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Irregular bone defects, characterized by unpredictable size, shape, and depth, pose a major challenge to clinical treatment. Although various bone grafts are available, none can fully meet the repair needs of the defective area. Here, this study fabricates a dough-type hydrogel (DR-Net), in which the first dynamic network is generated by coordination between thiol groups and silver ions, thereby possessing kneadability to adapt to various irregular bone defects. The second rigid covalent network is formed through photocrosslinking, maintaining the osteogenic space under external forces and achieving a better match with the bone regeneration process. In vitro, an irregular alveolar bone defect is established in the fresh porcine mandible, and the dough-type hydrogel exhibits outstanding shape adaptability, perfectly matching the morphology of the bone defect. After photocuring, the storage modulus of the hydrogel increases 8.6 times, from 3.7 kPa (before irradiation) to 32 kPa (after irradiation). Furthermore, this hydrogel enables effective loading of P24 peptide, which potently accelerates bone repair in Sprague–Dawley (SD) rats with critical calvarial defects. Overall, the dough-type hydrogel with kneadability, space-maintaining capability, and osteogenic activity exhibits exceptional potential for clinical translation in treating irregular bone defects.

With the escalation of global trade, the Chinese commodity futures market has ascended to a pivotal role within the international shipping landscape. The Shanghai Containerized Freight Index (SCFI), a leading indicator of the shipping industry’s health, is particularly sensitive to the vicissitudes of the Chinese commodity futures sector. Nevertheless, a significant research gap exists regarding the application of Chinese commodity futures prices as predictive tools for the SCFI. To address this gap, the present study employs a comprehensive dataset spanning daily observations from March 24, 2017, to May 27, 2022, encompassing a total of 29,308 data points. We have crafted an innovative deep learning model that synergistically combines Long Short-Term Memory (LSTM) and Convolutional Neural Network (CNN) architectures. The outcomes show that the CNN-LSTM model does a great job of finding the nonlinear dynamics in the SCFI dataset and accurately capturing its long-term temporal dependencies. The model can handle changes in random sample selection, data frequency, and structural shifts within the dataset. It achieved an impressive R² of 96.6% and did better than the LSTM and CNN models that were used alone. This research underscores the predictive prowess of the Chinese futures market in influencing the Shipping Cost Index, deepening our understanding of the intricate relationship between the shipping industry and the financial sphere. Furthermore, it broadens the scope of machine learning applications in maritime transportation management, paving the way for SCFI forecasting research. The study’s findings offer potent decision-support tools and risk management solutions for logistics enterprises, shipping corporations, and governmental entities.

Abstract Background The region-specific importance of carcinogenic HPV genotypes is required for optimizing HPV-based screening and promoting appropriate multivalent HPV prophylactic vaccines. This information is lacking for Ningbo, one of the first cities of China’s Healthy City Innovation Pilot Program for Cervical Cancer Elimination. Here, we investigated high-risk HPV (HR-HPV) genotype-specific distribution and attribution to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) before mass vaccination in Ningbo, China. Methods A total of 1393 eligible CIN2+ archived blocks (including 161 CIN2, 1107 CIN3, and 125 invasive cervical cancers [ICC]) were collected from 2017 to 2020 in Ningbo. HR-HPV DNA was genotyped using the SPF10-DEIA-LiPA25 version 1 detection system and the SureX HPV 25X Genotyping Kit. Genotype-specific attribution to CIN2+ was estimated using a fractional contribution approach. Results Ranking by the attributable proportions, HPV16 remained the most important genotype in both cervical precancers and cancers, accounting for 36.8% of CIN2, 53.2% of CIN3, and 73.3% of ICC cases. Among cervical precancers, HPV52 (17.3% in CIN2, 12.7% in CIN3) and HPV58 (13.9%, 14.9%) ranked second and third, while HPV33 (8.3%, 7.9%) and HPV31 (6.5%, 4.1%) ranked fourth and fifth, respectively. However, among ICCs, HPV18 (5.7%) accounted for the second highest proportion, followed by HPV33 (5.4%), HPV58 (4.0%), and HPV45 (3.2%). HPV18/45 together accounted for 46.8% of adenocarcinomas, which was slightly lower than that of HPV16 (47.7%). The remaining HR-HPV genotypes (HPV35/39/51/56/59/66/68) combined accounted for only 6.7% of CIN2, 2.9% of CIN3, and 4.2% of ICC. Conclusions With Ningbo’s strong medical resources, it will be important to continue HPV16/18 control efforts, and could broaden to HPV31/33/45/52/58 for maximum health benefits. However, different strategies should be proposed for other HR-HPV genotypes based on their lower carcinogenic risks.

Abstract Background Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer’s disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. Results Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. Conclusion Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

Extracellular vesicles (EVs) are nanoscale particles with a lipid bilayer membrane structure secreted by various cell types. Nearly all human cells secrete EVs, primarily mediating intercellular communication. In recent years, scientists have discovered that EVs can carry multiple biological cargos, such as DNA, non-coding RNAs (ncRNAs), proteins, cytokines, and lipids, and mediate intercellular signal transduction. Bone is a connective tissue with a nerve supply and high vascularization. The repair process after injury is highly complex, involving interactions among multiple cell types and biological signaling pathways. Bone regeneration consists of a series of coordinated osteoconductive and osteoinductive biological processes. As mediators of intercellular communication, EVs can promote bone regeneration by regulating osteoblast-mediated bone formation, osteoclast-mediated bone resorption, and other pathways. This review summarizes the biogenesis of EVs and the mechanisms by which EV-mediated intercellular communication promotes bone regeneration. Additionally, we focus on the research progress of EVs in various diseases related to bone regeneration. Finally, based on the above research, we explore the clinical applications of engineered EVs in the diagnosis and treatment of bone regeneration-related diseases.

Abstract The SARS-CoV-2 Omicron variant sparked the largest wave of infections worldwide. Mainland China eased its strict COVID-19 measures in late 2022 and experienced two nationwide Omicron waves in 2023. Here, we investigated lineage distribution and virus evolution in Guangdong, China, 2022-2023 by comparing 5813 local viral genomes with the datasets from other regions of China and worldwide. Additionally, we conducted three large-scale serological surveys involving 1696 participants to measure their immune response to the BA.5 and XBB.1.9 before and after the corresponding waves. Our findings revealed the Omicron variants, mainly the BA.5.2.48 lineage, causing infections in over 90% of individuals across different age groups within a month. This rapid spread led to the establishment of widespread immunity, limiting the virus’s ability to further adaptive mutation and dissemination. While similar immune responses to BA.5 were observed across all age groups after the initial wave, children aged 3 to 11 developed a stronger cross immune response to the XBB.1.9 strain, possibly explaining their lower infection rates in the following XBB.1 wave. Reinfection with Omicron XBB.1 variant triggered a more potent neutralizing immune response among older adults. These findings highlight the impact of age-specific immune responses on viral spread in potential future waves.

