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The all-d-metal Ni–Mn–Ti Heusler alloy with its good mechanical properties and colossal caloric effects has attracted significant attention for mechanocaloric refrigeration. However, the phase stability of the B2-type disordered structure at finite temperatures and the physical origin of large phase transformation entropy change in theoretical calculation remain unclear. In view of thermal and strongly anharmonic effects, we combined the first-principles and temperature dependent effective potential calculations to systematically study the phase stability, martensitic transformation mechanism, and vibrational entropy properties of B2 partial disordered structures for Ni8Mn5Ti3 and Ni8Mn6Ti2. Our results showed the austenitic structures of Ni8Mn5Ti3 and Ni8Mn6Ti2 both exhibit antiferromagnetic interaction behaviors at targeted temperatures, resolving the contradiction between previous calculations and experiments. By the analysis of phonon dispersion relations and Helmholtz free energies at low and high temperatures, we provided a deeper explanation for the underlying mechanism of martensitic transformation. Meanwhile, the phase transformation temperatures and vibrational entropy changes were accurately predicted compared with the experiment results. Specifically, we demonstrated that the large vibrational entropy change of Ni–Mn–Ti material originates from the contributions of both the tetragonal distortion ratio and volume change, which provides important theoretical guidance and has great practical significance for designing the solid-state material with large vibrational entropy change in the application of solid-state refrigeration.

Superelasticity of shape memory alloy associated with the martensitic transformation is extremely attractive for applications in sensors and biomedical. This application requires narrow stress hysteresis to reduce energy dissipation and a stable superelasticity cycle is an important factor in their practical applications. Co–V–Al alloys have inimitable advantages due to their narrow stress hysteresis, low-cost, and corrosion resistance, but the low number of superelasticity cycles restricts its development. Here, we report an intrinsic Co58V29Al13 polycrystalline alloy with a superelasticity stress hysteresis of 30 MPa at room temperature, the lowest among the alloys in this system, and a superelasticity strain of 3.6%. In addition, the sample shows no significant decay trend after 500 loading and unloading cycles. The high number of superelasticity cycles is mainly due to the elastic stress field generated around the dislocation during the cycle, which provides internal stress for martensite nucleation and reduces energy dissipation during martensitic transformation. This work provides essential guiding significance for the design of high-performance superelasticity alloys.

Abstract Talin2 is localized to large focal adhesions and is indispensable for traction force generation, invadopodium formation, cell invasion as well as metastasis. Talin2 has a higher affinity toward β-integrin tails than talin1. Moreover, disruption of the talin2-β-integrin interaction inhibits traction force generation, invadopodium formation and cell invasion, indicating that a strong talin2-β-integrin interaction is required for talin2 to fulfill these functions. Nevertheless, the role of talin2 in mediation of these processes remains unknown. Here we show that talin2 binds to the N-terminus of non-muscle myosin IIA (NMIIA) through its F3 subdomain. Moreover, talin2 co-localizes with NMIIA at cell edges as well as at some cytoplasmic spots. Talin2 also co-localizes with cortactin, an invadopodium marker. Furthermore, overexpression of NMIIA promoted the talin2 head binding to the β1-integrin tail, whereas knockdown of NMIIA reduced fibronectin and matrix metalloproteinase secretion as well as inhibited cell attachment on fibronectin-coated substrates. These results suggest that talin2 binds to NMIIA to control the secretion of extracellular matrix proteins and this interaction modulates cell adhesion.

Currently, practical applications of shape memory alloy (SMA) solid elastocaloric refrigeration materials are limited by low elastocaloric effect (eCE), high applied stress, and large stress hysteresis (Δσhys). Here, we introduce a composition design strategy using Ti-doped Co–V-Ga SMAs to address these challenges. We combine first-principles calculations and experiments to verify this strategy. Our results show that the lattice distortion caused by the significant difference in atomic radius after Ti doping produces a solid solution strengthening effect inside the alloy, which significantly improves the superelasticity of the alloy, delays the plastic deformation of the austenite phase, and the volume fraction of martensitic transformation increases significantly. The newly developed Co51.7V31.3Ga16Ti1 bulk polycrystalline alloy exhibits a remarkable adiabatic temperature change (ΔTad) of −10 K at room temperature under a low stress of 400 MPa, a minimum Δσhys of 18 MPa, and a high coefficient of performance COPmat of 31.9. Importantly, the 100-cycle loading-unloading test at 350 MPa is done, and it reveals that the ΔTad for the Ti0 alloy was only 3.9 K, while it reached 6.2 K for the Ti1 alloy, marking a noteworthy 59 % performance enhancement. From the simplicity of the fabrication process to the comprehensive performance of the material, it exhibits a promising advantage for practical cooling applications This study presents a feasible design strategy for large-scale production of high-performance bulk polycrystalline alloys with high eCE, low stress, and Δσhys.

The temperature of the surrounding rock in cold-region tunnels is crucial for antifreeze design, and the water-ice phase transition is essential to addressing the temperature field. This paper proposes a refined method that equates the latent heat of the ice-water phase transition to heat capacity and establishes a one-dimensional radial heat transfer model considering phase change. By defining an average thermal diffusivity coefficient through the concept of equal accumulated temperature, this method overcomes the limitations of classical heat transfer theory in directly solving the temperature field of three zone (unfrozen zone, freezing zone and frozen zone). Additionally, by employing the variable separation method and Fourier integral transformation method, the analytical formula for the transient temperature field considering phase change is derived. Then, the analytical solution was verified based on the field data. The results calculated using this method exhibit greater consistency with field temperature data and outperform the modified Stephan formula in determining the maximum frozen depth of the surrounding rock. Finally, the simplified form of the established analytical solution was further discussed. The research results can provide a theoretical basis for the analysis of the temperature field of the surrounding rock of the tunnel in cold regions and its antifreeze design.

Background Gamma delta (γδ) T cells play dual roles in human tumors, with both antitumor and tumor-promoting functions. However, the role of γδT cells in HPV-infected cervical cancer is still undetermined. Therefore, we aimed to identify γδT cell-related prognostic signatures in the cervical tumor microenvironment. Methods Single-cell RNA-sequencing (scRNA-seq) data, bulk RNA-seq data, and corresponding clinical information of cervical cancer patients were obtained from the TCGA and GEO databases. The Seurat R package was used for single-cell analysis, and machine learning algorithms were used to screen and construct a γδT cell-related prognostic signature. Real-time quantitative PCR (RT-qPCR) was performed to detect the expression of prognostic signature genes. Results Single-cell analysis indicated distinct populations of γδT cells between HPV-positive (HPV+) and HPV-negative (HPV-) cervical cancers. A trajectory analysis indicated γδT cells clustered into differential clusters with the pseudotime. High-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) identified the key γδT cell-related gene modules. Bulk RNA-seq analysis also demonstrated the heterogeneity of immune cells, and the γδT-score was positively associated with inflammatory response and negatively associated with MYC stemness. Eight γδT cell-related hub genes (GTRGs), including ITGAE, IKZF3, LSP1, NEDD9, CLEC2D, RBPJ, TRBC2, and OXNAD1, were selected and validated as a prognostic signature for cervical cancer. Conclusion We identified γδT cell-related prognostic signatures that can be considered independent factors for survival prediction in cervical cancer.

