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Background: As the population aging progresses, age-related osteoporosis has become one of the most common and severe chronic degenerative diseases. Due to insufficient understanding of its complex pathomechanisms, current clinical treatments often suffer from many negative effects. Type H vessels play critical role in bone remodeling owing to their specialized function in coupling angiogenesis and osteogenesis. Increasing evidences have shown a close association between the age-related decline of type H vessels and bone loss. However, the underlying mechanisms whereby the regression of type H vessels with aging remain largely unknown. Methods: Col2-CreERT/Foxo1flox/flox mice and FOXO1 inhibitor (AS1842856) treated adult (6 months) and middle aged (10 months) mice were utilized for evaluating the variations in bone volume, bone microarchitecture and type H vessels through micro-CT scanning analysis, histological staining and immunofluorescence staining. In vitro tube-forming and scratch assays were applied to evaluate the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) exposed to AS1842856 or conditioned culture milieu of Human Brain Vascular Pericytes (HBVPs). The expression of pericyte marker proteins, myofibroblast-related proteins and genes in inhibitors-stimulated HBVPs were detected via western blot analysis and Reverse transcription-quantitative PCR (RT-qPCR). Furthermore, perivascular myofibroblastic-like transformation was confirmed in AS1842856-treated animal models through immunofluorescence staining. We also constructed Adipoq-Cre/Foxo1flox/flox conditional knockout mice and measured their bone mass and type H vessels by micro-CT and immunofluorescence staining. Mechanistic experiments in vitro were conducted via detection of mTOR signalling expression in HBVPs with pharmacological intervention (AS1842856 and rapamycin), genetic knockdown of Foxo1, or FOXO1-overexpression plasmid treatment, verified by RT-qPCR, western blot analysis and cellular immunofluorescence staining. In vivo validation was conducted on Adipoq-Cre/Foxo1flox/flox mice using immunofluorescence staining. Finally, alterations in osteo-morphology and type H vessels were verified in AS1842856-treated and rapamycin-treated aged mouse models. Results: This study identified FOXO1 in pericytes as key components for the formation of type H vessels. We found that FOXO1 expression in pericytes decreases with aging, and pharmacological blocking with AS1842856 promoted type H vessels degeneration and increased bone loss in adult and middle-aged mice, while rapamycin prevented the above pathology in middle-aged mice. We further showed that the loss of FOXO1 in Adipoq+ pericytes led to degeneration of type H vessels and bone loss in mice. Mechanistically, the inhibition of FOXO1 by AS1842856 or knockdown of Foxo1 by siRNAs activated mTOR signaling, thereby resulting in the myofibroblastic transformation of pericytes. Furthermore, blocking mTOR signaling by rapamycin rescued the above effects in vitro and in vivo. Conclusion: Our findings uncover a hitherto unknown role of FOXO1 in maintaining the phenotype and function of pericytes, thereby promoting formation of type H vessels. This suggests that targeting the FOXO1-mTOR pathway in pericytes could be a potential therapeutic approach to overcome the regression of type H vessels and bone degeneration with aging. The translational potential of this article: Our research uncovers a previously unidentified role of FOXO1 in preserving pericyte characteristics and promoting the development of type H vessels. Future translational research targeting the FOXO1-mTOR pathway in pericytes may provide new strategies for the prevention and treatment of age-related osteoporosis in the clinic.

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

Abstract The nematode Caenorhabditis elegans is widely employed as a model organism to study basic biological mechanisms. However, transgenic C. elegans are generated by manual injection, which remains low-throughput and labor-intensive, limiting the scope of approaches benefitting from large-scale transgenesis. Here, we report a robotic microinjection system, integrating a microfluidic device capable of reliable worm immobilization, transfer, and rotation, for high-speed injection of C. elegans. The robotic system provides an injection speed 2-3 times faster than that of experts with 7–22 years of experience while maintaining comparable injection quality and only limited trials needed by users to become proficient. We further employ our system in a large-scale reverse genetic screen using multiplexed alternative splicing reporters, and find that the TDP-1 RNA-binding protein regulates alternative splicing of zoo-1 mRNA, which encodes variants of the zonula occludens tight junction proteins. With its high speed, high accuracy, and high efficiency in worm injection, this robotic system shows great potential for high-throughput transgenic studies of C. elegans.

Abstract Capsular polysaccharide is an important virulence factor of Glaesserella parasuis. An acapsular mutant displays multiple phenotype variations, while the underlying mechanism for these variations is unknown. In this study, we created an acapsular mutant by deleting the wza gene in the capsule locus. We then used transcriptome analysis to compare the gene expression profiles of the wza deletion mutant with those of the parental strain to understand the possible reasons for the phenotypic differences. The mutant Δwza, which has a deleted wza gene, secreted less polysaccharide and lost its capsule structure. The Δwza exhibited increased autoagglutination, biofilm formation and adherence to eukaryotic cells, while the complementary strain C-Δwza partially restored the phenotype. Transcriptome analysis revealed several differentially expressed genes (DEGs) in Δwza, including up-regulated outer membrane proteins and proteins involved in peptidoglycan biosynthesis, suggesting that wza deletion affects the cell wall homeostasis of G. parasuis. Transcriptome analysis revealed the contribution of non-coding RNAs in the regulation of DEGs. Moreover, a new virulence-associated trimeric autotransporter, VtaA31 is upregulated in Δwza. It is responsible for enhanced autoagglutination but not for enhanced biofilm formation and adherence to eukaryotic cells in Δwza. In conclusion, these data indicate that wza affects the expression of multiple genes, especially those related to cell wall synthesis. Furthermore, they provide evidence that vtaA31 is involved in the autoagglutination of G. parasuis.

Abstract The Canadian Arctic Archipelago consists of important international trade routes, and local surface air temperatures (SAT) greatly control sea ice melting in situ during boreal summer (June-July-August-September). However, the drivers of the Arctic Archipelago summer SAT variability have not yet been fully elucidated. Here, we find that the impact of tropical Indo-Pacific convection on the Arctic Archipelago SAT through induced poleward-propagating Rossby wave train is strongly modulated by Russian Arctic sea surface temperature anomalies (SSTA). Negative Russian Arctic SSTA lead to a weakened East Asia westerly jet via equatorward Rossby wave activity. The weakened westerly jet enhances the meridional gradient of the potential vorticity over the North Pacific, guiding the poleward-propagating Rossby wave to the Arctic Archipelago and therefore affecting the local SAT. Conversely, positive Russian Arctic SSTA impede the northward-propagating Rossby wave via enhancing the East Asia westerly jet, resulting in a weakened relationship between the tropical Indo-Pacific convection and Arctic Archipelago SAT. The present study proposes a mechanism whereby changes in the Tropical-Arctic connection stem from thermal conditions elsewhere in the Arctic, through shaping poleward-propagating Rossby waves by changing the background mean flow.