Exonic circular RNAs (ecircRNAs) in animal cells are generated by backsplicing, and the biogenesis of ecircRNAs is regulated by an array of RNA binding proteins (RBPs). HNRNPD is a heterogeneous nuclear ribonucleoprotein family member with both cytoplasmic and nuclear roles, and whether HNRNPD regulates the biogenesis of circRNAs remains unknown. In this study, we examine the role of HNRNPD in the biogenesis of ecircRNAs. The levels of ecircRNAs are primarily increased upon depletion of HNRNPD. HNRNPD preferentially binds to motifs enriched with A and U nucleotides, and the flanking introns of ecircRNAs tend to have more numbers and higher intensity of HNRNPD binding sites. The levels of mRNAs are generally not significantly altered in HNRNPD knockout cells. For a small set of genes, the circRNA:mRNA ratio is substantially affected, and the mRNA levels of some of these genes demonstrate a significant decrease in HNRNPD knockout cells. CDK1 is identified as a key gene modulated by HNRNPD in the context of circRNA biogenesis. HNRNPD suppresses the biogenesis of circCDK1 and favours the generation of CDK1 mRNA, and the CDK1 protein is a critical regulator of the cell cycle and apoptosis. HNRNPD can participate in cellular physiology, including the cell cycle and apoptosis, and plays roles in clear cell renal cell carcinoma (ccRCC) by modulating circRNA biogenesis and the mRNA levels of key genes, such as CDK1.

Abstract Background There are several surgical options for osteonecrosis of the lunate, and confirming the effectiveness of various surgical methods remains challenging. Here, we present a case of stage IIIB osteonecrosis of the lunate repaired with a free medial femoral condyle osteocutaneous flap. Case presentation A 43-year-old male construction worker was admitted to our hospital due to right wrist pain, impaired mobility, and pain aggravated by activity for 10 months. The patient was diagnosed with stage IIIB osteonecrosis of the lunate based on the orthopantomogram and magnetic resonance imaging of the right wrist. Considering the patient’s medical history, physical examination, auxiliary examination, and wishes, reconstruction was performed using a free medial femoral condyle osteocutaneous flap. After the flap survived completely, the K-wires were removed one month after the operation, the external brace was removed two months after the operation, and functional wrist rehabilitation was initiated. After six months of follow-up, the wrist swelling and pain resolved, and the reconstructed lunate bone was viable. Additionally, the last follow-up was conducted in the sixth month after surgery; the affected hand grip strength improved from about 70% (28 kg) to 80% (32 kg) compared with the healthy side (40 kg); the visual analog scale score decreased from 6.5 points before the operation to 1 point; and the MAYO score increased from 60 points before the operation to 85 points. Conclusions The success of this case reinforces the potential of the free medial femoral condyle osteocutaneous flap as a new treatment option for stage IIIB osteonecrosis of the lunate and further expands the existing treatment options. Using a free medial femoral condyle osteocutaneous flap to reconstruct the lunate and restore the carpal anatomy may.

Abstract Parking difficulties have become a social issue that people have to solve. Automated parking system is practicable for quick par operations without a driver which can also greatly reduces the probability of parking accidents. The paper proposes a Lyapunov-based nonlinear model predictive controller embedding an instructable solution which is generated by the modified rear-wheel feedback method (RF-LNMPC) in order to improve the overall path tracking accuracy in parking conditions. Firstly, A discrete-time RF-LNMPC considering the position and attitude of the parking vehicle is proposed to increase the success rate of automated parking effectively. Secondly, the RF-LNMPC problem with a multi-objective cost function is solved by the Interior-Point Optimization, of which the iterative initial values are described as the instructable solutions calculated by combining modified rear-wheel feedback to improve the performance of local optimal solution. Thirdly, the details on the computation of the terminal constraint and terminal cost for the linear time-varying case is presented. The closed-loop stability is verified via Lyapunov techniques by considering the terminal constraint and terminal cost theoretically. Finally, the proposed RF-LNMPC is implemented on a self-driving Lincoln MKZ platform and the experiment results have shown improved performance in parallel and vertical parking conditions. The Monte Carlo analysis also demonstrates good stability and repeatability of the proposed method which can be applied in practical use in the near future.

Abstract High thermal conductivity aluminium-based silicon carbide (Al/SiC) composites were successfully fabricated through post-oxidization of reaction-bonded silicon carbide preforms (RS preforms), utilizing vacuum pressure infiltration technology. The study investigated the regulation of interfacial reactions in conventional sintering and reaction sintering. Conventional sintering introduced a large amount of SiO2, which negatively impacted the thermal conductivity of the Al/SiC composite, but the reaction sintering not. The proposed post-oxidization treatment of RS preforms effectively removed residual carbon from the SiC particle surfaces, thereby forestalling the formation of Al4C3. Furthermore, the post-oxidization treatment effectively formed lightweight SiO2 deposits onto the surface of SiC particles, improving Al-SiC interfacial wettability and reducing thermal resistance, thereby enhancing composite thermal conductivity. Notably, the thermal conductivity of the post-oxidized sample exhibited an increase of 6.5% compared to the untreated sample. The study also evaluated the impact of particle size distribution on volume fraction and thermal properties. The optimized Al/SiC composites yielded thermal conductivity, coefficient of thermal expansion, bending strength, and Young’s modulus values of 237.3 W/m K, 8.5 × 10−6/°C, 325 MPa, and 75.9 GPa, respectively.

Abstract Physical layer key generation (PLKG) is a technique of information-theoretic security to tackle the problem of key distribution between resource-constrained legitimate users and is a promising candidate for the one time pad (OTP) technique. However, in quasi-static, the key rate is greatly limited due to low entropy. Reconfigurable intelligent surface (RIS) is introduced to adaptively reconfigure the radio environment. However, how to allocate time slots in the OTP to counter the increasingly powerful adversary model is an urgent problem to be solved. In this paper, we propose a very powerful adversary model and give an attack strategy called eavesdropping channel search, which allows Eve to use its search and eavesdropping capabilities to maximize the probability of successful attacks. Meanwhile, we propose a time slot allocation algorithm in the OTP to ensure the security of the key. Simulations validate that our proposed attack strategy is more powerful than any existing adversary model and our proposed time slot allocation algorithm does not have any security loss.