ABSTRACT Introduction Low body weight in patients with COPD is associated with a poor prognosis and more comorbidities. However, the impact of increased body weight in patients with COPD remains controversial. The aim of this study was to explore the clinical features of overweight patients with AECOPD. Methods In this multicenter cross‐sectional study, a total of 647 AECOPD patients were recruited. Finally, 269 normal weight and 162 overweight patients were included. Baseline characteristics and clinical and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was performed to determine potential features, which were substituted into binary logistic regression to reveal overweight‐associated clinical features. The nomogram and its associated curves were established to visualize and verify the logistic regression model. Results Six potential overweight‐associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that the rates of type 2 diabetes (T2DM) and hypertension and levels of lymphocytes (LYM)%, and alanine aminotransferase (ALT) were independent variables of overweight in AECOPD patients. The C‐index and AUC of the ROC curve of the nomogram were 0.671 and 0.666, respectively. The DCA curve revealed that the nomogram had more clinical benefits if the threshold was at a range of 0.22~0.78. Conclusions Collectively, we revealed that T2DM and hypertension were more common, and LYM% and ALT were higher in AECOPD patients with overweight than those with normal weight. The result suggests that AECOPD patients with overweight are at risk for additional comorbidities, potentially leading to worse outcomes.

Abstract As a new technology to mitigate the high outburst risk of the low permeability coal seam, it is essential to delve deeper into the law and mechanism of pressure relief associated with the diamond beaded rope saw slotting. The paper presents a numerical calculation model under small size that is based on the superimposed beam theory and the contact surface model. The model is compared with the experimental results of similar models in the laboratory to verify its applicability for simulating the numerical calculation of stress distribution in coal seam cut by diamond beaded rope saw. The study then goes on to investigate the influence of coal seam inclination, working face length, coal seam hardness, and seam advancing distance on the pressure relief effect of diamond beaded rope saw cutting seam under engineering scale. The mechanism of the diamond beaded rope saw cutting seam is also analyzed. The results indicate that the diamond beaded rope saw effectively reduces pressure in low permeability coal seams, with the impact range extending to the slit area. Additionally, stress concentration was observed at the front of the slit. Increasing the inclination of the coal seam, working face length, and advancing distance of the cutting seam enhances the pressure relief effect of the diamond beaded rope saw. The latter two factors’ influence is reflected in the direction along the working face and the direction of mining advance, respectively. The efficacy of pressure relief through this particular method is comparatively better in soft coal than in hard coal. This research is significant in promoting the widespread application of diamond beaded rope saws in the pressure relief of coal seam cutting.

Abstract Background The forgotten ureteral stents (FUS) is one of the late complications of stent placement. This systematic review summarized different aspects of FUS and focused on the problems and solutions related to FUS. Methods This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. PubMed® and Embase® were searched from inception until October 1st, 2022. Eligible studies were those defining FUS as a stent unintentionally left in situ longer than at least 2 months. Results Total 147 studies with 1292 patients were finally included. The mean indwelling time of FUS was 33.5 months (range from 3 months to 32 years). The most common initial cause for stent placement was adjunct treatment to urolithiasis (79.2%). The major forgetting reasons were patient-related (83.9%), which included poor compliance, lapse in memory, and misconceptions about the necessity of timely removal. Primary presenting complaints were flank pain (37.3%), lower urinary tract symptoms (33.3%), and hematuria (22.8%). Encrustation (80.8%) and urinary tract infections (40.2%) were the most common complications detected in patients with FUS. Computed tomography evolving as a preferred imaging test (76.1%) was indispensable for evaluating encrustation, migration, fracture and other complicated situations in patients with FUS. Besides, evaluation of kidney function and infection status was also of great importance. Multiple and multimodal procedures (59.0%) were often necessitated to achieve the stent-free status, and were mostly endoscopic procedures. Cystoscope was most commonly used (64.8%). Retrograde ureteroscopy (43.4%) and antegrade stent removal (31.6%) were often used when dealing with more complicated situations. Extracorporeal shockwave lithotripsy (30.4%) was often used as adjunctive to other endoscopic procedures, but it sometimes failed. The decision regarding the choice of treatment is based on the volume and site of encrustation, the direction of migration, the site of fracture, kidney function and other urinary comorbidities. Conclusions FUS not only pose hazard to patients’ health, but also impose a huge economic burden on medical care. Thorough preoperative evaluation is fundamental to developing the treatment strategy. The management of FUS should be individualized using different treatment modalities with their advantages to minimize patients’ morbidities. Prevention is better than cure. Strengthening health education and setting a tracking program are of great importance to the prevention of FUS.

Abstract Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein’s structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer’s disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson’s disease. Other neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

Abstract Background Antepartum depression has been reported to be associated with the intensity of maternal prenatal noise exposure; however, the association between noise exposure duration and the development of antepartum depression has not been established. This study aimed to determine the total and trimester-specific association of prenatal noise exposure duration with the development of antepartum depression. Methods From May 2018 to June 2021, we recruited 2,166 pregnant women from Shengjing Hospital, northeast China. We used a standardized questionnaire to assess women’s prenatal noise exposure and used the Edinburgh Postnatal Depression Scale to assess pregnant women’s antepartum depression during the 1st -, 2nd -, and 3rd - trimesters. We calculated a cumulative noise exposure score ranging from 0 to 3, with a higher score reflecting higher frequency and longer duration of noise exposure during pregnancy. Results Women who were exposed to noise for ≥ 15 min per day had an increased risk of antepartum depression compared with women who were not exposed to noise during pregnancy [odds ratio (OR) = 1.83, 95%CI:1.18, 2.83]. Noise exposure in a specific trimester was associated with higher risk of depression in the same trimester and subsequent trimesters. We observed increases in antepartum depression risk with increasing cumulative noise exposure scores (P for trend

BackgroundMaternal atmospheric pollution during pregnancy may alter fetal intrauterine development programming, thereby increasing the risk of childhood obesity in the future.ObjectiveTo investigate the effects of atmospheric pollution exposure during pregnancy on the incidence of childhood obesity in offspring.MethodsEnglish databases (PubMed, Web of Science, and Medline) and Chinese databases (Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure, and VIP Information Chinese Journal Service Platform) were searched for literature reporting exposure to atmospheric pollution during pregnancy and childhood obesity published from 1 January 2000 to 31 August 2023. The quality of the included literature was evaluated using the quality assessment tools for observational cohort and cross-sectional studies recommended by the US National Institutes of Health.ResultsTwenty-four studies meeting the inclusion criteria were identified and the associated atmospheric pollutants included particulate matter, ozone, nitrogen oxide, carbon oxide, and sulfur oxide. In comparison to the non-exposed group, prenatal exposure to various common atmospheric pollutants were significantly associated with an elevated risk of childhood obesity in offspring.ConclusionMaternal exposure to atmospheric pollution during pregnancy is associated with an elevated risk of childhood obesity in subsequent years. Future studies should pay more attention to the effects of atmospheric pollution on the distribution of children's body fat and metabolic development, and further identify potential mechanisms of atmospheric pollutant exposure leading to childhood obesity.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has many neurological manifestations, and its effects on the nervous system are increasingly recognized. There has been no systematic analysis of electroencephalography (EEG) characteristics in children exhibiting neurological symptoms of Coronavirus disease 2019 (COVID-19). The primary aim of this study was to describe the EEG characteristics caused by COVID-19 infection in children who were showing neurological symptoms and to assess the relationship between COVID-19-related EEG changes and clinical features in these children. Method: This study included 125 pediatric patients infected with SARS-CoV2 and showing neurological symptoms, and their continuous EEG was recorded. In addition, the demographic and clinical characteristics of these patients were analyzed and the correlation between the two was investigated. Results: Abnormal EEG findings were detected in 31.20% (N = 39) of the patients. Abnormal discharges (43.59%) were the most common EEG abnormalities, followed by background abnormalities (41.03%). The proportion of patients diagnosed with febrile seizure was higher in the normal EEG group than in the abnormal EEG group (P = 0.002), while the opposite was true for epilepsy and encephalitis/encephalopathy (P = 0.016 and P = 0.003, respectively). The independent associated factors of abnormal EEG were age and total length of stay (P