The research focused on addressing various challenges in intelligent top caving theory, intelligent perception and recognition key technology, intelligent caving comprehensive decision-making technology, and remote caving intelligent control technology of fully mechanized top coal caving face. This is being done under the “13th Five-Year” national key research and development plan, specifically designed for the key technology and demonstration of intelligent fully mechanized top coal caving mining method with annual production of 10 million of tons in extra-thick coal seam. The research has resulted in the following outcomes: ① Comprehensive experiments were conducted to understand the interaction process of crushing and migrating of roof and top coal combination (RTCC) and the fragmentation distribution of RTCC under different roof conditions. A three-dimensional laser goaf space detection technology has been developed, and the arching phenomenon of top coal blocks on contact, at coal discharge process with multiple coal discharge ports, has been validated. In addition, the numerical simulation of multi-port intelligent coal caving in extra-thick coal seam is carried out with the constraints of mining and caving coordination, high recovery rate, and low gangue ratio, and the number of coal caving ports is determined. those provide a reliable theoretical basis for optimizing intelligent coal-caving processes. ②The research has explored the geological information and physical characteristics of coal and gangue in the working face, along with full-cycle sensing elements of the top coal caving process. This has led to the development of a comprehensive sensing technology system, including real time detection of top coal thickness, accurate identification of coal and gangue, and dynamic measurement of coal flow, providing crucial data information support for decision making of intelligent coal top caving technology. ③A multi-source information database has been established for the man-machine-environment interface, and a decision-making model has been developed for fully mechanized top caving in extra-thick coal seams. An intelligent coal top caving decision-making software based on the Q-learning algorithm has been created, utilizing artificial intelligence for coal and gangue identification, top coal thickness detection, and coal quantity monitoring. ④A high-precision inertial navigation monitoring and control technology for intelligent fully mechanized caving faces has been developed, enabling real-time positioning, attitude monitoring, and action control for the shearer, hydraulic support, and scraper conveyor. An intelligent mine-integrated communication scheduling system and a remote-integrated control platform for fully mechanized caving have also been established. Those allow for the successful implementation of intelligent coal caving in remote one-button start mode. ⑤Advanced technologies such as ground-penetrating radar for top coal thickness detection, vibration-audio-hyperspectral for coal-gangue identification, and laser three-dimensional scanning for real-time coal caving monitoring are utilized in the 8222 Working Face of Tashan Mine. Intelligent coal caving decision software is applied in fully mechanized caving operations, leading to a control of errors within 10.71% for top coal thickness detection, 9.32% for mixed gangue rate, and 7.8% for coal caving amount. On average, each coal caving cycle now saves about 30 minutes, leading to intelligent and efficient coal caving operations with an annual output of 15 million tons.

Abstract Background Calcaneal osteomyelitis (CO) poses a formidable challenge in treatment due to the distinct anatomical structure and functional properties of the calcaneus. The present study endeavors to furnish a thorough and comprehensive understanding of the clinical manifestations, therapeutic strategies, and therapeutic outcomes pertaining to pediatric calcaneal osteomyelitis (PCO) by conducting a meticulous synthesis and analysis of cases reported in the literature. Methods A systematic search of the PubMed, Embase, and Cochrane Library databases was conducted to identify English-language studies analyzing PCO between 2000 and 2021. The quality of the included studies was assessed using the National Institutes of Health (NIH) assessment scale. Effective data were extracted and analyzed. Results A total of 42 studies, encompassing 128 patients, fulfilled the established inclusion criteria. The gender distribution revealed a male-to-female ratio of 2:1 (81 boys and 40 girls). The median age at the time of diagnosis was 8 years, while the median duration of symptoms was 0.6 month. Trauma emerged as the primary etiology (41 cases, 54%), and limited activity was the most prevalent symptom (68 cases). The positive rate for pathogen culture was 75.4% (49/65), with Staphylococcus aureus being the most commonly isolated pathogen (28 cases, 57.1%). Surgical intervention was performed in 51% (64/126) of the patients, with debridement serving as the primary surgical strategy. The rate of infection recurrence was 6.8% (8/118), and the risk of below-knee amputation was 0.8% (1/124). Conclusions PCO occurred more frequently in male patients, with trauma being the primary underlying cause and Staphylococcus aureus being the most prevalent bacterial pathogen isolated. Over half of the patients underwent surgical intervention. Nonetheless, it is imperative that treatment strategies undergo further refinement, as approximately 7% of patients experienced infection recurrence.

Abstract Anxiety among pregnant women can significantly impact their overall well-being. However, the development of data-driven HCI interventions for this demographic is often hindered by data scarcity and collection challenges. In this study, we leverage the Empatica E4 wristband to gather physiological data from pregnant women in both resting and relaxed states. Additionally, we collect subjective reports on their anxiety levels. We integrate features from signals including Blood Volume Pulse (BVP), Skin Temperature (SKT), and Inter-Beat Interval (IBI). Employing a Support Vector Machine (SVM) algorithm, we construct a model capable of evaluating anxiety levels in pregnant women. Our model attains an emotion recognition accuracy of 69.3%, marking achievements in HCI technology tailored for this specific user group. Furthermore, we introduce conceptual ideas for biofeedback on maternal emotions and its interactive mechanism, shedding light on improved monitoring and timely intervention strategies to enhance the emotional health of pregnant women.

In response to the challenges posed by frequent, widespread, long-lasting, large-scale, severe, and difficult-to-control debris flows in strong earthquake areas, this study, based on the results of the National Key R&D Program, investigates dozens of typical mega debris flow gullies in these regions. Through test verification and demonstration engineering application, the characteristics of typical debris flow ditches and their prevention and control engineering effects were studied, leading to the construction of a comprehensive technical system for the prevention and control of mega debris flows in strong earthquake areas. A key technical system for exploration, design, prevention, and control of mega debris flows in strong earthquake areas was formed. The exploration and design system introduced new technologies for identifying earthquake-induced fracturing sources and novel approaches for determining blocking coefficients based on existing exploration technologies. According to the morphology of debris flow valleys in seismic areas, debris flows are classified as narrow and steep or wide and gentle. The key technology system for prevention and control was established to comprehensively discuss and practice key technologies for preventing and controlling debris flows in different valley morphologies. Considering the characteristics of debris flow valleys in the upper, middle, and lower reaches of both narrow and steep or wide and gentle debris flow valleys, a combination of various comprehensive prevention and control measures was proposed. This led to the establishment of a hierarchical control system for major debris flows in seismic areas, from controlling the source to the process and ultimately mitigating disasters. This system not only provides technical support for comprehensive prevention and control of debris flows in seismic areas but also serves as a reference for comprehensive prevention and control of debris flows in non-seismic areas.

Abstract Background Owing to the lack of evidence-based medical studies with large sample sizes, the surgical approach for the radical resection of rectal neuroendocrine tumors remains controversial. Methods We retrospectively collected the medical records of patients with rectal neuroendocrine tumors who underwent radical resection at 17 large tertiary care hospitals in China between January 1, 2010, and April 30, 2022. All patients were divided into laparoscopic and open surgery groups. After propensity score matching to reduce confounders, the postoperative and oncologic outcomes were compared between the groups. Results We enrolled 174 patients with rectal neuroendocrine tumors who underwent radical surgery. After random matching, 124 patients were included in the comparison (62, laparoscopic surgery group; 62, open surgery group). The laparoscopic surgery group had fewer complications (14.5% vs. 35.5%, P = 0.007) and superior relapse-free survival (P = 0.048). Subgroup analysis revealed that the laparoscopic surgery group had fewer complications (10.9% vs. 34.7%, P = 0.004), shorter postoperative hospital stays (9.56 ± 5.21 days vs. 12.31 ± 8.61 days, P = 0.049) and superior relapse-free survival (P = 0.025) in the rectal neuroendocrine tumors ≤ 4 cm subgroup. Conclusions Laparoscopic surgery was associated with improved postoperative outcomes and oncologic prognosis for patients with rectal neuroendocrine tumors ≤ 4 cm; it can serve as a safe and feasible option for radical surgery of rectal neuroendocrine tumors.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

In order to solve the problem that current theory models cannot accurately describe thick-hard roof (THR) elastic energy and assess the mine tremor disasters, a theoretical method, a Timoshenko beam theory on Winkler foundation was adopted to establish the THR’s periodic breaking model. The superposition principle was used for this complex model to derive the calculation formulas of the elastic energy and impact load on hydraulic supports. Then, the influence of roof thickness h, cantilever length L1, and load q on THR’s elastic energy and impact load was analyzed. And, the effect of mine tremor disasters was assessed. Finally, it is revealed that: (1) The THR’s elastic energy U exhibits power-law variations, with the fitted relationships U=0.0096L13.5866, U=5943.9h−1.935, and U=21.049q2. (2) The impact load on hydraulic supports FZJ increases linearly with an increase in the cantilever length, thickness, and applied load. The fitted relationships are FZJ=1067.3L1+6361.1, FZJ=125.89h+15100, and FZJ=10420q+3912.6. (3) Ground hydraulic fracturing and liquid explosive deep-hole blasting techniques effectively reduce the THR’s cantilever length at periodic breakages, thus eliminating mine tremor disasters.