Abstract Background The energy/protein imbalance in a low-protein diet induces lipid metabolism disorders in late-phase laying hens. Reducing energy levels in the low-protein diet to adjust the energy-to-protein ratio may improve fat deposition, but this also decreases the laying performance of hens. This study investigated the mechanism by which different energy levels in the low-protein diet influences liver lipid metabolism in late-phase laying hens through the enterohepatic axis to guide feed optimization and nutrition strategies. A total of 288 laying hens were randomly allocated to the normal-energy and normal-protein diet group (positive control: CK) or 1 of 3 groups: low-energy and low-protein diet (LL), normal-energy and low-protein diet (NL), and high-energy and low-protein diet (HL) groups. The energy-to-protein ratios of the CK, LL, NL, and HL diets were 0.67, 0.74, 0.77, and 0.80, respectively. Results Compared with the CK group, egg quality deteriorated with increasing energy intake in late-phase laying hens fed low-protein diet. Hens fed LL, NL, and HL diets had significantly higher triglyceride, total cholesterol, acetyl-CoA carboxylase, and fatty acid synthase levels, but significantly lower hepatic lipase levels compared with the CK group. Liver transcriptome sequencing revealed that genes involved in fatty acid beta-oxidation (ACOX1, HADHA, EHHADH, and ACAA1) were downregulated, whereas genes related to fatty acid synthesis (SCD, FASN, and ACACA) were upregulated in LL group compared with the CK group. Comparison of the cecal microbiome showed that in hens fed an LL diet, Lactobacillus and Desulfovibrio were enriched, whereas riboflavin metabolism was suppressed. Cecal metabolites that were most significantly affected by the LL diet included several vitamins, such as riboflavin (vitamin B2), pantethine (vitamin B5 derivative), pyridoxine (vitamin B6), and 4-pyridoxic acid. Conclusion A lipid metabolism disorder due to deficiencies of vitamin B2 and pantethine originating from the metabolism of the cecal microbiome may be the underlying reason for fat accumulation in the liver of late-phase laying hens fed an LL diet. Based on the present study, we propose that targeting vitamin B2 and pantethine (vitamin B5 derivative) might be an effective strategy for improving lipid metabolism in late-phase laying hens fed a low-protein diet.

Complex formation structures lead to significant differences in the failure mechanisms of hobs. WC-reinforced medium entropy composite coatings exhibit excellent comprehensive properties. However, the wear mechanism of coatings in different formation structures is still unclear. In this study, FeNiCr-WCx (x = 0, 40, 50, 60 wt%) composite coatings were prepared on the surface of H13 steel using laser cladding technology. The friction and wear mechanism of FeNiCr-WC composite coatings under different friction pair conditions was discussed. The results show that FeNiCr-WC composite coatings mainly consist of reinforced phase, lamellar eutectic structure and solid solution phase. As the WC content increases, the content of M6C and carbide phases in these coatings increases. The average microhardness of 40WC, 50WC and 60WC coatings is 3.28 times, 3.61 times and 4.20 times that of H13 steel, respectively. The wear rates of 40WC, 50WC and 60WC coatings are respectively about 0.25, 0.10 and 0.06 times that of FeNiCr coating under Al2O3 friction pair conditions. Three-body wear and oxidation wear mainly occurred on the surface of FeNiCr-WC composite coatings. The wear rates of 40WC, 50WC and 60WC coatings are respectively about 0.34, 0.35 and 0.16 times that of FeNiCr coating under Si3N4 friction pair conditions. Glaze layers with high Si content were formed on the surface of 50WC and 60WC coatings. The glaze layer is prone to cracking and peeling, resulting in increased wear rates for both coatings. As the hardness of the coating increases, the GCr15 friction pair undergoes severe abrasive wear.

Gene therapy is capable of efficiently regulating the expression of abnormal genes in diseased tissues and expected to be a therapeutic option for refractory diseases. However, unidirectional targeting gene therapy is always desired at the tissue interface. In this study, inspired by the principle that like charges repulse each other, a positively charged micro-nano electrospun fibrous membrane with dual-layer structure was developed by electrospinning technology to achieve unidirectional delivery of siRNA-loaded cationic nanocarriers, thus realizing unidirectional gene therapy at the tendon-paratenon interface. Under the charge repulsion of positively charged layer, more cationic COX-2 siRNA nanocarriers were enriched in peritendinous tissue, which not only improved the bioavailability of the gene drug to prevent the peritendinous adhesion formation, but also avoided adverse effects on the fragile endogenous healing of tendon itself. In summary, this study provides an innovative strategy for unidirectional targeting gene therapy of tissue interface diseases by utilizing charge repulsion to facilitate unidirectional delivery of gene drugs.

Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration (IVDD). Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc. This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1 (TGF-β1) (T-NNPs) onto the surface of methacrylic acid gelatin anhydride microspheres (GM) via amide bonds. The nanoparticle-microsphere complex (GM@T-NNPs) sustained the long-term release of T-NNPs with excellent cell-like functions, effectively bound to pro-inflammatory cytokines, and improved the release kinetics of TGF-β1, maintaining a 36 day-acting release. GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro, downregulated the expression of inflammatory factors and matrix metalloproteinase, and upregulated the expression of collagen-II and aggrecan. GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model. The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.

Abstract Quantum heat engines and refrigerators are open quantum systems, whose dynamics can be well understood using a non-Hermitian formalism. A prominent feature of non-Hermiticity is the existence of exceptional points (EPs), which has no counterpart in closed quantum systems. It has been shown in classical systems that dynamical encirclement in the vicinity of an EP, whether the loop includes the EP or not, could lead to chiral mode conversion. Here, we show that this is valid also for quantum systems when dynamical encircling is performed in the vicinity of their Liouvillian EPs (LEPs), which include the effects of quantum jumps and associated noise—an important quantum feature not present in previous works. We demonstrate, using a Paul-trapped ultracold ion, the first chiral quantum heating and refrigeration by dynamically encircling a closed loop in the vicinity of an LEP. We witness the cycling direction to be associated with the chirality and heat release (absorption) of the quantum heat engine (quantum refrigerator). Our experiments have revealed that not only the adiabaticity breakdown but also the Landau–Zener–Stückelberg process play an essential role during dynamic encircling, resulting in chiral thermodynamic cycles. Our observations contribute to further understanding of chiral and topological features in non-Hermitian systems and pave a way to exploring the relation between chirality and quantum thermodynamics.

Abstract Background Autophagy is crucial for controlling the manifestation of tuberculosis. This study intends to discover autophagy-related molecular clusters as biomarkers for discriminating between latent tuberculosis (LTBI) and active tuberculosis (ATB) in children through gene expression profile analysis. Methods The expression of autophagy modulators was examined in pediatric patients with LTBI and ATB utilizing public datasets from the Gene Expression Omnibus (GEO) collection (GSE39939 and GSE39940). Results In a training dataset (GSE39939), patients with LTBI and ATB exhibited the expression of autophagy-related genes connected with their active immune responses. Two molecular clusters associated with autophagy were identified. Compared to Cluster 1, Cluster 2 was distinguished through decreased adaptive cellular immune response and enhanced inflammatory activation, according to single-sample gene set enrichment analysis (ssGSEA). Per the study of gene set variation, Cluster 2’s differentially expressed genes (DEGs) played a role in synthesizing transfer RNA, DNA repair and recombination, and primary immunodeficiency. The peak variation efficiency, root mean square error, and area under the curve (AUC) (AUC = 0.950) were all lowered in random forest models. Finally, a seven-gene-dependent random forest profile was created utilizing the CD247, MAN1C1, FAM84B, HSZFP36, SLC16A10, DTX3, and SIRT4 genes, which performed well against the validation dataset GSE139940 (AUC = 0.888). The nomogram calibration and decision curves performed well in identifying ATB from LTBI. Conclusions In summary, according to the present investigation, autophagy and the immunopathology of TB might be correlated. Furthermore, this investigation established a compelling prediction expression profile for measuring autophagy subtype development risks, which might be employed as possible biomarkers in children to differentiate ATB from LTBI.