With the rapid development of solid-state refrigeration technology, elastocaloric materials face higher requirements, such as a higher elastocaloric effect (eCE), better mechanical properties, and simpler and faster large-scale preparation. In this work, we propose a composition design strategy for Mn-doped Co–V-Ga shape memory alloys, which can enhance both the eCE and the mechanical properties. We combine first-principles calculations and experiments to demonstrate this strategy. Our results reveal that the lattice distortion caused by the difference in atomic radii produces a solid-solution-strengthening effect within the alloy, impeding dislocation motion and significantly improving the mechanical properties. Through composition optimization, the low-cost Co51.7V31.3Ga14.75Mn2.25 as-cast polycrystalline alloy exhibits a large adiabatic temperature change (ΔTad) of −11.2 K at room temperature, while its maximum compressive strength and strain can reach up to 1859 MPa and 26% at room temperature, respectively. Importantly, the alloy exhibits excellent cycle stability, and its ΔTad does not decay after 100 loading and unloading cycles, indicating that it has the potential for practical application. Further comparison with the annealed sample shows that the secondary defects deteriorate the ΔTad of the alloy. Our research provides an effective strategy for the simple, rapid and large-scale production of as-cast eCE alloys.

Abstract The occurrence of systemic inflammatory response after percutaneous transhepatic gallbladder drainage brings great risks to patients and is one of the challenges faced by clinicians. Therefore, it is of great significance to find a suitable prediction method for clinicians to intervene early and reduce the transformation of serious complications. Easy-to-obtain and objectively measured clinical features were screened, and logistic regression was used to construct a prediction model. The predictive ability of the model was evaluated by using the receiver operating characteristic curve and the decision curve in the validation set and the training set, respectively. Nine clinical features (CRP, Fever, DBIL, Obstruction, Bile properties, PCT, Length, Width, and Volume factor) were used to construct the prediction model, and the validation results showed that the prediction model had good performance in the training set (AUC = 0.83) and the validation set (AUC = 0.81). The decision curve also showed that the predictive ability of the model incorporating nine clinical features is better than that of a single clinical feature. The model we constructed can accurately predict the occurrence of SIRS, which can guide clinicians to take treatment measures and avoid the deterioration of complications.

Aims: Currently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis. Methods: The effects of melatonin on mitochondrial apoptosis protein, bmal1 gene, and related pathway proteins of RAW264.7 (mouse mononuclear macrophage leukaemia cells) were analyzed by western blot. Cell Counting Kit-8 was used to evaluate the effect of melatonin on cell viability. Flow cytometry was used to evaluate the effect of melatonin on the apoptosis of RAW264.7 cells and mitochondrial membrane potential. A reactive oxygen species (ROS) detection kit was used to evaluate the level of ROS in osteoclast precursors. We used bmal1-small interfering RNAs (siRNAs) to downregulate the Bmal1 gene. We established a postmenopausal mouse model and verified the effect of melatonin on the bone mass of postmenopausal osteoporosis in mice via micro-CT. Bmal1 lentiviral activation particles were used to establish an in vitro model of overexpression of the bmal1 gene. Results: Melatonin promoted apoptosis of RAW264.7 cells and increased the expression of BMAL1 to inhibit the activation of ROS and phosphorylation of mitogen-activated protein kinase (MAPK)-p38. Silencing the bmal1 gene weakened the above effects of melatonin. After that, we used dehydrocorydaline (DHC) to enhance the activation of MAPK-p38, and the effects of melatonin on reducing ROS levels and promoting apoptosis of RAW264.7 cells were also blocked. Then, we constructed a mouse model of postmenopausal osteoporosis and administered melatonin. The results showed that melatonin improves bone loss in ovariectomized mice. Finally, we established a model of overexpression of the bmal1 gene, and these results suggest that the bmal1 gene can regulate ROS activity and change the level of the MAPK-p38 signalling pathway. Conclusion: Our study confirmed that melatonin promotes the apoptosis of RAW264.7 cells through BMAL1/ROS/MAPK-p38, and revealed the therapeutic effect and mechanism of melatonin in postmenopausal osteoporosis. This finding enriches BMAL1 as a potential target for the treatment of osteoporosis and the pathogenesis of postmenopausal osteoporosis. Cite this article: Bone Joint Res 2023;12(11):677–690.

Oil and natural gas resources are crucial energy sources formed during the geological and biological evolution of the Earth [...]

Abstract Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age‐dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age‐gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β‐amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age‐dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age‐dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age‐dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age‐gradient changes in the autophagy–lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state.

Abstract Background Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule‐associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. Methods The levels of nucleotide‐binding oligomerisation domain (NOD)‐like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme‐linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test‐tube acetylation assay, co‐immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau‐overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno‐associated virus injection. The cognitive functions of Tau‐overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba‐1 IF staining and [18F]‐DPA‐714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau–NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. Results Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg‐AD mice, microtubule‐associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of ‘early’ phosphorylated‐Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau–K18 domain acetyltransferase activity‐dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV‐2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau–NLRP3‐binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. Conclusions In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

BackgroundThe relationship between inflammation-related genes (IRGs) and keloid disease (KD) is currently unclear. The aim of this study was to identify a new set of inflammation-related biomarkers in KD.MethodsGSE145725 and GSE7890 datasets were used in this study. A list of 3026 IRGs was obtained from the Molecular Signatures Database. Differentially expressed inflammation-related genes (DEGs) were obtained by taking the intersection of DEGs between KD and control samples and the list of IRGs. Candidate genes were selected using least absolute shrinkage and selection operator (LASSO) regression analysis. Candidate genes with consistent expression differences between KD and control in both GSE145725 and GSE7890 datasets were screened as biomarkers. An alignment diagram was constructed and validated, and in silico immune infiltration analysis and drug prediction were performed. Finally, RT-qPCR was performed on KD samples to analyze the expression of the identified biomarkers.ResultsA total of 889 DEGs were identified from the GSE145725 dataset, 169 of which were IRGs. Three candidate genes (TRIM32, LPAR1 and FOXF1) were identified by the LASSO regression analysis, and expression validation analysis suggested that FOXF1 and LPAR1 were down-regulated in KD samples and TRIM32 was up-regulated. All three candidate genes had consistent changes in expression in both the GSE145725 and GSE7890 datasets. An alignment diagram was constructed to predict KD. Effector memory CD4 T cells, T follicular helper cell, Myeloid derived suppressor cell, activated dendritic cell, Immature dendritic cell and Monocyte were differentially expressed between the KD and control group. Sixty-seven compounds that may act on FOXF1, 108 compounds that may act on LPAR1 and 56 compounds that may act on TRIM32 were predicted. Finally, RT-qPCR showed that the expression of LPAR1 was significantly lower in KD samples compared to normal samples whereas TRIM32 was significantly higher, while there was no difference in the expression of FOXF1.ConclusionThis study provides a new perspective to study the relationship between IRGs and KD.