Abstract Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases.

Summary Background The descending genicular artery (DGA) and medial thigh region have been underused as donor sites for perforator flaps. This study evaluated the anatomical relationship between the perforators of the DGA and the saphenous vein (SV) to review the clinical applications of the free descending genicular artery perforator (DGAP) flap for locoregional reconstruction. Methods Fifteen cadavers were arterially perfused with red latex and dissected. Thirty-one patients with extremity tissue defects were treated with a free DGAP flap, including six patients who received a chimeric flap. The minimum distance between the DGAP and the SV was measured during surgery. Results In all patients, the skin branch of the descending genicular artery was found in the medial femoral condyle plane in front of the SV. The average distance between the descending genicular artery perforator and the SV was 3.71 ± 0.38 cm (range: 2.9–4.3 cm). Thirty flaps survived completely, and one flap developed partial necrosis; however, this flap healed two weeks after skin grafting. The average follow-up time was 11.23 months. Conclusions We conclude that the SV can be preserved when harvesting the descending genicular artery perforator flap, causing less damage to the donor site and having no effect on flap survival. The free descending genicular artery perforator flap without the SV is a better therapy for complicated tissue defects.

Abstract The Shibing Karst constitutes a pivotal component of the "South China Karst," and its ecosystem health integrity crucially influences the Outstanding Universal Value (OUV) of the corresponding Natural World Heritage (NWH). Consequently, robust ecosystem health assessment (EHA) is imperative for the judicious conservation and management of this heritage, as well as for the sustainable progression of the region. This research assessed the health of the Shibing Karst ecosystem from 2004 to 2020 by employing changes in landscape patterns through the Vigor-Organization-Resilience-Ecosystem Services (VORS) model. Spatial autocorrelation was employed to discern the spatial coherence and evolutionary patterns of ecosystem health, whereas a geo-detector ascertained the pivotal determinants impacting regional ecosystem vitality. The findings revealed that: (1) The landscape patterns distribution in the study area exhibited considerable constancy, primarily comprising forest land, with a rising trajectory in construction land and water, juxtaposed with a recession in shrubland, grassland, paddy land, and dryland expanses. (2) From 2004 to 2020, the ecosystem of the study area maintained its health and remained stable, with mean values of 0.8303, 0.7689, 0.6976, and 0.7824, respectively, showing an evolutionary trend of an initial downtrend trend followed by an upswing, with 2016 marking a pivotal juncture. (3) Spatial clustering analysis highlighted significant clustering characteristics of ecosystem health, with a nominal decrease in the Global Moran's I index from 0.666 to 0.665, which is indicative of a subtle decrease in clustering over time. High-high clustering areas were predominantly located within the World Heritage Site (WHS), while low-low clustering areas were mainly distributed in the southeastern part of buffer zone. (4) Land use and cover change (LUCC) and Ecosystem Services (ESs) were identified as the primary indexes of EHA, with Ecosystem Resilience (ER), Ecosystem Vigor (EV), and Ecosystem Organization (EO) exerting relatively mild influences. This study provides a scientific framework for policymakers in local governance to devise strategies for ecosystem conservation and management, enhances the analytical perspective on the integrity and conservation of Karst Natural World Heritage (KNWH).

ObjectivesGastric papillary adenocarcinoma (GPA), a well-differentiated gastric adenocarcinoma, is associated with a worse prognosis compared to other differentiated gastric adenocarcinomas. Therefore, there is an urgent need to characterize its endoscopic manifestations for guiding biopsy site selection and achieving accurate diagnosis.MethodsFrom January 1, 2016, to December 31, 2022, the data of 46 cases of early gastric papillary adenocarcinoma (EGPA) and 183 cases of early gastric differentiated tubular adenocarcinoma (EGDTA) diagnosed via pathological examination following endoscopic submucosal dissection (ESD) at the Second Hospital of Shandong University were collected. Propensity score matching (PSM) was employed to match 92 EGDTA patients at a ratio of 1:2, serving as the control group. Differences between the two groups were analyzed using multivariable logistic regression. Lastly, the relationship between vessels within epithelial circle (VEC) structures in EGPA and the degree of malignancy was assessed.ResultsCompared with EGDTA, EGPA was more likely to infiltrate the submucosa, more frequently associated with poorly differentiated cancer components, and more prone to invading lymphatic and blood vessels. EGPA was primarily located in the lower stomach and manifested as a uniformly elevated pattern under endoscopy, while VEC structural positivity could be visualized under ME-NBI. Moreover, EGPA lesions had larger diameters and were characterized by high expression of gastric mucins, namely MUC5AC and MUC6. When EGPA infiltrated the submucosa or contained poorly differentiated cancer components, the VEC structures were smaller.ConclusionsThe present study demonstrated that EGPA exhibits a higher degree of malignancy. Endoscopic findings of a raised lesion with a uniform color under endoscopy and the presence of VEC structures under ME-NBI suggest a high possibility of EGPA. Moreover, smaller VEC structures were associated with a higher degree of malignancy, which may assist in guiding the selection of biopsy sites under endoscopy.

ObjectivesWe focus on utilizing the Labyrinth system for the detection of circulating tumor cells (CTCs) in patients with lung nodules. Our aim is to evaluate CTCs isolated through the Labyrinth system as a biomarker for early-stage lung cancer (LC) detection.Methods167 patients with low dose computed tomography (LDCT) diagnostic results for lung nodules and 31 healthy volunteers (HV) were enrolled. Blood samples were processed for CTC detection. LDCT positive (LDCT+) patients underwent surgery and were categorized into those with LC and those with benign lung diseases (BLD) based on their biopsy results. BLD Patients, LDCT negative (LDCT-) patients and HV served as controls. The correlation of CTC counts with LC, BLD, LDCT- and HV was investigated. Receiver operating characteristic (ROC) curves were used to assess the Labyrinth system’s diagnostic potential for early-stage LC.ResultsMedian CTC counts for LC, BLD, LDCT- and HV were 2.7 CTC/mL, 0.6 CTC/mL, 0.4 CTC/mL, 0 CTC/mL, respectively. Statistical analysis indicated CTC counts could distinguish LC from BLD, LDCT- and HV (p-Values < 0.001). Using a cut-off of 1 CTC/mL, the study showed 84.4% sensitivity and 82.4% specificity for LDCT+ patients. Specificity increased to 85.9% for patients with lung nodules and 88.2% for all participants. In conclusion, CTCs detected by the Labyrinth system can serve as a biomarker for early-stage LC detection for patients with lung nodules.ConclusionsCTCs identified by the Labyrinth system are a promising biomarker for early-stage LC detection in clinical practice.

To conduct a comprehensive investigation of the sarcoma immune cell infiltration (ImmCI) patterns and tumoral microenvironment (TME). We utilized transcriptomic, clinical, and mutation data of sarcoma patients (training cohort) obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) server. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithms were applied to decipher the immune cell infiltration landscape and TME profiles of sarcomas. An unsupervised clustering method was utilized for classifying ImmCI clusters (initial clustering) and ImmCI-based differentially expressed gene-driven clusters (secondary clustering). Mortality rates and immune checkpoint gene levels was analyzed among the identified clusters. We calculated the ImmCI score through principal component analysis. The tumor immune dysfunction evaluation (TIDE) score was also employed to quantify immunotherapy efficacy between two ImmCI score groups. We further validated the biomarkers for ImmCI and gene-driven clusters via experimental verification and the accuracy of the ImmCI score in predicting survival outcomes and immunotherapy efficacy by external validation cohorts (testing cohort). We demonstrated that ImmCI cluster A and gene-driven cluster A, were beneficial prognostic biomarkers and indicators of immune checkpoint blockade response in sarcomas via in-silico and laboratory experiments. Additionally, the ImmCI score exhibited independent prognostic significance and was predictive of immunotherapy response. Our research underscores the clinical significance of ImmCI scores in identifying sarcoma patients likely to respond to immunotherapy.