Abstract As a facilitator of smart upgrading, digital twin (DT) is emerging as a driving force in prognostics and health management (PHM). Faults can lead to degradation or malfunction of industrial assets. Accordingly, DT-driven PHM studies are conducted to improve reliability and reduce maintenance costs of industrial assets. However, there is a lack of systematic research to analyze and summarize current DT-driven PHM applications and methodologies for industrial assets. Therefore, this paper first analyzes the application of DT in PHM from the application field, aspect, and hierarchy at application layer. The paper next deepens into the core and mechanism of DT in PHM at theory layer. Then enabling technologies and tools for DT modeling and DT system are investigated and summarized at implementation layer. Finally, observations and future research suggestions are presented.

Abstract Background Cerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development. Methods Bulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs. Results Our study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis. Conclusion This study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes—PFDN4, CEMIP, and BTBD10—may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.

Abstract Background Chrysanthemum morifolium Ramat, a traditional Chinese medicine, has the effects on liver clearing, vision improving, and anti-inflammation. C. morifolium and probiotics have been individually studied for their beneficial effects on metabolic diseases. However, the underlying molecular mechanisms were not completely elucidated. This study aims to elucidate the potential molecular mechanisms of C. morifolium and probiotics combination (CP) on alleviating nonalcoholic fatty liver disease (NAFLD) and the dysregulation of glucose metabolism in high-fat diet (HFD)-fed mice. Methods The therapeutic effect of CP on metabolism was evaluated by liver histology and serum biochemical analysis, as well as glucose tolerance test. The impact of CP on gut microbiota was analyzed by 16S rRNA sequencing and fecal microbiota transplantation. Hepatic transcriptomic analysis was performed with the key genes and proteins validated by RT-qPCR and western blotting. In addition, whole body Pparα knockout (Pparα −/−) mice were used to confirm the CP-mediated pathway. Results CP supplementation ameliorated metabolic disorders by reducing body weight and hepatic steatosis, and improving glucose intolerance and insulin resistance in HFD fed mice. CP intervention mitigated the HFD-induced gut microbiota dysbiosis, which contributed at least in part, to the beneficial effect of improving glucose metabolism. In addition, hepatic transcriptomic analysis showed that CP modulated the expression of genes associated with lipid metabolism. CP downregulated the mRNA level of lipid droplet-binding proteins, such as Cidea and Cidec in the liver, leading to more substrates for fatty acid oxidation (FAO). Meanwhile, the expression of CPT1α, the rate-limiting enzyme of FAO, was significantly increased upon CP treatment. Mechanistically, though CP didn’t affect the total PPARα level, it promoted the nuclear localization of PPARα, which contributed to the reduced expression of Cidea and Cidec, and increased expression of CPT1α, leading to activated FAO. Moreover, whole body PPARα deficiency abolished the anti-NAFLD effect of CP, suggesting the importance of PPARα in CP-mediated beneficial effect. Conclusion This study revealed the hypoglycemic and hepatoprotective effect of CP by regulating gut microbiota composition and PPARα subcellular localization, highlighting its potential for therapeutic candidate for metabolic disorders.

CircRNAs are a class of single-stranded RNAs characterized by covalently looped structures. Emerging advances have promoted our understanding of circRNA biogenesis, nuclear export, biological functions, and functional mechanisms. Roles of circRNAs in diverse diseases have been increasingly recognized in the past decade, with novel approaches in bioinformatics analysis and new strategies in modulating circRNA levels, which have made circRNAs the hot spot for therapeutic applications. Moreover, due to the intrinsic features of circRNAs such as high stability, conservation, and tissue-/stage-specific expression, circRNAs are believed to be promising prognostic and diagnostic markers for diseases. Aiming cardiovascular disease (CVD), one of the leading causes of mortality worldwide, we briefly summarize the current understanding of circRNAs, provide the recent progress in circRNA functions and functional mechanisms in CVD, and discuss the future perspectives both in circRNA research and therapeutics based on existing knowledge.

Abstract Hydrogen emerges as a promising alternative energy source, particularly in fuel cell applications, necessitating efficient and safe charging and storage systems. This paper presents the design and development of a specialized regulator tailored for high-pressure hydrogen environments. Focusing on precision control, the regulator ensures optimal performance and safety during charging and storage phases. In order to improve the unstable response characteristics of the existing commercial hydrogen regulator, which has the same differential pressure generation site and pressure control site, a regulator operating at an ultra-high pressure of 105 MPa was designed by separating the differential pressure site and the control site. And structural safety and performance of the regulator were predicted through structural and flow analysis. The results of structural and flow analysis of a 105 MPa high-pressure regulator that can be used for high-pressure hydrogen charging and storage systems were compared with the experimentally measured values.

Abstract Timely understanding of the preservation status of archaeological human bones is the foundation for conducting scientific archaeological work. This paper applies Micro-CT technology to analyze the microscopic preservation status of ancient human femora unearthed from the Rui State site in Liangdai Village, Hancheng, Shaanxi, the Chejiasi Cemetery in Baoji, and the Ouerping Cemetery in Xizhou Village, Yushe, Shanxi, and obtained imaging results and cortical bone porosity (Ct.Po), bone volume fraction (BV/TV), and bone density (BMD) parameters for 9 samples. The results show that the poorly preserved fragile group has lower Ct.Po, BV/TV, and BMD, and macroscopically presents fragile and porous features; while the well-preserved dense group has relatively higher Ct.Po, BV/TV, and BMD, and macroscopically appears solid and dense. This study employs Micro-CT technology to analyze the micro-preservation status of human bones from historical periods, confirming the effectiveness of this technology in revealing the microstructure of ancient human bones, and providing a reference for establishing a human bone preservation status evaluation system.

Highlights Analyze the primary causes of cathode failure in three representative batteries, illustrating their underlying regeneration mechanism. The latest research status of direct regeneration of spent lithium–ion batteries was reviewed and summarized in focus. The application examples of direct regeneration technology in production practice are introduced for the first time, and the problems exposed in the initial stage of industrialization were revealed.