Abstract Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.

Thermally-induced changes in the fracture properties of geological reservoir rocks can influence their stability, transport characteristics, and performance related to various deep subsurface energy projects. The modified maximum tangential stress (MMTS) criterion is a classical theory for predicting the fracture instability of rocks. However, there is a lack of research on the accuracy of MMTS theory when rocks are subjected to different temperatures. In this study, mechanical theoretical analysis and failure and fracture mechanics experiments of granite under the influence of temperatures ranging from 20 °C to 600 °C are carried out. The results showed that the theoretical estimated value of MMTS differs significantly from the experimental data at 20 °C−600 °C. The Keff/KIC ratio is less than the experimental test value due to the critical crack growth radius (rc) estimated by the conventional method being larger than the critical crack growth radius (rce) derived from the experimental data. Varied temperatures affect the fracture process zone size of fine-grained, compact granite, and the MMTS theoretical estimation results. Therefore, it is essential to modify the critical crack growth radius for MMTS theory to accurately predict the fracture characteristics of thermally damaged rocks. In addition, the variation of the rock’s mechanical properties with temperature and its causes are obtained. Between 20 °C and 600 °C, the mode-I, mode-II, and mixed-mode (α = 30° and 45°) fracture toughness and Brazilian splitting strength of the granite decrease by 80% and 73%, respectively. When the rock is heated above 400 °C, its deterioration is mainly caused by a widening of its original cracks.

To mitigate freeze-thaw damage in tunnels located in high-altitude cold regions, insulation layers are implemented to prevent the freezing of surrounding rocks. Currently, the selection of laying methods lacks a solid scientific basis, with the merits and demerits of various techniques remaining insufficiently evaluated. This study seeks to establish a scientifically grounded equilibrium between the anti-freezing efficacy and the construction impact of tunnel insulation in cold regions through the optimization of insulation design via numerical calculations. First, the advantages and disadvantages of the four insulation layer laying methods were summarized. Then, a multilayer media heat transfer model that accounts for the latent heat of phase change was developed, grounded in solid heat transfer and porous media heat transfer theories, and corroborated by typical case studies. Finally, taking Duolong tunnel as a case study, the insulation effect of various laying methods at different positions of the tunnel was analyzed based on the finite element method. The results show that the unfavorable position of the four laying methods is at the inverted arch of the tunnel, and the unfavorable time point occurs when the temperature rises from below 0℃ to above 0℃. Among the four laying methods, off-wall laying exhibits the superior insulation performance at tunnel vault, while sandwich laying has best insulation effect at the arch foot and inverted arch. The research results can provide reference and basis for the thermal insulation and anti-freezing design of tunnels in high-altitude cold regions.

Abstract Background A prognostic assessment method with good sensitivity and specificity plays an important role in the treatment of pancreatic cancer patients. Finding a way to evaluate the prognosis of pancreatic cancer is of great significance for the treatment of pancreatic cancer. Methods In this study, GTEx dataset and TCGA dataset were merged together for differential gene expression analysis. Univariate Cox regression and Lasso regression were used to screen variables in the TCGA dataset. Screening the optimal prognostic assessment model is then performed by gaussian finite mixture model. Receiver operating characteristic (ROC) curves were used as an indicator to assess the predictive ability of the prognostic model, the validation process was performed on the GEO datasets. Results Gaussian finite mixture model was then used to build 5-gene signature (ANKRD22, ARNTL2, DSG3, KRT7, PRSS3). Receiver operating characteristic (ROC) curves suggested the 5-gene signature performed well on both the training and validation datasets. Conclusions This 5-gene signature performed well on both our chosen training dataset and validation dataset and provided a new way to predict the prognosis of pancreatic cancer patients.

Abstract The present study aims to investigate the genotype distribution of Human papillomavirus (HPV) and variations of HPV18 and HPV58 infection among 6538 females in Luoyang city during 2019–2021. The overall positive rate of females with HPV infection was 12.34%, with 9.74% were infected with single HPV and 2.60% with multiple HPVs. The prevalent rate of high-risk HPV (HR-HPV) was 9.85% and the top five HR-HPV genotypes were HPV52 (1.94%), HPV16 (1.93%), HPV58 (1.48%), HPV51 (1.02%) and HPVV39 (0.99%). Two peaks of HPV infections rates were observed in females aged ≤ 20 and 61–65 years old. To characterize mutations, 39 HPV18 and 56 HPV58 L1, E6 and E7 genes were sequenced and submitted to GenBank. In the HPV18 E6-E7-L1 sequences, 38 nucleotides changes were observed with 10/38 were non-synonymous mutations (5 in E6 gene, 1 in E7 gene and 4 in L1 gene). In the HPV58 E6-E7-L1 sequences, 53 nucleotides changes were observed with 23/53 were non-synonymous mutations (3 in E6 gene, 5 in E7 gene and 15 in L1 gene). Phylogenetic analysis based on L1 gene showed that 92.3% (36/39) of HPV18 isolates fell into sublineage A1 and 7.7% (3/39) belonged to A5. For HPV58, 75.0% (42/56) isolates belonged to sublineage A1 and 25.0% (14/56) were sublineage A2. There was no association between amino mutation and cervical lesions. The present study provides basic information about the distribution, genotypes and variations of HPV among females population in Luoyang city, which would assist in the formulation of HPV screening and vaccination programs and preventive strategies for HPV-attributable cancer in this region.

Background Methamphetamine (METH) addiction causes a huge burden on society. The prefrontal cortex (PFC), associated with emotion and cognitive behaviours, is also involved in addiction neurocircuitry. Although bulk RNA sequencing has shown METH-induced gene alterations in the mouse PFC, the impact on different cell types remains unknown.Aims To clarify the effects of METH treatment on different cell types of the PFC and the potential pathways involved in METH-related disorders.Methods We performed single-nucleus RNA sequencing (snRNA-seq) to examine the transcriptomes of 20 465 nuclei isolated from the PFC of chronic METH-treated and control mice. Main cell types and differentially expressed genes (DEGs) were identified and confirmed by RNA fluorescence in situ hybridization(FISH).Results Six main cell types were identified depending on the single-cell nucleus sequencing; of particular interest were the mature oligodendrocytes in the PFC. The DEGs of mature oligodendrocytes were enriched in the myelin sheath, adenosine triphosphate (ATP) metabolic process, mitochondrial function and components, and so on. The messenger RNA levels of Aldoc and Atp5l (FISH) and the protein level of the mitochondrial membrane pore subunit TOM40 (immunofluorescence) decreased in the mature oligodendrocytes. Fast blue staining and transmission electron microscopy image indicated myelin damage, and the myelin thickness decreased in METH brains.Conclusions snRNA-seq reveals altered transcriptomes of different cell types in mouse PFC induced by chronic METH treatment, underscoring potential relationships with psychiatric disorders.