Injury to the peripheral nervous system disconnects targets to the central nervous system, disrupts signal transmission, and results in functional disability. Although surgical and therapeutic treatments improve nerve regeneration, it is generally hard to achieve fully functional recovery after severe peripheral nerve injury. A better understanding of pathological changes after peripheral nerve injury helps the development of promising treatments for nerve regeneration. Single-cell analyses of the peripheral nervous system under physiological and injury conditions define the diversity of cells in peripheral nerves and reveal cell-specific injury responses. Herein, we review recent findings on the single-cell transcriptome status in the dorsal root ganglia and peripheral nerves following peripheral nerve injury, identify the cell heterogeneity of peripheral nerves, and delineate changes in injured peripheral nerves, especially molecular changes in neurons, glial cells, and immune cells. Cell-cell interactions in peripheral nerves are also characterized based on ligand-receptor pairs from coordinated gene expressions. The understanding of cellular changes following peripheral nerve injury at a single-cell resolution offers a comprehensive and insightful view for the peripheral nerve repair process, provides an important basis for the exploration of the key regulators of neuronal growth and microenvironment reconstruction, and benefits the development of novel therapeutic drugs for the treatment of peripheral nerve injury.

β-nicotinamide mononucleotide (NMN) is a naturally occurring biologically active nucleotide widely present in organisms and an inherent substance in the human body. As a critical intermediate in synthesizing coenzyme I (NAD+), it widely participates in multiple biochemical reactions in the human body and is closely related to immunity, metabolism, and other factors. In recent years, NMN has rapidly developed and made significant progress in medicine, food, and healthcare. However, there is currently a lack of comprehensive reports on the research progress of NMN, as well as exploration and analysis of the current research achievements and progress of NMN. Therefore, this review is based on retrieving relevant research on NMN from multiple databases at home and abroad, with the retrieval time from database establishment to 20 May 2024. Subsequently, literature search, reading, key information extraction, organization, and summarization were conducted with the aim of providing a comprehensive and in-depth analysis of the characteristics, metabolic pathways, pharmacological effects, progress in human clinical trials, and wide applications of NMN in drug development and food applications. Furthermore, it offers personal insights into NMN’s potential future developments and advancements to present the current development state and existing challenges comprehensively. Ultimately, this review aims to provide guidance and serve as a reference for the future application, innovation, and progression of NMN research.

Currently, prosthesis users rely on visual cues to control their prosthesis. One reason for this is that prostheses cannot provide users with proprioceptive functional signals. For this reason, we propose an agonist-antagonist myoneural interface (AMI) surgery. We examined how this surgery affects the restoration of motor function and proprioceptive reconstruction in the hind limb of Sprague–Dawley rats. The procedure entails grafting the soleus muscle, suturing the two tendon ends of the soleus muscle, and anastomosing the tibial and common peroneal nerves to the soleus muscle. We found that, following surgery, AMI rats exhibited improved neurological repair, shorter walking swings, braking, propulsion, and stance times, and greater compound action potentials than control rats. This means that in rats with neurological impairment of the hind limb, the proposed AMI surgical method significantly improves postoperative walking stability and muscle synergy. AMI surgery may become an option for regaining proprioception in the lost limb.

Currently, despite advancements in diagnostic and therapeutic modalities, osteomyelitis and prosthetic joint infection (PJI) continue to pose significant challenges for orthopaedic surgeons. These challenges are primarily attributed to the high degree of heterogeneity exhibited by these disorders, which are influenced by a combination of environmental and host factors. Recent research efforts have delved into the pathogenesis of osteomyelitis and PJI by investigating single nucleotide polymorphisms (SNPs). This review comprehensively summarizes the current evidence regarding the associations between SNPs and the predisposition to osteomyelitis and PJI across diverse populations. The findings suggest potential linkages between SNPs in genes such as IL-1, IL-6, IFN-γ, TNF-α, VDR, tPA, CTSG, COX-2, MMP1, SLC11A1, Bax, NOS2, and NLRP3 with the development of osteomyelitis. Furthermore, SNPs in genes like IL-1, IL-6, TNF-α, MBL, OPG, RANK, and GCSFR are implicated in susceptibility to PJI. However, it is noted that most of these studies are single-center reports, lacking in-depth mechanistic research. To gain a more profound understanding of the roles played by various SNPs in the development of osteomyelitis and PJI, future multi-center studies and fundamental investigations are deemed necessary.

Objective: Antibiotic-loaded bone cement (ALBC) plays an indispensable role in the treatment of infectious diseases of bone and joint. Here, we intended to analyze the research status, hot spots and frontiers in the field of ALBC, and to provide reference for future research ideas. Methods: The related English literature in the field of ALBC in the Web of Science Core Collection database was retrieved from January 1, 2009 to July 11, 2023. VOSviewer was used to extract the information of research constituents or bibliometric items such as authors, institutions, countries, and journals. CiteSpace was used to perform cluster analysis and frontier analysis of key words in ALBC research field. Results: A total of 1091 literatures related to ALBC research were retrieved, and the annual number of publications showed a steady upward trend in the past 15 years. The high-yield countries and regions are mainly represented by the United States, China (including Taiwan, China) and several European countries, such as Germany, England, Spain, Italy, the Netherlands, etc. The top three institutions with the highest number of publications were Shanghai Jiao Tong University, Chang Gung University and Chang Gung Memorial Hospital in China. Four of the top 10 influential scholars come from Germany, namely Konstantinos Anagnostakos, Volker Alt, Andrej Trampuz, and Bernd Fink. The top 10 high-yield journals had an average of 25 articles per journal and an average of 618.9 citations. The top 3 high-yield journals were Journal of Arthroplasty (57 articles, 1213 citations), Clinical Orthopaedics and Related Research (35 articles, 1119 times cited), and Journal of Orthopaedic Research (29 papers, 488 times cited). The keywords with high frequency were infection (266 times), vancomycin (239 times), bone-cement (219 times), gentamicin (216 times), antibiotics (168 times), osteomyelitis (163 times), etc. The clustering knowledge map of high-frequency keywords could be divided into 4 categories: (1) elution, release, mechanical and antibacterial properties of ALBC; (2) Application of ALBC in revision of prosthetic joint infections (PJIs); (3) Antibiotic types and application forms of ALBC; (4) Application of ALBC in the treatment of osteomyelitis. The keywords with the strongest citation bursts analysis revealed a core (''replacement/arthroplasty'') and two stages of development in the field of ALBC research. The first stage (2009–2018) focused more on ALBC drug delivery, release, and infection prevention, while the second stage (2018–2023) mainly focused on ALBC drug elution, mechanical properties, and PJIs revision. Starting from 2018, the keyword with the strongest citation bursts had shifted from ''acrylic bone cement'' to ''periprosthetic joint infection''. Conclusion: ALBC research is steadily on the rise. Arthroplasty related applications continue to be the core of ALBC research. The research hotspot and trend are mainly the application in the prevention and treatment of bone and joint infectious diseases and the elution, release, mechanical and antibacterial properties of ALBC.