Purpose: To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis. Methods: A total of 282 healthy young male volunteers aged 18 – 20 years participated in this cohort study. Injury location, degree, and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries. The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly. The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5, 50, 100 and 200 kHz to obtain 4 impedance values. The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution. Data of normal distribution were shown as mean ± SD and analyzed by t-test, while those of non-normal distribution were shown as median (Q1, Q3) and analyzed by Wilcoxon rank sum test. The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy. Results: Among the 282 subjects, 78 (27.7%) developed training injuries. Lower extremity training injuries revealed the highest incidence, accounting for 23.4% (66 cases). These patients showed higher percentages of lean body mass (p = 0.001), total body water (TBW, p = 0.006), extracellular water (p = 0.020) and intracellular water (p = 0.010) as well as a larger ratio of basal metabolic rate/total weight (p = 0.006), compared with those without lower extremity muscle injuries. On the contrary, the percentage of body fat (p = 0.001) and body fat mass index (p = 0.002) were lower. Logistic regression analysis showed that TBW percentage > 65.35% (p = 0.050, odds ratio = 3.114) and 3rd space water > 0.95% (p = 0.045, odds ratio = 2.342) were independent risk factors for lower extremity muscle injuries. Conclusion: TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower extremity muscle injuries in young males following training.

Abstract Background Comprehending the patterns of alteration in boar semen quality and identifying effective nutritional interventions are crucial for enhancing the productivity of commercial pig systems. This study aimed to examine the alteration in semen quality in boars, and assess the impact of protocatechuic acid (PCA) on semen quality during the phase of declining semen quality. Methods In Exp. 1, a total of 38 Pig Improvement Company (PIC) boars were selected and their semen quality data were recorded from the age of 9 to 37 months. In Exp. 2, 18 PIC boars (28 months old) were randomly assigned into three groups (n = 6) and fed a basal diet, a basal diet containing 500 or 1,000 mg/kg PCA, respectively. The experiment lasted for 12 weeks. Results The semen volume, concentration, and total number of spermatozoa in boars exhibited an increase from 9 to 19 months old and showed a significant linear decreased trend in 28, 24, and 22 months old. Sperm motility displayed an upward trajectory, reaching its peak at 20 months of age, and showed a significant linear decreased trend at 20 months old. Dietary supplementation of PCA demonstrated an effect to mitigate the decrease in semen volume, concentration of spermatozoa, total number of spermatozoa (P > 0.05), and significantly increased the sperm motility (P

Abstract The highly unique zigzag-shaped stem phenotype in tea plants boasts significant ornamental value and is exceptionally rare. To investigate the genetic mechanism behind this trait, we developed BC1 artificial hybrid populations. Our genetic analysis revealed the zigzag-shaped trait as a qualitative trait. Utilizing whole-genome resequencing, we constructed a high-density genetic map from the BC1 population, incorporating 5,250 SNP markers across 15 linkage groups, covering 3,328.51 cM with an average marker interval distance of 0.68 cM. A quantitative trait locus (QTL) for the zigzag-shaped trait was identified on chromosome 4, within a 61.2 to 97.2 Mb range, accounting for a phenotypic variation explained (PVE) value of 13.62%. Within this QTL, six candidate genes were pinpointed. To better understand their roles, we analyzed gene expression in various tissues and individuals with erect and zigzag-shaped stems. The results implicated CsXTH (CSS0035625) and CsCIPK14 (CSS0044366) as potential key contributors to the zigzag-shaped stem formation. These discoveries lay a robust foundation for future functional genetic mapping and tea plant genetic enhancement.

Chemically protected sodium butyrate (CSB) is a novel form of sodium butyrate. This study aimed to investigate the effect of CSB supplementation on the gut mucosal immune, gut microbiota, and SCFAs in piglets. Results showed that supplementation with 2000 mg/kg (high CSB, HCSB) improved the average daily gain by 18.5 %, while supplementation with 1000 mg/kg (low CSB, LCSB) improved it by 6.9 %. qPCR results indicated HCSB treatment dramatically upregulated the mRNA expression levels of IL-10 by 47.1 %, CAT by 17.4 %, SOD1 by 48.2 %, and Claudin-1 by 50 %. Additionally, the SCFAs-producing bacteria Parabacteroides and Eubacterium coprostanoligenes were increased by HCSB supplementation. The levels of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid were significantly enhanced in the jejunal, duodenal, cecal, and colonic chyme of piglets by HCSB supplementation. Collectively, CSB supplementation improves anti-inflammatory and antioxidant capacities potentially through modulating gut microbiota and SCFAs in piglets.

Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation in vitro, but its in vivo effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU0.89@LA, WPU0.99@LA, WPU1.09@LA, and WPU1.19@LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU0.99@LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU0.99@LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene (mcr-1) by more than 45.1-fold. In vivo toxicity assessment demonstrated that 10 mg/kg/day WPU0.99@LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU0.99@LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.

Abstract Nanographene oxide (nGO) flakes—graphene oxide with a lateral size of ≈100 nm or less—hold great promise for superior flux and energy‐efficient nanofiltration membranes for desalination and precise ionic sieving owing to their unique high‐density water channels with less tortuousness. However, their potential usage is currently limited by several challenges, including the tricky self‐assembly of nano‐sized flakes on substrates with micron‐sized pores, severe swelling in aqueous solutions, and mechanical instability. Herein, the successful fabrication of a robust membrane stacked with nGO flakes on a substrate with a pore size of 0.22 µm by vacuum filtration is reported. This membrane achieved an unprecedented water permeance above 819.1 LMH bar−1, with a high rejection rate of 99.7% for multivalent metal ions. The nGO flakes prepared using an electron beam irradiation method, have uniquely pure hydroxyl groups and abundant aromatic regions. The calculations revealed the strong hydrogen bonds between two nGO flakes, which arise from hydroxyl groups, coupled with hydrophobic aromatic regions, greatly enhance the stability of stacked flakes in aqueous solutions and increase their effective lateral size. The research presents a simple yet effective approach toward the fabrication of advanced 2D nanographene membranes with superior performance for ion sieving applications.

ObjectiveVulvar carcinoma exhibits a robust correlation alongside HPV infection; however, the impact of HPV rank on the prognostic outcomes of radiation therapy within vulvar malignancies stays ambiguous. In the present study, we performed a comprehensive examination as well as meta-analysis to assess the influence of infection with HPV upon the long-term outlook as well as sensitivity of individuals with vulvar cancer undergoing radiation therapy.MethodsA meticulous examination of the existing research was conducted in accordance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A thorough search was conducted in the PubMed, Embase, Web of Science, as well as Cochrane Library databases, covering the entire available literature till April 1, 2023. The studies that met the inclusion criteria contained data about HPV infection and oncological outcomes in patients with vulvar cancer who received radiation therapy. This study was registered in PROSPERO (CRD42023417957).ResultsWe identified 12 retrospective studies meeting our inclusion criteria, which included a total of 3967 patients. Patients with HPV-associated vulvar cancer achieved a better overall survival rate after radiotherapy (HR=0.71, 95%CI: 0.54-0.93, P=0.01), and showed a significant improvement in disease-free survival (HR=0.75, 95%CI: 0.58-0.97, P=0.09) and progression-free survival (HR=0.31, 95%CI: 0.22-0.45, P,