Major Histocompatibility Complex Class II (MHC II) deficiency is a rare primary immunodeficiency disorder (PID) with autosomal recessive inheritance pattern. The outcome is almost fatal owing to delayed diagnosis and lacking of effective therapy. Therefore, prompt diagnosis, timely and effective treatment are critical. Here, we report a 117-day-old boy with diarrhea, cough, cyanosis and tachypnea who was failed to be cured by empiric antimicrobial therapy initially and progressed to severe pneumonia and respiratory failure. The patient was admitted to the pediatric intensive care unit (PICU) immediately and underwent a series of tests. Blood examination revealed elevated levels of inflammatory markers and cytomegalovirus DNA. Imaging findings showed signs of severe infection of lungs. Finally, the diagnosis was obtained mainly through next-generation sequencing (NGS). We found out what pathogenic microorganism he was infected via repeated conventional detection methods and metagenomic next-generation sequencing (mNGS) of sputum and bronchoalveolar lavage fluid (BALF). And his whole exome sequencing (WES) examination suggested that CIITA gene was heterozygous mutation, a kind of MHC II deficiency diseases. After aggressive respiratory support and repeated adjustment of antimicrobial regimens, the patient was weaned from ventilator on the 56th day of admission and transferred to the immunology ward on the 60th day. The patient was successful discharged after hospitalizing for 91 days, taking antimicrobials orally to prevent infections post-discharge and waiting for stem cell transplantation. This case highlights the potential importance of NGS in providing better diagnostic testing for unexplained infection and illness. Furthermore, pathogens would be identified more accurately if conventional detection techniques were combined with mNGS.

Abstract Background Hyponatremia is an independent predictor of poor prognosis, including increased mortality and readmission, in COPD patients. Identifying modifiable etiologies of hyponatremia may help reduce adverse events in patients with AECOPD. Therefore, the aim of this study was to explore the risk factors and underlying etiologies of hyponatremia in AECOPD patients. Methods A total of 586 AECOPD patients were enrolled in this multicenter cross-sectional study. Finally, 323 had normonatremia, and 90 had hyponatremia. Demographics, underlying diseases, comorbidities, symptoms, and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was used to select potential risk factors, which were substituted into binary logistic regression to identify independent risk factors. Nomogram was built to visualize and validate binary logistics regression model. Results Nine potential hyponatremia-associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that smoking status, rate of community-acquired pneumonia (CAP), anion gap (AG), erythrocyte sedimentation rate (ESR), and serum magnesium (Mg2+) were independent variables of hyponatremia in AECOPD patients. The AUC of ROC curve of nomogram was 0.756. The DCA curve revealed that the nomogram could yielded more clinical benefits if the threshold was between 10% and 52%. Conclusions Collectively, our results showed that smoking status, CAP, AG, ESR, and serum Mg2+ were independently associated with hyponatremia in AECOPD patients. Then, these findings indicate that pneumonia, metabolic acidosis, and hypomagnesemia were the underlying etiologies of hyponatremia in AECOPD patients. However, their internal connections need further exploration.

Abstract Normal Tau promotes the assembly and stabilization of microtubules, thus, maintaining axon transport. In Alzheimer’s disease (AD), Tau aggregation causes it to lose these above-mentioned functions. However, the molecular mechanism leading to Tau aggregation in AD remains ambiguous. Here, we report that USP10, one of the important deubiquitinases (DUBs), is involved in Tau aggregation. We found that USP10 is upregulated in postmortem human AD and APP/PS1 mice brains, but not in P301S mice brains. Moreover, in primary neuronal cultures, Aβ42 induces a dose-dependent USP10 upregulation, an increase in the levels of both total and phosphorylated Tau, as well as a markedly elevated Tau binding with USP10, that is accompanied by a significantly decreased Tau ubiquitination. In addition, overexpression of USP10 directly causes an increase in the levels of total and phosphorylated Tau, induces Tau aggregation, and delays in Tau degradation. Results from mass spectrometry, reciprocal immunoprecipitation, and immunofluorescence assays strongly prove Tau’s interaction with USP10. This is further supported by the Tau307–326K and Tau341–378K peptides’ competitive inhibition of Tau binding with USP10, attenuating Tau hyperphosphorylation and Tau deubiquitination. Together, our data strongly indicate that USP10 plays a critical role in mediating Tau aggregation via downregulating its ubiquitination and thus slowing down Tau turnover. Inhibition of USP10-Tau interaction might be therapeutically useful in the management of AD and related tauopathies.

IntroductionDepression is the most common comorbidity of rheumatoid arthritis (RA). In particular, major depressive disorder (MDD) and rheumatoid arthritis share highly overlapping mental and physical manifestations, such as depressed mood, sleep disturbance, fatigue, pain, and worthlessness. This overlap and indistinguishability often lead to the misattribution of physical and mental symptoms of RA patients to depression, and even, the depressive symptoms of MDD patients are ignored when receiving RA treatment. This has serious consequences, since the development of objective diagnostic tools to distinguish psychiatric symptoms from similar symptoms caused by physical diseases is urgent.MethodsBioinformatics analysis and machine learning.ResultsThe common genetic characteristics of rheumatoid arthritis and major depressive disorder are EAF1, SDCBP and RNF19B.DiscussionWe discovered a connection between RA and MDD through immune infiltration studies: monocyte infiltration. Futhermore, we explored the correlation between the expression of the 3 marker genes and immune cell infiltration using the TIMER 2.0 database. This may help to explain the potential molecular mechanism by which RA and MDD increase the morbidity of each other.

The adequate assessment of the spontaneous combustion and oxidation characteristics of coking coal can help to reduce its spontaneous combustion potential. In this study, the natural ignition period of the Hex coking coal seam at Ping Coal was calculated based on the programmed-temperature-rise test and the thermal property parameters measured during the spontaneous combustion of the coal. Typical gas concentrations were measured at different oxygen concentrations and coal particle sizes to investigate the changes in the oxygen, carbon–oxygen, and hydrocarbon gas concentrations during the low-temperature oxidation of the coking coal and to determine the indicator gases at different oxidation stages. The following results were obtained: The minimum critical oxygen concentration required for spontaneous ignition was 8%, and fire prevention measures should be implemented below 200 °C. When the temperature of the coal sample reaches 50–60 °C, the rates of CO and CO2 production increase, and when the temperature of the coal sample reaches 100–120 °C, the spontaneous combustion and oxidation of the coal generates alkane gas, in which the coal particle size has a negligible effect on the concentration of each generated gas. CO and C2H4 were selected as the indicator gases for different coking coal oxidation stages, and C2H6 and the C2H4/C2H6 ratio were used as secondary indicators to assist in the analysis. Utilizing the enhanced mathematical model for the shortest spontaneous combustion period of coal seams, in conjunction with a programmed-temperature test device, experimental calculations were conducted to determine the adiabatic spontaneous combustion period. The results indicate that the natural ignition period for the Hex coking coal seam at Ping Coal is approximately 60 days, representing a brief timeframe, and the coal seam is characterized by a high risk of spontaneous combustion.