Abstract Background The association between exposure to PM2.5 chemical constituents and obesity remains to be elucidated, as most studies have used a single measure of obesity. This study aimed to investigate the associations of exposure to PM2.5 chemical constituents with general, abdominal, and visceral obesity, and the mediation effect of physical activity (PA) in the associations. Methods Based on a total of 49,819 adults from the baseline of the Yunnan Behavior and Disease Surveillance cohort (YBDS) in southern China in 2021, we used multiple linear regression, weighted quantile sum regression, and quantile regression to estimate independent and joint effects of PM2.5 chemical constituents on elevated BMI, waist circumference (WC) and visceral adiposity index (VAI) and whether these effects changed in quantiles. Mediation analysis was used to examine whether physical activity acts as a mediator in these pathways. Results Per IQR μg/m3 increase in all PM2.5 chemical constituents was significantly associated with the elevated BMI (β [95% CI]: 0.170 [0.127, 0.214]), WC (0.316 [0.217, 0.415]) and VAI (0.102 [0.075, 0.129]), with the largest weights from OM (53.89, 81.67, and 89.82%, respectively). The effects of PM2.5 chemical constituents on obesity showed an overall upward trend from quantiles 1–4 of BMI, WC, and VAI, especially with a rapid upward trend from the sixth decile of VAI. Reduced PA mediated 3.16, 7.08, and 3.78% of the associations between PM2.5 chemical constituents and elevated BMI, WC, and VAI, respectively. Conclusions Exposure to PM2.5 chemical constituents, especially OM, was significantly associated with increased risks for obesity in adults. The effects of associations increased with obesity severity, with PA playing a mediation role.

Abstract Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand–receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Abstract Introduction Heel puncture (HP) in neonates can result in osteomyelitis if done non-aseptically or with incorrect technique. This study summarizes clinical experience with heel puncture-related osteomyelitis of the calcaneus (HP-CO) in newborns. Methods We systematically reviewed studies that examined HP-CO in newborn patients using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our search included the PubMed, Embase, and Cochrane Library databases until December 31, 2023. We used the National Institutes of Health (NIH) assessment scale to evaluate the quality of our analyzed studies. Results This study analyzed 15 neonatal calcaneal osteomyelitis (CO) cases due to HP conducted in six countries from 1976 to 2016. The average age of the cases was 8.87 ± 6.13 days, with an average birth weight of 2367.27 ± 947.59 g. The infants had undergone an average of 9.00 ± 8.90 HP, with 93.33% exhibiting swelling. Staphylococcus aureus was present in 80% of cases. Beta-lactam antibiotics were used, with satisfactory outcomes in 53.33% of cases. However, in seven cases, three patients had flatfoot due to calcaneal deformity, and other complications were observed in some patients after 7–8 years. Conclusions This study offers valuable insights into a rare condition, including its epidemiology, clinical and laboratory characteristics, and treatment options for infants with HP-CO. To prevent the risk of osteomyelitis in this vulnerable group of patients, increasing awareness and maintaining strict aseptic techniques is necessary. We recommend that infants presenting with tenderness, redness, purulent discharge, erythema, or fever and with a history of repeated HP and swollen ankles should be evaluated for suspicion of osteomyelitis. A graphical abstract is avilable for this article. Graphical Abstract

Abstract Background It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates in this pathological process remains unknown. Here, we report that platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts in the bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), a nonspecific transcytosis marker, was upregulated during HFD challenge. Main body Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations in the circulation recapitulated the HFD-induced neuroinflammation and transcytosis shift. Preosteoclast-specific Pdgfb knockout mice were partially rescued from hippocampal neuroinflammation and transcytosis shifts in HFD-challenged mice. HFD-induced PDGF-BB elevation aggravated microglia-associated neuroinflammation and interleukin-1β (IL-1β) secretion, which increased ALPL expression and transcytosis shift through enhancing protein 1 (SP1) translocation in endothelial cells. Conclusion Our findings confirm the role of bone-secreted PDGF-BB in neuroinflammation and the transcytosis shift in the hippocampal region during HFD challenge and identify a novel mechanism of microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

Abstract Purpose The aim of this study was to investigate the clinical efficacy of full endoscopic lumbar annulus fibrosus suture in the treatment of single-segment lumbar disc herniation (LDH). Methods The clinical data of patients with single-segment LDH who underwent full endoscopic lumbar discectomy from January 2017 to January 2019 in our hospital were retrospectively analysed. Patients with full endoscopic lumbar discectomy combined with annulus fibrosus suture were divided into group A, and those with simple full endoscopic lumbar discectomy were divided into group B. The general information, surgery-related data, visual analog scale (VAS), Oswestry disability index (ODI), modified MacNab score at the last follow-up, reoperation rate and recurrence were compared between the two groups. Results All patients were followed up for 12 to 24 months, and the surgical time was 133.6 ± 9.6 min in group A and 129.0 ± 11.7 min in group B. The difference was not statistically significant (p > 0.05). The blood loss of group A was higher than that of group B, and the difference was statistically significant when comparing the groups (p 0.05). The excellent rate of MacNab at the last follow-up in the two groups were 93.55% and 87.80%, respectively, with no statistically significant difference (p > 0.05). At the last follow-up, the recurrence rate of group A was significantly lower than that of group B, and the difference was statistically significant (p 0.05). Conclusions Full endoscopic lumbar discectomy combined with annulus fibrosus repair reduces the postoperative recurrence rate and achieves satisfactory clinical outcomes.

Abstract Background Traditional biochemical screening for neonatal inherited metabolic diseases has high false-positive rates and low positive predictive values, which are not conducive to early diagnosis and increase parents’ anxiety. This study analysed the relationship between gene variant carriers and their biochemical indicators in traditional biochemical screening, aiming to find explanations for false positives in newborns. Results This retrospective study included 962 newborns. Newborns underwent traditional biochemical screening at birth using blood staining and genomic sequencing of their stored blood staining using the NeoSeq Pro panel, which was able to detect 154 pathogenic genes and 86 diseases. A total of 632 newborns were carriers of gene variants. 56% of congenital hypothyroidism carriers had higher thyroid-stimulating hormone levels than normal newborns. Abnormal biochemical indices were detected in 71% of carriers of organic acid metabolic diseases, 69% of carriers of amino acid metabolic diseases, and 85% of carriers of fatty acid β oxidation disorders. In carriers associated with organic acid metabolic diseases, the propionylcarnitine (C3), C3/acetylcarnitine (C2), and methylmalonylcarnitine (C4DC) + 3-hydroxyisovalerylcarnitine (C5OH) levels were higher than those in non-carriers (C3: 4.12 vs. 1.66 µmol/L; C3/C2: 0.15 vs. 0.09; C4DC + C5OH: 0.22 vs. 0.19 µmol/L). In carriers associated with amino acid metabolic diseases, phenylalanine levels were higher than those in non-carriers (68.00 vs. 52.05 µmol/L). For carriers of fatty acid β oxidation disorders, butyrylcarnitine levels were higher than those in non-carriers (0.31 vs. 0.21 µmol/L), while the free carnitine levels were lower than those in non-carriers (14.65 vs. 21.87 µmol/L). There was a higher occurrence of carriers among newborns who received false-positive results for amino acid metabolic diseases compared to those who received negative results (15.52% vs. 6.71%). Similarly, there was a higher occurrence of carriers among newborns who received false-positive results for fatty acid β oxidation disorders compared to those who received negative results (28.30% vs. 7.29%). Conclusions This study showed that the carriers comprised a large number of newborns. Carriers had abnormal biochemical indicators compared with non-carriers, which could explain the false-positive rate for newborns using traditional newborn biochemical screening, especially in amino acid metabolic and fatty acid β oxidation disorders.