Summary: The strategy of lowering cholesterol levels by promoting cholesterol excretion is still lacking, and few molecular targets act on multiple cholesterol metabolic processes. In this study, we find that Nogo-B deficiency/inhibition simultaneously promotes hepatic uptake of cholesterol and cholesterol excretion. Nogo-B deficiency decreases cholesterol levels by activating ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR) expression. We discover that Nogo-B interacts with liver X receptor α (LXRα), and Nogo-B deficiency inhibits ubiquitination degradation of LXRα, thereby enhancing its function on cholesterol excretion. Decreased cellular cholesterol levels further activate SREBP2 and LDLR expression, thereby promoting hepatic uptake of cholesterol. Nogo-B inhibition decreases atherosclerotic plaques and cholesterol levels in mice, and Nogo-B levels are correlated to cholesterol levels in human plasma. In this study, Nogo-B deficiency/inhibition not only promotes hepatic uptake of blood cholesterol but also facilitates cholesterol excretion. This study reports a strategy to lower cholesterol levels by inhibiting Nogo-B expression to promote hepatic cholesterol uptake and cholesterol excretion.

Targeting nucleotide enzymes emerges as a promising avenue for impeding tumor proliferation and fortifying anti-tumor immunogenicity. The non-canonical role of nucleotide enzymes remains poorly understood. In this study, we have identified that Phosphoglucomutase 2 (PGM2) rapidly accumulates at the DNA damage site to govern the DNA damage response mediated by the phosphorylation at Serine 165 and by forming a complex with Rho-associated coiled-coil-containing protein kinase 2 (ROCK2). Silencing PGM2 in Glioblastoma Multiforme (GBM) cells heightens DNA damage in vitro and enhances the sensitivity of temozolomide (TMZ) treatment by activating anti-tumor immunity in vivo. Furthermore, we demonstrate that pharmacological inhibition of ROCK2 synergistically complements TMZ treatment and pembrolizumab (PD-L1) checkpoint immunotherapy, augmenting anti-tumor immunity. This study reveals the non-canonical role of the nucleotide enzyme PGM2 in the regulation of DNA damage response and anti-tumor immunity, with implications for the development of therapeutic approaches in cancer treatment.

Working fluid selection for closed-cycle turbo-refrigerators (CCTRs) for deep freezing, as a more fundamental topic, has not yet received careful consideration, leading to limitations in attempts to optimizing CCTR design in the early stages of cycle design. This paper proposed the working fluid selection criteria that to select the one leading to the lowest system weight and volume without compromising the system energy efficiency. Design criteria, such as specific speed and Reynolds number, and their dependence on fluid properties are introduced to ensure uncompromising-efficiency design of turbomachinery. Normalized heat transfer area of recuperator correlated with fluid properties is derived as the evaluation criterion for system weight and volume. Applying the proposed criteria, the comparison between potential pure gases shows the normalized heat transfer areas required for nitrogen, neon, and argon are 1, 1.54 and 2.18, respectively. Therefore, nitrogen among all pure gases has the greatest potential to reduce system weight and volume. The comparison among potential binary mixtures highlights the methane-nitrogen mixture with the molar mass of 24.1 g/mol which reduces the required heat transfer area by approximately 20 % compared to pure-nitrogen-based system and may reduce it by nearly up to 30 % for systems with larger cooling capacity levels.

There is a gradual increase in the discharge of saline wastewater which is harmful to the environment and human health. A novel heat pump air circulation evaporating separation (HP-ACES) system for saline wastewater treatment is proposed and experimentally investigated. The results show that the system evaporation efficiency (SEE) initially decreases before increasing with the expansion valve opening at different refrigerant charges. However, the SER increases by 0.67 kg/h at 1.21 kg refrigerant charge while they descend and then rise at 1.53 and 1.86 kg refrigerant charges. Noted that the effects of expansion valve opening on the SER and SEE are lessened with refrigerant charge. Moreover, there exist the optimal values of total air flow and air flow proportion of packing concentration tower at which the SER and SEE peak, and both of the solution concentration and cooling water flow negatively affect the SER and SEE. Besides, compared with similar evaporating separation systems, the HP-ACES system has higher energy efficiency for treating high saline wastewater and the SEE ranges from 0.86 to 1.64 kg/kWh (5–25 % CaCl2 solution). However, the SEE is low, and it is necessary to reveal the cause and propose the optimization schemes in the future.

Assessing carbon emissions in China’s swine industry and understanding its spatial–temporal characteristics under carbon peak and carbon neutrality goals are vital for promoting low-carbon farming. This study measures the swine industry’s carbon emissions across 30 provinces in China from 2006 to 2022 using life cycle assessment and IPCC coefficient methods. Spatial and temporal patterns were analyzed with exploratory spatial data analysis, and an XGBoost model was used to predict emissions from 2023 to 2032. The results show a “W”-shaped oscillating trend in total carbon emissions, with phases of rapid decline, fluctuating rise, fluctuating decline, and rapid resurgence. Emissions were highest in the Central region, followed by the West, East, and Northeast. Manure management and Feed crop cultivation were the primary emission sources, accounting for 59.7% and 29.9% of total emissions, respectively. The spatial pattern of high and low emission regions remained stable, with dynamic changes in moderate emission regions. High emissions were concentrated in the major grain-producing and livestock-raising and the South China coastal farming regions. The XGBoost model projects that China’s green development measures in the swine industry will have a significant future impact. The carbon emission intensity shows a trend of initial decline followed by stabilization, whereas total carbon emissions are projected to remain high and gradually increase, primarily due to continuous growth in production capacity. The conclusions of this study provide a reference basis for the green and low-carbon transformation of the swine industry and the optimization of the regional layout of the livestock industry.

Lipopolysaccharide (LPS) acts as a trigger that disrupts metabolic functions and the immune system. While bile acids (BA) have detoxification and anti-inflammatory effects, their role in promoting LPS excretion in broiler chickens remains unclear. This study aimed to investigate the potential of exogenous BA to enhance hepatic clearance of LPS and thereby potentially alleviate LPS-induced liver injury in broiler chickens. Forty-five 21-day-old male broiler chickens were randomly assigned to three groups: the control group, which received daily intraperitoneal injections of a solvent for LPS treatment and a gavage solvent for BA treatment; the LPS group, which received daily intraperitoneal injections of 0.5 mg/kg body weight LPS and a gavage solvent for BA treatment; the LPS + BA group, which received daily intraperitoneal injections of 0.5 mg/kg body weight LPS and 60 mg/kg body weight BA by gavage. BA administered by gavage protected the broiler chickens from increases in liver and spleen indices, systemic inflammatory response, and hepatic damage induced by LPS. Hepatic clearance of LPS was enhanced, as evidenced by decreased serum LPS levels and accelerated excretion into the gallbladder. Additionally, the LPS-induced downregulation of detoxification genes, including those for the lipoprotein receptor and bile acids export pump, was reversed by BA administered by gavage. Furthermore, nuclear transcription factors such as the Farnesoid X receptor (FXR) and Liver X receptor α (LXRα) were enhanced in BA-treated broiler chickens. These findings suggest that BA administration via gavage enhances hepatic LPS clearance through the upregulation of hepatic uptake and efflux proteins, likely mediated by the activation of nuclear transcription factors FXR and LXRα.