Abstract Background Fever of unknown origin (FUO) has been difficult to diagnose in pediatric clinical practice. With the gradual change in the disease spectrum, genetic factors have received increasing attention. Limited studies have shown an association between FUO and chromosomal abnormalities. In this study, we investigated the clinical and genetic characteristics of patients with FUO presenting with chromosomal abnormalities in a Chinese pediatric cohort. Results Chromosomal abnormalities were detected in 5.5% (8/145) of the patients with FUO. Six patients with inflammatory fever presented with pharyngitis/amygdalitis (4/6), oral aphthous ulcer (2/6), digestive symptoms (3/6), developmental delay (4/6) and elevated C-reactive protein levels (6/6) during fever. These patients were often considered to have systemic inflammatory diseases, such as Behcet’s disease or systemic juvenile idiopathic arthritis. Trisomy 8, 7q11.23 dup, 3p26.3-p26.1 del/17q12 dup, 22q11.21 del, and 6q23.3-q24.1 del were identified in patients with inflammatory fever. The TNFAIP3 gene was included in the 6q23.3-q24.1 deletion fragment. Two patients with central fever were characterized by facial anomalies, developmental delay, seizures and no response to antipyretic drugs and were identified as carrying the de novo 18q22.3-q23 del. By performing a literature review, an additional 19 patients who had FUO and chromosomal abnormalities were identified. Trisomy 8, 6q23.2-q24.3 del and 18q22.3-q23 del were reported to present as fever, similar to the findings of our study. Conclusions We emphasized the important role of detecting chromosomal abnormalities in patients with FUO, especially in patients with systemic inflammatory manifestations or developmental delay. Identifying chromosomal abnormalities may change the diagnosis and management of patients with FUO.

Abstract Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration, including Alzheimer’s disease (AD). A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development. The interaction between mitophagy deficits and Aβ or Tau pathology may form a vicious cycle and cause neuronal damage and death. Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD. Defective mitophagy is a potential target for AD prevention and treatment.

Abstract Background Persistent high-risk Human papillomavirus (HPV) subtypes infection has been implicated as a causative of cervical cancer. Distribution and genotypes of HPV infection among females and their variations would assist in the formulation of preventive strategy for cervical cancer. The purpose of the present study is to investigate the prevalence of HPV among females in central China. Methods The distribution and genotypes of HPV among 9943 females attending the gynecological examinations in central of China during 2015–2021 were investigated. HPV genotypes were detected using a commercial kit. Nucleotides sequences of L1, E6 and E7 genes in HPV16 or HPV52 positive samples collected in 2021 were amplified by polymerase chain reaction (PCR). Variations of L1, E6 and E7 in HPV16 and HPV52 were gained by sequencing and compared with the reference sequence. Sublineages of HPV16 and HPV52 were determined by the construction of phylogenetic tree based on L1 gene. Results The overall prevalence of HPV infection was 22.81%, with the infection rate of high-risk human papillomavirus (HR-HPV) was 19.02% and low-risk human papillomavirus (LR-HPV) was 6.40%. The most top five genotypes of HPV infection were HPV16 (7.49%), HPV52 (3.04%), HPV58 (2.36%), HPV18 (1.65%) and HPV51 (1.61%). Plots of the age-infection rate showed that the single HPV, multiple HPV, HR-HPV, LR-HPV infection revealed the same tendency with two peaks of HPV infection were observed among females aged ≤ 20 year-old and 60–65 year-old. The predominant sublineage of HPV16 was A1 and B2 for HPV52. For HPV16, The most prevalent mutations were T266A (27/27) and N181T (7/27) for L1, D32E for E6 and S63F for E7 in HPV16. For HPV52, all of the nucleotide changes were synonymous mutation in L1 (except L5S) and E7 genes. The K93R mutation was observed in most HPV52 E6 protein. Conclusions The present study provides basic information about the distribution, genotypes and variations of HPV among females population in Henan province, which would assist in the formulation of preventive strategies and improvements of diagnostic probe and vaccine for HPV in this region.

Abstract Background Traumatic brain injury (TBI) is a debilitating disorder due to trauma caused by an external mechanical force eventually leading to disruption in the normal function of the brain, with possible outcomes including permanent or temporary dysfunction of cognitive, physical, and psychosocial abilities. There have been several studies focusing on the search and innovation of neuroprotective agents that could have therapeutic relevance in TBI management. Due to its complexity, TBI is divided into two major components. The first initial event is known as the primary injury; it is a result of the mechanical insult itself and is known to be irreversible and resistant to a vast variety of therapeutics. The secondary event or secondary brain injury is viewed as a cellular injury that does not manifest immediately after the trauma but evolved after a delay period of hours or several days. This category of injury is known to respond favorably to different pharmacological treatment approaches. Main body Due to the complexity in the pathophysiology of the secondary injury, the therapeutic strategy needs to be in a multi-facets model and to have the ability to simultaneously regulate different cellular changes. Several studies have investigated in deep the possible approaches relying on natural compounds as an alternative therapeutic strategy for the management of TBI. In addition, many natural compounds have the potential to target numerous different components of the secondary injury including neuroinflammation, apoptosis, PP2A, tau, and Aβ among others. Here, we review past and current strategies in the therapeutic management of TBI, focusing on the PP2A-tau axis both in animal and human subjects. This review uncovers, in addition, a variety of compounds used in TBI therapy. Conclusion Despite beneficial therapeutic effects observed in animals for many compounds, studies are still needed to be conducted on human subjects to validate their therapeutic virtues. Furthermore, potential therapeutic virtues observed among studies might likely be dependent on the TBI animal model used and the type of induced injury. In addition, specificity and side effects are challenges in TBI therapy specifically which site of PP2A dysfunction to be targeted.

ObjectiveThe bacterial cellulose membrane (BCM) has been widely studied and applied as a new biomaterial for wound healing, but causes pain with frequent dressing changes. Local application of bone marrow mesenchymal stem cells (BMSCs) requires a niche. Furthermore, the effect and mechanism of the BCM combined with BMSCs have not been reported.MethodsMorphological and chemical identifications of BCMs were investigated by porosity analyses, scanning electron microscopy, and Fourier-transform infrared spectroscopy. Biological wound dressings (BWDs) were prepared by the BCM in combination with BMSCs. The biological effects of BWDs on human dermal fibroblast (HDF) and VEGF-A in human vascular endothelial cells (HuVECs) were detected in vitro, and the effect of BWDs on acute wounds in mice was detected in vivo. Collagen and angiogenesis were evaluated through hematoxylin–eosin staining and Masson staining. The expressions of COL-1 and VEGF-A and the activation of the Notch signaling pathway in vivo and in vitro were detected by quantitative reverse-transcriptase polymerase chain reaction.ResultsThe BCM had a nanoscale structure and provided a partial niche for the survival and proliferation of BMSCs. BWDs were successfully prepared and regulated the biological behaviors of wound healing-related cells in vitro and upregulated the expressions of COL-1 in HDF and VEGF-A in HuVECs. BWDs promoted wound healing by increasing collagen type I synthesis and angiogenesis in acute wounds in mice.ConclusionsBWDs prepared by the combination of nanomaterial BCMs and BMSCs facilitated acute wound healing, which may be regulated by activating the Notch signaling pathway.