Histone methylation plays crucial roles in regulating chromatin structure and gene transcription in epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases. LSD1 dysregulation is closely associated with cancer, viral infections, and neurodegenerative diseases, etc., making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage. LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9 (H3K4 or H3K9), resulting in either transcription repression or activation. While the roles of LSD1 in transcriptional regulation are well-established, studies have revealed that LSD1 can also be dynamically regulated by other factors. For example, the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1. Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression or its demethylase activity. Therefore, in this review, we will systematically summarize how proteins involved in the transcriptional corepressor complex, various post-translational modifications, and metabolites act as regulatory factors for LSD1 activity.

The traditional Chinese herbal prescription Buyang Huanwu decoction (BHD), effectively treats atherosclerosis. However, the mechanism of BHD in atherosclerosis remains unclear. We aimed to determine whether BHD could alleviate atherosclerosis by altering the microbiome-associated metabolic changes in atherosclerotic mice. An atherosclerotic model was established in apolipoprotein E-deficient mice fed high-fat diet, and BHD was administered through gavage for 12 weeks at 8.4 g/kg/d and 16.8 g/kg/d. The atherosclerotic plaque size, composition, serum lipid profile, and inflammatory cytokines, were assessed. Mechanistically, metabolomic and microbiota profiles were analyzed by liquid chromatography-mass spectrometry and 16S rRNA gene sequencing, respectively. Furthermore, intestinal microbiota and atherosclerosis-related metabolic parameters were correlated using Spearman analysis. Atherosclerotic mice treated with BHD exhibited reduced plaque area, aortic lumen occlusion, and lipid accumulation in the aortic root. Nine perturbed serum metabolites were significantly restored along with the relative abundance of microbiota at the family and genus levels but not at the phylum level. Gut microbiome improvement was strongly negatively correlated with improved metabolite levels. BHD treatment effectively slows the progression of atherosclerosis by regulating altered intestinal microbiota and perturbed metabolites.

Abstract Each joint of a hydraulic-driven legged robot adopts a highly integrated hydraulic drive unit (HDU), which features a high power–weight ratio. However, most HDUs are throttling-valve-controlled cylinder systems, which exhibit high energy losses. By contrast, pump control systems offer a high efficiency. Nevertheless, their response ability is unsatisfactory. To fully utilize the advantages of pump and valve control systems, in this study, a new type of pump–valve compound drive system (PCDS) is designed, which can not only effectively reduce the energy loss, but can also ensure the response speed and response accuracy of the HDUs in robot joints to satisfy the performance requirements of robots. Herein, considering the force control requirements of energy conservation, high precision, and fast response of the robot joint HDU, a nonlinear mathematical model of the PCDS force control system is first introduced. In addition, pressure–flow nonlinearity, friction nonlinearity, load complexity and variability, and other factors affecting the system are considered, and a novel force control method based on quantitative feedback theory (QFT) and a disturbance torque observer (DTO) is designed, which is denoted as QFT–DTOC herein. This method improves the control accuracy and robustness of the force control system, reduces the effect of the disturbance torque on the control performance of the servo motor, and improves the overall force control performance of the system. Finally, experimental verification is performed using the PCDS performance test platform. The experimental results and quantitative data show that the QFT–DTOC proposed herein can significantly improve the force control performance of the PCDS. The relevant force control method can be used as a bottom-control method for the hydraulic servo system to provide a foundation for implementing the top-level trajectory planning of the robot.

Abstract To assess the anatomy of the inferior mesenteric artery (IMA) and its branches by reviewing laparoscopic left-sided colorectal cancer surgery videos and comparing them with preoperative three-dimensional computed tomography (3D-CT) angiography, to verify the accuracy of 3D-CT vascular reconstruction techniques. High-definition surgical videos and preoperative imaging data of 200 patients who underwent laparoscopic left-sided colorectal cancer surgery were analysed, and the alignment of the IMA and its branches in relation to the inferior mesenteric vein (IMV) was observed and summarized. The above two methods were used to measure the length of the IMA and its branches. Of 200 patients, 47.0% had the sigmoid arteries (SAs) arise from the common trunk with the superior rectal artery (SRA), and 30.5% had the SAs arise from the common trunk with the left colic artery (LCA). In 3.5% of patients, the SAs arising from both the LCA and SRA. The LCA, SA, and SRA emanated from the same point in 13.5% of patients, and the LCA was absent in 5.5% of patients. The range of D cm (IMA length measured by intraoperative silk thread) and d cm (IMA length measured by 3D-CT vascular reconstruction) in all cases was 1.84–6.62 cm and 1.85–6.52 cm, respectively, and there was a significant difference between them. (p

Abstract Background Inflammation is a part of tumours, and inflammatory cells can affect the proliferation, invasion, and development of tumour cells. An increasing number of peripheral blood inflammatory markers have been found to play very important roles in the treatment and prognosis of cancer patients. The systemic inflammatory response index (SIRI) is a newer inflammatory marker, and its role in colorectal cancer, especially in locally advanced rectal cancer, is still unclear. Methods From 2015 to 2020, 198 patients with locally advanced rectal cancer (LARC) who underwent surgery following neoadjuvant chemoradiotherapy (Neo-CRT) were analysed. Patients were categorized into good- and poor- response groups according to their pathological results, and clinical characteristics and baseline parameters were compared between the two groups. The optimal cutoff values for inflammatory indicators were determined using receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using the Cox proportional hazard model. Survival analysis was performed via the Kaplan‒Meier method. Results After patients were grouped into good and poor response groups, indicator differences were found in CEA, neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and SIRI. According to the ROC analysis, the NLR (P = 0.015), SII (P = 0.001), and SIRI (P = 0.029) were significant prognostic factors. After univariate and multivariate analyses of the Cox proportional hazards regression model, only the SIRI was found to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Finally, Kaplan‒Meier survival curves also confirmed the ability of the SIRI to predict survival. Conclusion The preoperative SIRI can be used to predict the response to Neo-CRT in LARC patients and is an independent predictor of OS and DFS in postoperative patients. A high SIRI was associated with poor radiotherapy response and predicted poor OS and DFS.

Abstract The North Pacific Oscillation (NPO), an important mode of atmospheric variability, is a crucial trigger for the development of El Niño-Southern Oscillation (ENSO) via the seasonal footprinting mechanism. How the NPO effect on ENSO changes in response to greenhouse warming remains unclear, however. Here, using climate model simulations under high-emission scenarios, we show that greenhouse warming leads to an enhanced influence of NPO on ENSO as is manifested by enhanced responses of winter sea surface temperature (SST), precipitation and wind anomalies in the equatorial Pacific to the preceding winter NPO. The strengthened NPO impact is also reflected in an increased frequency of NPO events that are followed by ENSO events. Warmer background SST enhances the wind-evaporation-SST feedback over the subtropical North Pacific due to a nonlinear SST-evaporation relationship. This strengthens the NPO-generated surface zonal wind anomalies over the equatorial western-central Pacific, which trigger ENSO. Increased impact of winter NPO on ENSO could enable prediction of interannual variability at longer leads.

Abstract MicroRNAs (miRNAs) play a key role in regulating gene expression and their biogenesis is precisely controlled through modulating the activity of microprocessor. Here, we report that CWC15, a spliceosome-associated protein, acts as a positive regulator of miRNA biogenesis. CWC15 binds the promoters of genes encoding miRNAs (MIRs), promotes their activity, and increases the occupancy of DNA-dependent RNA polymerases at MIR promoters, suggesting that CWC15 positively regulates the transcription of primary miRNA transcripts (pri-miRNAs). In addition, CWC15 interacts with Serrate (SE) and HYL1, two key components of microprocessor, and is required for efficient pri-miRNA processing and the HYL1-pri-miRNA interaction. Moreover, CWC15 interacts with the 20 S proteasome and PRP4KA, facilitating SE phosphorylation by PRP4KA, and subsequent non-functional SE degradation by the 20 S proteasome. These data reveal that CWC15 ensures optimal miRNA biogenesis by maintaining proper SE levels and by modulating pri-miRNA levels. Taken together, this study uncovers the role of a conserved splicing-related protein in miRNA biogenesis.

