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Abstract Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments. One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser, which employs narrow laser beams to stimulate dermal collagen deposition. Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes. Here, we examine the efficacy and safety of a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors, referred to as combined therapy, for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors, referred to as monotherapy. Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy), which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data. Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P

Abstract This was a multicenter, single-arm, open-label, phase Ib/II study (NCT04255576), aimed to evaluate the efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone (GCTB). JMT103 (2 mg/kg) was administered subcutaneously every four weeks, with loading doses on days 8 and 15. The primary endpoint was the objective tumor response rate (OTR) based on best response, defined as the proportion of patients who achieved elimination of at least 90% of the giant cells or radiologic complete or partial response per the modified Inverse Choi density/size (mICDS) or modified European Organization for Research and Treatment of Cancer (mEORTC) within 12 weeks. Secondary endpoints included objective response rate (ORR) per mICDS and mEORTC, and safety. A total of 139 patients were enrolled, and 135 were analyzed for efficacy. OTR, determined by the independent review committee (IRC) was 93.3% (95% CI 87.7-96.9). Treatment-related adverse events occurred in 90 (64.7%) patients, with hypophosphatemia and hypocalcemia being the most common. No serious treatment-related adverse events were observed. Thus, JMT103 demonstrates potential as a therapeutic option for GCTB.

Abstract Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68+PD-L1+ PD-1+ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC.

Abstract Objective To evaluate value of Nomogram prediction model based on CTA imaging features for selecting treatment methods for isolated superior mesenteric artery dissection (ISMAD). Methods Symptomatic ISMAD patients were randomly divided into a training set and a validation set in a 7:3 ratio. In the training set, relevant risk factors for conservative treatment failure in ISMAD patients were analyzed, and a Nomogram prediction model for treatment outcome of ISMAD was constructed with risk factors. The predictive value of the model was evaluated. Results Low true lumen residual ratio (TLRR), long dissection length, and large arterial angle (superior mesenteric artery [SMA]/abdominal aorta [AA]) were identified as independent high-risk factors for conservative treatment failure (P

The use of weak passwords is a significant vulnerability in computer information system security, and this issue is also present in the digital applications of grain storage information systems. Simple hashing algorithms have obvious limitations when dealing with weak passwords. Based on the actual application of grain storage software systems, this paper proposed a method to enhance weak password protection by using a hashing algorithm as the foundation, combined with the introduction of salt values and high-order reflections for strengthening, along with multiple rehashing operations. Validation and analysis showed that this method increased the hashing strength of weak passwords, and effectively prevented dictionary attacks or rainbow table attacks, which could achieve the effective protection for the transmission and storage of weak passwords. Additionally, it had low complexity, and was easy to implement. It also had an average computational latency of approximately 2.5 ms, which was imperceptible to users. This method is suitable for the construction and management of digital grain storage information systems, providing robust security protection.

Abstract Osteoarthritis is a degenerative joint disease with joint pain as the main symptom, caused by fibrosis and loss of articular cartilage. Due to the complexity and heterogeneity of osteoarthritis, there is a lack of effective individualized disease-modifying osteoarthritis drugs in clinical practice. Chondrocyte senescence is reported to participate in occurrence and progression of osteoarthritis. Here we show that small molecule 10-hydroxy-2-decenoic acid suppresses cartilage degeneration and relieves pain in the chondrocytes, cartilage explants from osteoarthritis patients, surgery-induced medial meniscus destabilization or naturally aged male mice. We further confirm that 10-hydroxy-2-decenoic acid exerts a protective effect by targeting the glycosylation site in the Asp_Arg_Hydrox domain of aspartyl β-hydroxylase. Mechanistically, 10-hydroxy-2-decenoic acid alleviate cellular senescence through the ERK/p53/p21 and GSK3β/p16 pathways in the chondrocytes. Our study uncovers that 10-hydroxy-2-decenoic acid modulate cartilage metabolism by targeting aspartyl β-hydroxylase to inhibit chondrocyte senescence in osteoarthritis. 10-hydroxy-2-decenoic acid may be a promising therapeutic drug against osteoarthritis.

Abstract Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.

Abstract The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P

Abstract This research explores the spatial distribution patterns of water engineering facilities along the Grand Canal during the Ming and Qing dynasties. It employs the entropy method to assess the social development status of prefectures during these periods and uses the Tobit model to examine the primary indicators influencing the distribution of water engineering facilities. The results show that the spatial distribution pattern of water engineering facilities was characterized by aggregation during the Ming and Qing dynasties. In contrast, the Qing dynasty’s distribution was more dispersed, with a shift in the construction focus of water engineering facilities towards the south. The spatial distribution pattern of water engineering facilities in the Ming Dynasty centered around the hotspot areas of Shuntian Prefecture, Yanzhou Prefecture, and Yangzhou Prefecture. During continuous improvements, these facilities exhibited a multi-point-regional aggregation phenomenon.The influence of commercial development indicator on the spatial distribution of water engineering facilities is positively correlated in both the Ming and Qing dynasties. However, the impacts of the indicator on different types of water engineering facilities vary between the two dynasties. During the Ming Dynasty, the indicators of transportation accessibility and cultural prosperity facilitated the construction of regional water engineering facilities, whereas in the Qing Dynasty, they significantly influenced several types of water engineering facilities. During the Ming and Qing Dynasties, neither the agricultural development indicator nor the population size indicator significantly affected the distribution of water engineering facilities. However, there was a negative correlation between the population size indicator and the distribution of water distribution facilities in the Ming Dynasty. This study enhances the importance of environmental protection in historical societies and provides a valuable reference for other international studies of linear cultural and material heritage.