We aimed to investigate the immunological mechanisms of the Toll-like receptor (TLR) signaling pathways in different types of Epstein-Barr virus (EBV) infection. We retrospectively summarized the clinical data, routine laboratory tests and the immunological function of the infectious mononucleosis (IM) and chronic active EBV infection (CAEBV) patients. A real-time quantitative PCR array was used to detect the mRNA expression levels of TLR7/TLR9 and myeloid-differentiation factor 88 (MyD88). Flow cytometry was used to detect the protein expression of TLR7/TLR9. The MyD88 and nuclear factor-κB (NF-κB) (p65) protein were detected by western blotting. A cytometric bead array (CBA) assay was used to detect the expression of downstream cytokines. CAEBV patients presented with increased expression of TLR7/TLR9 in monocytes and B lymphocytes. TLR9 expression in the B lymphocytes of IM patients was decreased compared with the CAEBV pateints. Downstream signaling mediators, including MyD88 and NF-κB, were revealed to be increased in EBV-infected patients. Moreover, the expression of MyD88 and NF-κB was higher in CAEBV patients, leading to disrupted balance of downstream cytokines. EBV may activate the immune system via TLR7/TLR9 signaling pathways. Moreover, the overactivated TLR7/TLR9 pathway in CAEBV patients resulted in excessive inflammation, which might be relevant to the poor prognosis.

Due to the improvement in miniaturization and practicability of polarization conversion devices, the terahertz polarization control technology has been paid more and more attention. Nevertheless, a critical factor in restricting its development is short of dynamic and multifunctional materials. Ferromagnetic shape memory alloys (FSMAs) provide a novelty solution for tunable metamaterials because of their excellent recovery deformation, non-contact control, and fast response. Here, a new magnetic-induced tunable THz metamaterial is proposed, composed of Ni-Mn-Sn FSMAs resonator in strip structure, polyimide dielectric, and metal copper substrate. Numerical results reveal that the polarization converter can realize any in a broad band between 1.04 and 1.96 THz by applying different magnetic fields to adjust the elastic deformation of Ni-Mn-Sn. Notably, the device can also realize line circularly polarized light conversion in the range of 0.87–0.92 THz and 2.07–2.12 THz. Compared to the current state-of-the-art double functional polarization converter, the THz converter proposed in this work offers benefits in many respects, including the 61.3% relative bandwidth and high conversion efficiency. Our study provides an excellent strategy to develop actively tunable and multifunctional THz compact devices.

Morphology of hydraulic fracture surface has significant effects on oil and gas flow, proppant migration and fracture closure, which plays an important role in oil and gas fracturing stimulation. In this paper, we analyzed the fracture surface characteristics induced by supercritical carbon dioxide (SC-CO2) and water in open-hole and perforation completion conditions under triaxial stresses. A simple calculation method was proposed to quantitatively analyze the fracture surface area and roughness in macro-level based on three-dimensional (3D) scanning data. In micro-level, scanning electron micrograph (SEM) was used to analyze the features of fracture surface. The results showed that the surface area of the induced fracture increases with perforation angle for both SC-CO2 and water fracturing, and the surface area of SC-CO2-induced fracture is 6.49%–58.57% larger than that of water-induced fracture. The fractal dimension and surface roughness of water-induced fractures increase with the increase in perforation angle, while those of SC-CO2-induced fractures decrease with the increasing perforation angle. A considerable number of microcracks and particle peeling pits can be observed on SC-CO2-induced fracture surface while there are more flat particle surfaces in water-induced fracture surface through SEM images, indicating that fractures tend to propagate along the boundary of the particle for SC-CO2 fracturing while water-induced fractures prefer to cut through particles. These findings are of great significance for analyzing fracture mechanism and evaluating fracturing stimulation performance.

Abstract Background Macular corneal dystrophy (MCD) is a rare corneal stromal dystrophy with bilateral progressive vision loss. The pathogenic gene of MCD is carbohydrate sulfotransferase 6 (CHST6). Herein, we report a novel missense mutation and a rare exon deletion mutation in the CHST6 gene in a Chinese family with MCD. Methods Genomic DNA was extracted from the peripheral blood, and next generation sequencing was used to analyse the gene sequence. The pathogenic mutations were identified in all affected family members. The proband successively received binocular penetrating keratoplasty (PKP), and the corneas were examined by histopathology and colloidal iron staining to prove the diagnosis. A long-term follow-up was made to observe the changes after PKP. Results Genetic analysis demonstrated hemizygous mutations in the proband, including a novel c.520A>C (p.K174Q) missense mutation and a rarely reported exon 3 deletion mutation, which were co-segregated with the MCD phenotypes in the pedigree. The positive colloidal iron staining confirmed the diagnosis of MCD in the proband. However, the clinical phenotype and pathological manifestation of both eyes were different from each other because of complicated keratitis in the left eye. During the nine years of follow-up, visual acuity was improved significantly, and the cornea was transparent without rejection and postoperative recurrence in both eyes. Conclusions The novel hemizygous mutations were thought to contribute to the loss of CHST6 function, which induced typical clinical and pathological features of MCD. PKP was an effective treatment for MCD.

The burn wound is a dynamic living environment that is affected by many factors. It may present a progressive expansion of necrosis into the initially viable zone of stasis within a short time postburn. Therefore, how to salvage of the zone of stasis is of crucial importance in prevention and treatment strategies of burn wound progressive deepening. This review focuses on the cellular basis of tissue injury and the current progress of prevention and treatment strategies of burn wound progressive deepening, in order to provide references for the treatment of burn wounds in the early phase.

Purpose: Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency can lead to reduced nicotinamide adenine dinucleotide phosphate oxidase activity in phagocytes, resulting in immunodeficiency, with a limited number of reported cases. Here, we aimed to report a child with severe G6PD deficiency in China and investigate the mechanism of his recurrent infections.Methods: The clinical manifestations and immunological phenotypes of this patient were retrospectively collected. Gene mutation was detected by whole-exome sequencing and confirmed by Sanger sequencing. Dihydrorhodamine (DHR) analysis was performed to measure the respiratory burst of neutrophils. Messenger ribonucleic acid and protein levels were detected in the patient under lipopolysaccharide stimulation by real-time quantitative reverse transcription polymerase chain reaction and Western blot. A review of the literature was performed.Results: A male child with G6PD deficiency presented with recurrent respiratory infections, Epstein‒Barr virus infection and tonsillitis from 8 months of age. Gene testing revealed that the proband had one hemizygous mutation in the G6PD gene (c.496 C>T, p. R166C), inherited from his mother. This mutation might affect hydrophobic binding, and the G6PD enzyme activity of the patient was 0. The stimulation indexes of the neutrophils in the patient and mother were 22 and 37, respectively. Compared with healthy controls, decreased reactive oxygen species (ROS) production was observed in the patient. Activation of nuclear factor kappa-B (NF-κB) signaling was found to be influenced, and the synthesis of tumor necrosis factor alpha (TNF-α) was downregulated in the patient-derived cells. In neutrophils of his mother, 74.71% of the X chromosome carrying the mutated gene was inactivated. By performing a systematic literature review, an additional 15 patients with severe G6PD deficiency and recurrent infections were identified. Four other G6PD gene mutations have been reported, including c.1157T>A, c.180_182del, c.514C>T, and c.953_976del.Conclusion: Severe G6PD deficiency, not only class I but also class II, can contribute to a chronic granulomatous disease-like phenotype. Decreased reactive oxygen species synthesis led to decreased activation of the NF-κB pathway in G6PD-deficient patients. Children with severe G6PD deficiency should be aware of immunodeficiency disease, and the DHR assay is recommended to evaluate neutrophil function for early identification.