Aim: The aim of this study was to provide a comprehensive overview of floating hip injury and attempt to provide a management algorithm. Methods: PubMed was searched using the terms ‘Floating hip’ or ‘acetabular fracture’ and ‘Ipsilateral femoral fracture’ or ‘pelvic fracture’ and ‘Ipsilateral femoral fracture’. One author performed a preliminary review of the abstracts and references of the retrieved articles. Results: The mean injury severe score reported was higher than 20. Chest and abdominal injuries, as well as fractures at other sites, were the most common associated injuries. Despite the high disability rate, surgery remained the preferred option for managing these injuries. The surgical timing varied from a few hours to several days and was subjected to the principles of damage control orthopedics. Although, in most cases, fixation of femoral fractures took precedence over pelvic or acetabular fractures, there was still a need to consider the impact of damage control orthopedics, associated injuries, and surgeon's considerations and preferences. Posttraumatic arthritis, neurological deficits, heterotopic ossification, femoral head necrosis, femoral nonunion, and limb inequality were common complications of the floating hip injury. Conclusions: The severity of such injuries often exceeds that of an isolated injury and often requires specialized multidisciplinary treatment. In the management of these complex cases, the complexity and severity of the injury should be fully assessed, and an appropriate surgical plan should be developed to perform definitive surgery as early as possible, with attention to prevention of complications during the perioperative period.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP–SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

Abstract The 2021 heatwave over Western North America (WNA) led to record‐breaking air temperatures and human‐perceived heat stress (humidex) values. The event was accompanied by drier conditions driven by prolonged atmospheric blocking. During the heatwave, the maximum 6‐day means of humidex and temperature (HX‐6 and TX‐6) exhibited larger anomalies (6.70 and 5.57°C) compared to the 95th percentiles (HX95 and TX95) (4.12 and 3.73°C), relative to 1981–2021 extended summer (June‐September) averages. Extreme indices of humidex show faster and larger increases than those of temperature, reflecting the nonlinear positive relationship between humidex and temperature. Future projections from a multi‐model ensemble of 19 Coupled Model Intercomparison Project Phase six (CMIP6) Global Climate Models (GCMs) clearly show an increase in humidex and temperature extremes, especially under intermediate and high emissions scenarios. Humidex indices (HX‐6 and HX95) show faster and larger increases than temperature indices (TX‐6 and TX95) for the same future years and global warming levels. Controlling for differences in GCM climate sensitivity to greenhouse gas forcing yields robust projections at various global warming levels, reducing the ranges of projected changes from the multi‐model ensemble. At 3.0°C global warming from pre‐industrial, the multi‐model ensemble projects occurrences of HX‐6, TX‐6, HX95, and TX95 over WNA that exceed 2021 levels to occur every 3.9, 1.7, 1.4, and 2.2 years, respectively, increasing to almost annually at 4.0°C.

Glaesserella parasuis is the pathogen that causes Glässer’s disease in pigs, which is characterized by fibrinous polyserositis, arthritis and meningitis. Research on ribosomal protein L32 in microorganisms has mainly focused on regulating gene transcription and translation, but its effect on bacterial virulence is unclear. The role of L32 gene in G. parasuis is not clear, and in order to study the function of L32 gene, a suicide plasmid-mediated natural transformation method was used to construct a L32 gene deletion mutant. We found that although L32 was shown to be non-essential for cell proliferation, the growth curve of ΔL32 is clearly different compared with that of ZJ1208. ΔL32 produced more outer membrane vesicles (OMVs) with a variety of irregular shapes, but produced similar biofilm to the parental strain. ΔL32 is more sensitive to osmotic pressure, oxidation pressure and heat shock stress. Meanwhile, ΔL32 is significantly more susceptible to antimicrobials such as spectinomycin, apramycin, sulfafurazole, but not to other antibiotics used in this study. In the mouse challenge experiment, the mortality of mice infected with the mutant strain decreased by 40% compared to those infected with the wild-type strain, indicating that L32 is a virulence-associated factor which contributes to bacterial fitness in host environments. The above results show that L32 is important for the growth, stress resistance and virulence of G. parasuis, and this study also confirms for the first time that L32 plays an important role in antibiotic resistance against aminoglycosides and sulfonamides.

Background Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic.

Abstract Chondrocyte senescence and reduced lubrication play pivotal roles in the pathogenesis of age‐related osteoarthritis (OA). In the present study, highly lubricated and drug‐loaded hydrogel microspheres are designed and fabricated through the radical polymerization of sulfobetaine (SB)‐modified hyaluronic acid methacrylate using microfluidic technology. The copolymer contains a large number of SB and carboxyl groups that can provide a high degree of lubrication through hydration and form electrostatic loading interactions with metformin (Met@SBHA), producing a high drug load for anti‐chondrocyte senescence. Mechanical, tribological, and drug release analyses demonstrated enhanced lubricative properties and prolonged drug dissemination of the Met@SBHA microspheres. RNA sequencing (RNA‐seq) analysis, network pharmacology, and in vitro assays revealed the extraordinary capacity of Met@SBHA to combat chondrocyte senescence. Additionally, inducible nitric oxide synthase (iNOS) has been identified as a promising protein modulated by Met in senescent chondrocytes, thereby exerting a significant influence on the iNOS/ONOO‐/P53 pathway. Notably, the intra‐articular administration of Met@SBHA in aged mice ameliorated cartilage senescence and OA pathogenesis. Based on the findings of this study, Met@SBHA emerges as an innovative and promising strategy in tackling age‐related OA serving the dual function of enhancing joint lubrication and mitigating cartilage senescence.

Abstract The optoelectronic resistive random‐access memory (RRAM) with the integrated function of perception, storage and intrinsic randomness displays promising applications in the hardware level in‐sensor image cryptography. In this work, 2D hexagonal boron nitride based optoelectronic RRAM is fabricated with semitransparent noble metal (Ag or Au) as top electrodes, which can simultaneous capture color image and generate physically unclonable function (PUF) key for in‐sensor color image cryptography. Surface plasmons of noble metals enable the strong light absorption to realize an efficient modulation of filament growth at nanoscale. Resistive switching curves show that the optical stimuli can impede the filament aggregation and promote the filament annihilation, which originates from photothermal effects and photogenerated hot electrons in localized surface plasmon resonance of noble metals. By selecting noble metals, the optoelectronic RRAM array can respond to distinct wavelengths and mimic the biological dichromatic cone cells to perform the color perception. Due to the intrinsic and high‐quality randomness, the optoelectronic RRAM can produce a PUF key in every exposure cycle, which can be applied in the reconfigurable cryptography. The findings demonstrate an effective strategy to build optoelectronic RRAM for in‐sensor color image cryptography applications.

Abstract Triboelectric nanogenerators (TENGs), a promising strategy for harvesting distributed low‐quality power sources, face inevitable bottlenecks regarding long‐term abrasion and poor durability. Herein, both issues are addressed by selecting an earthworm‐inspired self‐replenishing bionic film (ERB) as the tribo‐material of sliding‐freestanding TENGs (SF‐TENGs), it consists of an interconnected 3D porous network structure capable of storing and releasing lubricant under cyclic mechanical stimuli. Thanks to the superiority of self‐replenishing property, there is no need for periodic replenishment and accurate content control of lubricant over the interfacial‐lubricating SF‐TENGs based on dense tribo‐layers. Additionally, an SF‐TENG based on ERB film (ERB‐TENG) demonstrates remarkable output stability with only a slight attenuation of 1% after continuous operation for 100 000 cycles. Moreover, the ERB‐TENG displays a distinguished anti‐wear property, exhibiting no distinct abrasion with an ultra‐low coefficient of friction (0.077) and maintaining output stability over a prolonged period of 35 days. Furthermore, integration with an energy management circuit enables the ERB‐TENG to achieve a 39‐fold boost in charging speed. This work proposes a creative approach to enhance the durability and extend the lifespan of TENG devices, which is also successfully applied to wind energy harvesting and intelligent sports monitoring.