To effectively mitigate failures in interdependent systems during targeted-attack scenarios, a common approach is to pre-store repair resources. The question arises: what constitutes an appropriate quantity of these pre-stored repair resources? The paper introduces a novel recovery strategy aimed at providing guidance for this issue. Current recovery strategies frequently emphasize the dynamic interplay between cascading failures and recovery processes, indicating that interventions during the recovery phase are permissible. In this context, the recovery strategy focus on recovering a predetermined number of failed nodes that are adjacent to the largest connected component of each individual network, along with their dependent nodes, at each recovery stage. Simulation results demonstrate that this strategy significantly enhances the capacity to prevent system breakdowns for interdependent networks subjected to targeted attacks. Therefore, by determining the necessary recovery steps to prevent system failures and the appropriate repair resources required for each step, this novel strategy can serve as a valuable reference for the pre-storage of repair resources. Significantly, the strategy can be effectively applied to interdependent networks associated with critical infrastructure, such as power grids and communication networks.

AimTo identify optimally therapeutic exercise interventions for improving motor ability among patients with Parkinson’s disease (PD), we conducted a network meta-analysis (NMA) of randomized controlled trials comparing different exercise regimens.MethodsRelevant RCTs were retrieved by searching PubMed, Embase, Cochrane, Web of Science, CINAHL, CBM, China National Knowledge Infrastructure (CNKI), Wan fang, VIP, and other databases from inception to July 9, 2023 is available in English as the primary language. Exercise outcomes as measured by Movement Disorder Society- Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) score change were evaluated and ranked using STATA software version 18.0. All included studies were assessed for methodological quality using the Cochrane Risk of Bias tool.ResultsThe final NMA included 71 studies involving 3,732 participants, 87 intervention experiments, and 27distinct interventions. Although most exercise interventions showed some efficacy (reducing MDS-UPDRS-III score), cumulative ranking probability surface (SUCRA) values indicated that the best exercise interventions for motor function improvement were archery (95.6%), riding a bicycle (80.9%), and binary rhythm dance (80.8%).ConclusionAn exercise intervention comprising archery, cycling, and(or) binary rhythm dance may yield superior improvements in motor function among patients with Parkinson’s disease.

Abstract: Based on the summary and review of the pedagogical application of Singing as primary Chinese teaching method in the University of N'Djamena, the Republic of Chad, this paper illustrates the problem of "what to sing and how to sing" in learning Chinese. It also demonstrates that it is feasible to use singing Chinese songs as the main teaching tool in teaching oral Chinese at the basic level by combining theoretical demonstration and case analysis. With regard to the compilation of the lyrics of Chinese songs for teaching, this paper puts forward the principle of "concise and practical, harmonious rhyme and artistic conception". For the music arrangement, the author puts forward the method of using new words to modify old songs. This paper illustrates with examples that "learning Chinese by singing" still has broad development space and requires further study. Keywords: Learning Chinese through songs; Singing as primary Chinese teaching method; Theoretical basis; Lyrics compilation; Music orchestration.

Carbon fibre dispersion exerts a critical influence on the characteristics of carbon fibre-reinforced cement mortars (CFRCMs). This study accordingly investigated the dispersion of chopped carbon fibres (CCFs) in mortar using physical experiments with a transparent simulated mortar system comprising colloidal silica and silica sand as replacements for cement and aggregate, respectively, and evaluated the microstructures and conductive performances of corresponding CFRCM specimens. In the simulated solutions, bundled CCFs in order were more prone to disperse into single fibres than clustered ones in disorder due to no physical fixation, colloidal silica prevented the formation of CCF clusters during stirring, and the shear force of moving sand dispersed but also broke CCFs. In the CFRCMs, sand aggregates reaggregated dispersed CCFs while larger sand particles increased CCF dispersion and improved specimen conductivity. Thus, decreasing the amount of CCFs clusters before dispersion, and a short stirring time in a single direction should be provided to prepare CFRCMs with well-dispersed CCFs. Meanwhile, a more dispersible aggregate and less formation of void should be also essential.