BackgroundSevere drug hypersensitivity reactions (DHRs) refer to allergic reactions caused by drugs and usually present with severe skin rashes and internal damage as the main symptoms. Reporting of severe DHRs in hospitals now solely occurs through spontaneous reporting systems (SRSs), which clinicians in charge operate. An automatic identification system scrutinizes clinical notes and reports potential severe DHR cases. ObjectiveThe goal of the research was to develop an automatic identification system for mining severe DHR cases and discover more DHR cases for further study. The proposed method was applied to 9 years of data in pediatrics electronic health records (EHRs) of Beijing Children’s Hospital. MethodsThe phenotyping task was approached as a document classification problem. A DHR dataset containing tagged documents for training was prepared. Each document contains all the clinical notes generated during 1 inpatient visit in this data set. Document-level tags correspond to DHR types and a negative category. Strategies were evaluated for long document classification on the openly available National NLP Clinical Challenges 2016 smoking task. Four strategies were evaluated in this work: document truncation, hierarchy representation, efficient self-attention, and key sentence selection. In-domain and open-domain pretrained embeddings were evaluated on the DHR dataset. An automatic grid search was performed to tune statistical classifiers for the best performance over the transformed data. Inference efficiency and memory requirements of the best performing models were analyzed. The most efficient model for mining DHR cases from millions of documents in the EHR system was run. ResultsFor long document classification, key sentence selection with guideline keywords achieved the best performance and was 9 times faster than hierarchy representation models for inference. The best model discovered 1155 DHR cases in Beijing Children’s Hospital EHR system. After double-checking by clinician experts, 357 cases of severe DHRs were finally identified. For the smoking challenge, our model reached the record of state-of-the-art performance (94.1% vs 94.2%). ConclusionsThe proposed method discovered 357 positive DHR cases from a large archive of EHR records, about 90% of which were missed by SRSs. SRSs reported only 36 cases during the same period. The case analysis also found more suspected drugs associated with severe DHRs in pediatrics.

Concerning the ubiquity of social media, this research tried to examine the impacts of using Telegram on Iranian EFL learners’ foreign language motivation, foreign language anxiety, and attitude toward learning. To achieve these purposes, 60 Iranian EFL learners at the intermediate level were selected and randomly divided into two groups: experimental and control. After that, both groups were pretested on motivation and anxiety variables. After pretesting, the participants in the experimental class received treatment via using the Telegram application, and the control students were trained traditionally without using any social media. After an 18-session instruction, a post-test of motivation and a post-test of anxiety were given to both groups, and also an attitude questionnaire was distributed among the experimental group to inspect their attitudes toward the Telegram application in language learning. The results of using two one-way ANCOVA tests showed significant differences between the post-tests of the control and experimental groups in favor of the experimental group. The findings demonstrated that using the Telegram application increased the motivation of the experimental group and decreased their level of foreign language anxiety. Also, the results of one sample t-test showed that the participants of the experimental group held positive attitudes toward using the Telegram application in English language learning. The implications of this research can encourage both teachers and learners to use social media-based instruments in English teaching and learning.

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen. Patients with inborn errors of immunity (IEI) have been increasingly diagnosed with T. marneffei in recent years. The disseminated infection of T. marneffei can be life-threatening without timely and effective antifungal therapy. Rapid and accurate pathogenic microbiological diagnosis is particularly critical for these patients. A total of 505 patients with IEI were admitted to our hospital between January 2019 and June 2022, among whom T. marneffei was detected in 6 patients by metagenomic next-generation sequencing (mNGS), and their clinical and immunological characteristics were summarized. We performed a systematic literature review on T. marneffei infections with published immunodeficiency-related gene mutations. All patients in our cohort were confirmed to have genetic mutations in IL12RB1, IFNGR1, STAT1, STAT3, and CD40LG. T. marneffei was detected in both the blood and lymph nodes of P1 with IL12RB1 mutations, and the clinical manifestations were serious and included recurrent fever, weight loss, severe anemia, splenomegaly and lymphadenopathy, all requiring long-term antifungal therapy. These six patients received antifungal treatment, which relieved symptoms and improved imaging findings. Five patients survived, while one patient died of sepsis after hematopoietic stem cell transplantation. The application of mNGS methods for pathogen detection in IEI patients and comparison with traditional diagnosis methods were investigated. Traditional diagnostic methods and mNGS tests were performed simultaneously in 232 patients with IEI. Compared to the traditional methods, the sensitivity and specificity of mNGS in diagnosing T. marneffei infection were 100% and 98.7%, respectively. The reporting time for T. marneffei detection was approximately 26 hours by mNGS, 3-14 days by culture, and 6-11 days by histopathology. T. marneffei infection was first reported in IEI patients with IL12RB1 gene mutation, which expanded the IEI lineage susceptible to T. marneffei. For IEI patients with T. marneffei infection, we highlight the application of mNGS in pathogenic detection. mNGS is recommended as a front-line diagnostic test for rapidly identifying pathogens in complex and severe infections.

Terahertz absorbers have been extensively investigated by researchers due to their applications in thermophotovoltaic energy conversion and sensors, but a key factor limiting their development is the lack of vital and versatile materials. Ferromagnetic shape memory alloys (FSMAs) offer a novel remedy for tunable metamaterials due to their brilliant recovery of deformation, remote control, and transient response. In this study, we propose a tunable absorber based on magnetic field tuning, consisting of Ni–Mn–Sn ferro-magnetic shape memory alloy films in fractal geometry and optically excited Si plates. Numerical analysis shows that the proposed absorber has an absorbance bandwidth of 1.129 THz above 90% between 1.950 THz and 3.079 THz. The absorber geometry can be regulated by an external magnetic field, allowing dynamic switching between broadband and narrowband absorption modes, the latter showing an ultra-narrow bandwidth and a high-quality factor Q of ~25.8. The proposed terahertz absorber has several advantages over current state-of-the-art bifunctional absorbers, including its ultra-thin structure of 10.39 μm and an additional switching function. The absorption can be continuously tuned from 90% to 5% when the light-excited silicon plate is transferred from the insulator state to the metal state. This study presents a promising alternative strategy for developing actively regulated and versatile terahertz-integrated devices.

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.

BackgroundActivated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM.ObjectiveTo explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS.MethodsClinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells.ResultsThe patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient’s DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes.ConclusionsThe present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.