L H2SO4 solution，the obtained compound always showed good corrosion inhibition with a corrosion inhibition rate above 90%.And when both CHL and KI were mixed with a concentration of 100 mg/L，the synergistic effect was the best，with a corrosion inhibition rate up to 98.04%.The compound of CHL and KI was a kind of mixed corrosion inhibitor that mainly inhibited the cathode.The corrosion inhibition behavior of CHL and its complex with KI conformed to Langmuir isothermal adsorption equation，which was a spontaneous adsorption process and formed a dense protective film on the surface of Q235 steel.In 0.5 mol/L H2SO4 solution，CHL molecules were adsorbed on the surface of Q235 steel through physical and chemical adsorption to prevent corrosion reaction.The addition of KI could assist CHL molecules to adsorb on the surface of Q235 steel，improving the adsorption rate of CHL molecules.In this way，the corrosion rate as well as the amount of CHL and KI required for the inhibition were both reduced.Therefore，the synergistic effect of CHL and KI was enhanced and the inhibition efficiency was improved.

TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ25–35) to stimulate human microglia to construct microglia models of Alzheimer’s disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ25–35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer’s disease treatment.

Deoxyribonucleic acid (DNA) genetic markers and ribonucleic acid (RNA) molecular markers have been widely used in forensic practices including individual identification, parentage testing, body fluid identification, determination of the age of stains, and molecular pathological diagnosis. Variant information of biological evidence and their interrelation could be revealed by the integrated detection of DNA/RNA markers. The integrated detection workflow aims to simplify working procedures, reduce time consuming and save valuable samples collected from crime scenes. Next-generation sequencing (NGS) may be an effective method for integrated DNA/RNA detection. In this review, DNA/RNA co-extraction strategies, simultaneous detection methods based on capillary electrophoresis were summarized. Research on NGS-based integrated detection methods of DNA and RNA markers was reviewed to provide a reference for forensic medicine researches and applications.