Nerve injuries significantly impact the quality of life for patients, with severe cases posing life-threatening risks. A comprehensive understanding of the pathophysiological mechanisms underlying nerve injury is crucial to the development of effective strategies to promote nerve regeneration. Circular RNAs (circRNAs), a recently characterized class of RNAs distinguished by their covalently closed-loop structures, have been shown to play an important role in various biological processes. Numerous studies have highlighted the pivotal role of circRNAs in nerve regeneration, identifying them as potential therapeutic targets. This review aims to succinctly outline the latest advances in the role of circRNAs related to nerve injury repair and the underlying mechanisms, including peripheral nerve injury, traumatic brain injury, spinal cord injury, and neuropathic pain. Finally, we discuss the potential applications of circRNAs in drug development and consider the potential directions for future research in this field to provide insights into circRNAs in nerve injury repair.

IntroductionPathogens causing diabetic foot infections (DFIs) vary by region globally; however, knowledge of the causative organism is essential for effective empirical treatment. We aimed to determine the incidence and antibiotic susceptibility of DFI pathogens worldwide, focusing on Asia and China.MethodsThrough a comprehensive literature search, we identified published studies on organisms isolated from DFI wounds from January 2000 to December 2020.ResultsBased on our inclusion criteria, we analyzed 245 studies that cumulatively reported 38,744 patients and 41,427 isolated microorganisms. DFI pathogens varied according to time and region. Over time, the incidence of Gram-positive and Gram-negative aerobic bacteria have decreased and increased, respectively. America and Asia have the highest (62.74%) and lowest (44.82%) incidence of Gram-negative bacteria, respectively. Africa has the highest incidence (26.90%) of methicillin-resistant Staphylococcus aureus. Asia has the highest incidence (49.36%) of Gram-negative aerobic bacteria with species infection rates as follows: Escherichia coli, 10.77%; Enterobacter spp., 3.95%; and Pseudomonas aeruginosa, 11.08%, with higher local rates in China and Southeast Asia. Linezolid, vancomycin, and teicoplanin were the most active agents against Gram-positive aerobes, while imipenem and cefoperazone-sulbactam were the most active agents against Gram-negative aerobes.DiscussionThis systematic review showed that over 20 years, the pathogens causing DFIs varied considerably over time and region. This data may inform local clinical guidelines on empirical antibiotic therapy for DFI in China and globally. Regular large-scale epidemiological studies are necessary to identify trends in DFI pathogenic bacteria.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023447645.

Dust removal coatings for polyimide (PI)-based photovoltaic modules used in lunar rovers were fabricated successfully through the blade-coating method using silicon dioxide (SiO2) nanoparticles and γ-aminopropyltriethoxysilane (KH550). The dust removal performance, morphology, transparency, and adhesive force of the coating can be optimized by adjusting the pH and the mass ratios of SiO2 and KH550. The designed coating demonstrates excellent dust removal performance, achieving an percentage of over 85 %. Moreover, the coating has minimal impact on the transparency of the PI substrate and exhibits strong adhesion to it. Additionally, the coating shows remarkable resistance to both high and low temperatures. Even after undergoing five cycles of thermal treatment ranging from −196 to 160 °C, there were no significant changes in the morphology or dust removal performance of the coating. Therefore, this coating exhibits tremendous potential for application in the dust removal of photovoltaic modules in lunar rovers.

Abstract The visible light localization system holds great promise as a highly accurate indoor positioning method. However, it still suffers deficiencies including high latency and power consumption, and large area cost. To address these issues, a high energy efficient spiking localization system inspired by the biological spatial representation system is presented. This system utilizes an optical neuromorphic sensor, consisting of a compact NbOx‐based threshold switching memristor and a photoresistor. The key lies in the system's ability to convert analog light information into electrical spikes, resembling the behavior of sensory neurons, which enables the encoding of light illuminance through spiking frequency. Consequently, the system achieves high uniformity, high linearity (≈10%), and high sensitivity (≈1.1 kHz Lux−1 and ≈72.7 kHz cm−1 for light illuminance and distance detection, respectively), indicating its potential suitability for visible light localizations. By leveraging a spiking neural network classifier, the system successfully distinguishes locations with different illuminances. After 150 epochs, it achieves an accuracy of 97%, showcasing the feasibility of using the spiking localization system in real‐world applications. The approach of spike‐based light positioning is a leap forward toward the development of future compact, highly energy‐efficient visible light localization systems.

Summary: Background: Long-term exposure to PM2.5 is known to increase the risks for diabetes and obesity, but its effects on their coexistence, termed diabesity, remain uncertain. This study aimed to investigate the associations of long-term exposure to PM2.5 and its chemical constituents with the risks for diabesity, diabetes, and obesity. Methods: This cross-sectional study used the baseline data of a multi-center cohort, consisting of three provincially representative cohorts comprising a total of 134,403 participants from the eastern (Fujian Province), central (Hubei Province), and western (Yunnan Province) regions of China. Obesity and diabetes, and diabesity were identified by a body mass index (BMI) ≥28 kg/m2 and fasting plasma glucose (FPG) ≥126 mg/dL. The average concentrations of PM2.5 and five chemical constituents (NO3−, SO42−, NH4+, organic matter, and black carbon) over participants’ residence during the past three years were estimated using machine learning models. Logistic regression models with double robust estimators, Bayesian kernel machine regression, and weighted quantile sum regression were employed to estimate independent and joint effects of PM2.5 chemical constituents on the risks for diabesity, diabetes, and obesity, as well as the differences from the effects on obesity. Stratified analyses were performed to examine effect modification of sociodemographic and lifestyle factors. Findings: There were 129,244 participants with a mean age of 54.1 ± 13.8 years included in the study. Each interquartile range increase in PM2.5 concentration (8.53 μg/m3) was associated with an increased risk for diabesity (OR = 1.23 [1.17, 1.30]), diabetes only (OR = 1.16 [1.13, 1.19]), and obesity only (OR = 1.03 [1.00, 1.05]). Long-term exposure to each PM2.5 chemical constituent was associated with an increased risk for diabesity, where organic matter exposure, with maximum weight (48%), was associated with a higher risk for diabesity (OR = 1.21 [1.16, 1.27]). Among those with obesity, black carbon contributed most (68%) to the joint effect of PM2.5 chemical constituents on diabesity (OR = 1.16 [1.11, 1.22]). Physical activity reduced adverse effects of PM2.5 on diabesity. Also, additive rather than multiplicative effects of obesity on the PM2.5-diabetes association were observed. Interpretation: Long-term exposure to PM2.5 and its chemical constituents was associated with an increased risk for diabesity, stronger than associations for diabetes and obesity alone. The main constituents associated with diabesity and obesity were black carbon and organic matter. Funding: National Natural Science Foundation of China (42271433, 723B2017), National Key R&D Program of China (2023YFC3604702), Fundamental Research Funds for the Central Universities (2042023kfyq04, 2042024kf1024), the Science and Technology Major Project of Tibetan Autonomous Region of China (XZ202201ZD0001G), Science and technology project of Tibet Autonomous Region（XZ202303ZY0007G), Key R&D Project of Sichuan Province (2023YFS0251), Renmin Hospital of Wuhan University (JCRCYG-2022-003), Jiangxi Provincial 03 Special Foundation and 5G Program (20224ABC03A05), Wuhan University Specific Fund for Major School-level Internationalization Initiatives (WHU-GJZDZX-PT07).