The Kirkpatrick–Baez (KB) microscope is an effective instrument for x-ray imaging of hot spot. However, the non-uniform distribution of response efficiency in the field of view is a drawback of the KB microscope. A more accurate hot spot image requires the correction of the measured image by combining the hot spot position and the response efficiency distribution. Here, we describe a method to locate the position of the hot spot in the field of view during hot spot imaging with a KB microscope. The position of the hot spot in the field of view can be obtained by measuring the grazing incidence angle change during hot spot imaging. In the experiment of hot spot self-emission imaging with a four-channel KB microscope, the location of the hot spot with an accuracy of 15 μm was realized, and the intensity corrected hot spot image was obtained. This will solve the problem of the non-uniform distribution of the response efficiency of the KB microscope and enable quantitative measurement of hot spot radiation intensity.

Holographic display is considered the holy grail of photorealistic three-dimensional (3D) visualization technology because it can provide arbitrary wavefronts related to the essential visual cues of 3D images. Metasurfaces with exceptional high-pixel light modulation capability are increasingly favored for implementing high-quality 3D holography. However, current 3D metasurface holography always has some trade-offs among lots of algorithmic data, acceptable time, image quality, and structure complexity. Therefore, the development of a high-efficiency 3D metasurface holography device is still necessary to meet the increasing high space bandwidth product (SBP) of 3D technology. Here, based on the holographic-lens (HL) computer-generated hologram (CGH) algorithm, we experimentally demonstrate a new 3D metasurface holography device that integrates the 3D image phase cues and multiple layers of virtual lenses with different focal lengths, which exhibits significant capabilities in terms of ultra-high spatial pixel modulation and the generation of high-quality 3D holography characterized by high-efficiency, broadband response, low-crosstalk, and reduced acceptable time. The HL-CGH algorithm was efficiently integrated into parameter-optimized α-Si nanopillar meta-atoms, enabling enhanced visualization of 3D clues in a lens-free system. The prepared 3D HL-metasurface holography presented the presence of multiple depths of a 3D holographic image across a broad spectral range (400–900 nm), providing enhanced 3D visual cues. Our work provides a new perspective on designing metasurface-driven high-SBP 3D holography.

Introduction The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC. Methods and analysis This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events. Ethics and dissemination Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events. Trial registration numbers Clinicaltrials.gov identifier NCT06198387.

IntroductionThe immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk.MethodsEmploying data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19.ResultsThe inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699–0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013–1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits.ConclusionIn this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease.

IntroductionEnterobacter chengduensis was defined as a novel species in the genus. Enterobacter in 2019, however, antimicrobial resistance, such as carbapenem resistance, has rarely been described in E. chengduensis. This study described the molecular features of four carbapenem-resistant E. chengduensis strains collected from a tertiary health care hospital in Southwest China.MethodsWhole genome sequencing (WGS) was used to determine the genome sequence of four E. chengduensis strains. The precise species of strains were identified by average nucleotide identity (ANI) and in silico DNA-DNA hybridization (isDDH). The clonal relatedness of four E. chengduensis strains and additional 15 ones from NCBI were examined through phylogenetic analysis. The molecular features of E. chengduensis and genetic structure of carbapenemase- encoding plasmids were characterized through genomic annotation and analysis.ResultsThe results revealed the emergence of blaNDM–1-carrying E. chengduensis strains in China. Multilocus sequence typing (MLST) analysis showed that all 19 E. chengduensis belonged to the same sequence type of ST414. Core SNP analysis suggested the potential intrahospital clonal transmission of ST414 E. chengduensis. The carbapenemase-encoding gene blaNDM–1 was harbored by an IncC-type plasmid, which was experimentally confirmed to be able to conjugate.DiscussionThis study reports the first emergence and potential clonal transmission of blaNDM–1-carrying E. chengduensis. Further surveillance should be advocated to monitor the dissemination of carbapenem-resistant E. chengduensis and blaNDM–1-harboring IncC-type plasmids in China.

As a low-toxicity metal, aluminum has garnered increasing attention in relation to its impact on the human body; however, the specific mechanism of action remains unclear. To bridge this knowledge gap and facilitate practical applications, this study took 8-week-old ICR mice as the research object to study the effects of dietary addition of aluminum potassium sulfate on intestinal flora structure and liver. As the concentration of aluminum increased, it inhibited mice weight growth rate and significantly altered the composition of white blood cells in their bloodstream. Histological examination revealed liver inflammation through HE staining sections. The oxidative stress markers MDA increased, GSH-PX and CAT decreased significantly. And liver function index MAO increased, TC and ALP decreased first and then increased. Moreover, there was a significant increase in pro-inflammatory factor TNF-α content. Further 16S rRNA sequencing analysis demonstrated substantial changes in both composition and structure of mouse intestinal microbiota induced by aluminum exposure; microbial phenotype prediction indicated that aluminum-induced oxidative stress promoted an increase in abundance of oxidation-resistant microbial types. Alterations in gut flora structure also influenced the liver via the gut-liver axis. These findings lay a foundation for further research on the regulation and interaction of aluminum on intestinal flora.

Background: The variability of humeral head angulation in proximal humerus fractures (PHFs) is a noteworthy observation. The purpose of this study was to investigate the potential association between humeral head angulation and bone void within the humeral head in PHFs. Methods: We used the reconstruction function in Mimics software to generate three-dimensional models of fractures. Bony landmarks were employed to accurately define the calcar and humeral head zone. Boolean subtraction was performed to calculate the volume of head bone void. Results: The cohort consisted of 60 (74.1 %) varus, 21 (25.9 %) valgus, and 23 (22.1 %) neutral angulated PHFs. The mean percentage of humeral head bone void was 38.5 ± 17.8 in varus, 36.3 ± 15.7 in valgus, and 30.1 ± 10.6 in neutral angulated PHFs. A significant difference was observed between the varus and neutral groups (P = 0.035). In addition, an analysis of humeral head bone void was conducted among patients aged over 65 years old, revealing a mean percentage of 42.7 ± 16.4 in varus (27 cases), 34.8 ± 14.5 in valgus (13 cases), and 28.1 ± 11.8 in neutral (8 cases) angulated PHFs. The difference between the varus and neutral groups was also significant (P = 0.023). Conclusion: All types of angulation patterns exhibited humeral head bone void to some extent, with the varus-displaced PHFs demonstrating more obvious defects in comparison to the neutral angulated type.

BackgroundTunneling technique has shown preliminary promise in lung segmentectomy which requires the use of staplers in specific procedures. However, the obstacle when staples pass is the most obvious factor hindering the implementation and development of this technique. This study investigated whether the obstacle of the technology could be addressed by using an innovative self-designed stapler tractor and analyzed the combined and respective advantages of them.MethodsThe clinical data of patients with lung nodules located near anatomical sites with potential tunnel creation treated by segmentectomy were analyzed in this retrospective case-control study. The data were divided into four groups according to four distinct surgical strategies: In Group A, the tunneling technique was performed with a stapler tractor; in Group B, the tunneling technique was performed without a stapler tractor; in Group C, didn’t perform the tunneling technique but using stapler tractor in a normal approach; and in Group D, neither performed the technique nor used the stapler tractor. The general linear data, operation times, intraoperative adverse events, postoperative recovery and complications were compared.ResultsCompared with other groups, Group A exhibited the best surgical outcomes in comprehensive aspects. Separately, the tunnel groups (Group A&B) had better outcomes in the macro implementation of operation, including resection margin, the number of sampled intrapulmonary lymph nodes and resected subsegments, while the staple tractor groups (Group A&C) performed better on details of the procedure, including operation time, conversion to thoracotomy, and intraoperative bleeding (p < 0.05). Both of them were beneficial for shorter hospital stay, and the tunnel group was more advantageous.ConclusionThe tunneling technique is an advanced and beneficial surgical strategy for performing precise resection of lung segments while a stapler tractor can promote and facilitate it as a supplementary instrument. They show more combined benefits in effectively minimizing the occurrence of erroneous injuries and enhancing the operational efficacy.

Abstract Immunosuppression is a major hallmark of tumor progression in non‐small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro‐tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di‐methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di‐methylation of CD147 at Lys148 (CD147‐K148me2) is identified as a common post‐translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147‐K148me2. Further analysis demonstrates that CD147‐K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38‐ZBTB32 signaling, leading to increased NSCLC cell‐derived CCL5 secretion. Subsequently, CD147‐K148me2‐mediated CCL5 upregulation facilitates M2‐like tumor‐associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis‐dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147‐K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147‐K148me2‐driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM‐targeted NSCLC therapy.

ABSTRACT Staphylococcus aureus is a leading cause of healthcare-associated infections globally. Vancomycin-resistant S. aureus (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC) of 16–32 µg/mL vancomycin], are uncommon, whereas vancomycin-intermediate S. aureus (VISA; MIC of 4–8 µg/mL), are isolated more frequently and develop during long-term and/or repeated use of the antibiotic. VISA can be difficult to eradicate and infections may persist. Our knowledge of mechanisms that underlie the development of VISA is incomplete. We used a genomics approach to investigate the VISA phenotype in three prominent S. aureus lineages. All VISA clinical isolates tested had increased cell wall thickness compared with vancomycin-susceptible S. aureus strains. Growth rates of clonal complex (CC) 5, CC8, and CC45 clinical isolates were reduced in 2 µg/mL vancomycin compared to media alone. Culture in 2 and 4 µg/mL vancomycin sequentially for two weeks reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin in a majority of CC5, CC8, and CC45 isolates tested. We identified alleles reported previously to contribute to the VISA phenotype, but unexpectedly, these alleles were unique to each CC. A subtherapeutic concentration of vancomycin elicited changes in the VISA transcriptome—common and unique—among the three CCs tested. Multiple genes, including those encoding a glycerate kinase, an M50 family metallopeptidase, and an uncharacterized membrane protein, were upregulated among all three lineages and not reported previously as associated with VISA. Although there are lineage-specific changes in DNA sequence, our findings suggest changes in the VISA transcriptome constitute a general response to stress that confers reduced susceptibility to multiple antibiotics.IMPORTANCEOur understanding of the mechanisms that underlie the development of vancomycin-intermediate Staphylococcus aureus (VISA) is incomplete. To provide a more comprehensive view of this process, we compared genome sequences of clonal complex (CC) 5, CC8, and CC45 VISA clinical isolates and measured changes in the transcriptomes of these isolates during culture with a subtherapeutic concentration of vancomycin. Notably, we identified differentially expressed genes that were lineage-specific or common to the lineages tested, including genes that have not been previously reported to contribute to a VISA phenotype. Changes in gene expression were accompanied by reduced growth rate, increased cell wall thickness, and reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin. Our results provide support to the idea that changes in gene expression contribute to the development of VISA among three CCs that are a prominent cause of human infections.

Summary: R-loops play diverse functional roles, but controversial genomic localization of R-loops have emerged from experimental approaches, posing significant challenges for R-loop research. The development and application of an accurate computational tool for studying human R-loops remains an unmet need. Here, we introduce DeepER, a deep learning-enhanced R-loop prediction tool. DeepER showcases outstanding performance compared to existing tools, facilitating accurate genome-wide annotation of R-loops and a deeper understanding of the position- and context-dependent effects of nucleotide composition on R-loop formation. DeepER also unveils a strong association between certain tandem repeats and R-loop formation, opening a new avenue for understanding the mechanisms underlying some repeat expansion diseases. To facilitate broader utilization, we have developed a user-friendly web server as an integral component of R-loopBase. We anticipate that DeepER will find extensive applications in the field of R-loop research.

The emergence and dissemination of antibiotic resistance genes (ARGs) in the ecosystem are global public health concerns. One Health emphasizes the interconnectivity between different habitats and seeks to optimize animal, human, and environmental health. However, information on the dissemination of antibiotic resistance genes (ARGs) within complex microbiomes in natural habitats is scarce. We investigated the prevalence of antibiotic resistant bacteria (ARB) and the spread of ARGs in intensive bullfrog (Rana catesbeiana) farms in the Shantou area of China. Antibiotic susceptibilities of 361 strains, combined with microbiome analyses, revealed Escherichia coli, Edwardsiella tarda, Citrobacter and Klebsiella sp. as prevalent multidrug resistant bacteria on these farms. Whole genome sequencing of 95 ARB identified 250 large plasmids that harbored a wide range of ARGs. Plasmid sequences and sediment metagenomes revealed an abundance of tetA, sul1, and aph(3″)-Ib ARGs. Notably, antibiotic resistance (against 15 antibiotics) highly correlated with plasmid-borne rather than chromosome-borne ARGs. Based on sequence similarities, most plasmids (62%) fell into 32 distinct groups, indicating a potential for horizontal plasmid transfer (HPT) within the frog farm microbiome. HPT was confirmed in inter- and intra-species conjugation experiments. Furthermore, identical mobile ARGs, flanked by mobile genetic elements (MGEs), were found in different locations on the same plasmid, or on different plasmids residing in the same or different hosts. Our results suggest a synergy between MGEs and HPT to facilitate ARGs dissemination in frog farms. Mining public databases retrieved similar plasmids from different bacterial species found in other environmental niches globally. Our findings underscore the importance of HPT in mediating the spread of ARGs in frog farms and other microbiomes of the ecosystem.