Abstract Background Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. Methods RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. Results PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. Conclusions PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Abstract The purpose of this study is to compare the relative efficacy and safety of long-acting growth hormone (LAGH) as a growth hormone replacement therapy in prepubertal children with growth hormone deficiency (GHD). We searched the PubMed, Embase, CNKI, and Wanfang databases from inception to July 2023 and identified eleven relevant studies. PEG-LAGH showed better effect on height velocity (mean difference [MD]: − 0.031, 95% credibility interval [CrI]: − 0.278, 0.215) than somatrogon (MD: 0.105, 95% CrI: − 0.419, 0.636), somapacitan (MD: 0.802, 95% CrI: − 0.451, 2.068) and lonapegsomatropin (MD: 1.335, 95% CrI: − 0.3, 2.989) when compared with daily growth hormone (DGH). Furthermore, in terms of height standard deviation score, PEG-LAGH demonstrated better improvement (MD: − 0.15, 95% CrI: − 1.1, 0.66) than somatrogon (MD: − 0.055, 95% CrI: − 1.3, 0.51) and somapacitan (MD: 0.22, 95% CrI: − 0.91, 1.3). PEG-LAGH (risk ratio [RR]: 1.00, 95% CrI: 0.82, 1.2) reduced the risk of adverse events compared with other LAGH (somatrogon, RR: 1.1, 95% CrI: 0.98, 1.2; somapacitan, RR: 1.1, 95% CrI: 0.96, 1.4; lonapegsomatropin, RR, 1.1, 95% CrI: 0.91, 1.3) and was comparable with DGH. This is the first study to indirectly compare the LAGH thorough a network meta-analysis and provide evidence of the optimal efficacy of various LAGH specifically PEG-LAGH and acceptable safety profile in prepubertal children with GHD.

The high sulfate content and low pH of wastewater from ionic rare earth mine in southern Jiangxi Province affect the treatment of other components（NH4+-N，NO3--N） of the wastewater by downstream microorganisms. Particle-encapsulated sulfate-reducing bacteria（SRB） can effectively remove sulfate ions and increase the pH of water. In the present study， four components of SRB embedded particles including surface adsorption materials，reduction activation materials，cohesive carbon sources and solid acid hydrolysis materials were researched. The optimization results indicated that the application effect of attapulgite powder as the surface adsorption material for SRB embedded particles was relatively good，and the reduction activation effect of nano-zero-valent iron was relatively better. The combination of a cohesive carbon source and solid acid hydrolysis material consisting of corn kernel，peanut shell and zeolite powder，Fe3O4 powder yielded the relatively favorable outcome. On this basis，four types of embedded particles were screened and prepared，and their removal efficiencies of SO42- in simulated wastewater were verified through anaerobic triangular flasks. It was found that the four prepared embedded particles had removal rates of over 60% for SO42- after 10 days of experimentation，and the highest removal rate was attributed to the peanut shell-Fe3O4 combined embedded particles，which was 80.20%.

In this work, an Ag–Ti2SnC composite was fabricated by the hot-pressing sintering method, and the erosion behavior of Ag–Ti2SnC with volume percentages of 10–40% was studied at a load voltage of 10 kV. The arc life and breakdown current were observed at about 31–36 ms and 39 A, respectively. The cathode spot traveled the fastest on the surface of the Ag–40 vol% Ti2SnC composite. Due to emission center model, the temperature of the minor protrusions on the cathode surface increased, resulting in Ag ions, Ti ions, and Sn ions being generated. Combining with the ionized oxygen, Ag2O, AgO, TiO2, and SnO2 were formed on the eroded Ag–Ti2SnC surface after arc erosion. The research results will broaden the application range of Ag–Ti2SnC electrical contact material and enrich the arc erosion mechanism.

Abstract Background The aim of the study was to investigate whether the expression of CD27−CD38+ in interferon (IFN)-γ+CD4+ T cells stimulated by the specific antigen early secreted antigenic target-6 (ESAT-6)/culture filter protein-10 (CFP-10) could be a potential new therapeutic evaluation indicator for anti-tuberculosis (TB) treatment. Methods Newly diagnosed active pulmonary TB patients, latent TB infection (LTBI) and healthy controls were enrolled from January 2021 to December 2021. PTB patients were treated by standard anti-TB regimen 2HREZ/4HR (2 months of isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (Z) followed by 4 months of isoniazid (H) and rifampin (R)). The difference of CD27−CD38+ expression in IFN-γ+CD4+ T cells before treatment, 2 months after treatment, and 6 months after treatment were compared. Results Total 45 PTB patients, 38 LTBI cases and 43 healthy controls were enrolled. The expression of CD27−CD38+ decreased significantly after anti-TB treatment and was comparable with that in LTBI and healthy controls when the 6-month anti-TB treatment course was completed. The decline rate of CD27−CD38+ between 6 months after treatment and baseline was positively correlated with erythrocyte sedimentation rate (r = 0.766, P

Compared with engineering materials for earth structures subjected to prolonged, sustained hydraulic loading, the internal erosion process of widely graded loose soils (WGLS) under short-term, fluctuating hydraulic loading conditions remains insufficiently elucidated. Therefore, a novel fixed-wall permeameter is developed, capable of applying hydraulic loading at a constant flow rate and collecting effluent flowing out of specimens. A testing protocol is proposed to separate eroded silty clay particles, sandy gravel particles, and seepage water from the collected effluent. Several seepage tests are conducted on remolded specimens with various initial porosity at different inflow rates. The test results show that under a constant inflow rate, the WGLS specimens may undergo suffusion, suffosion, and stabilization stages while seeking the ultimate equilibrium state. The proposed particle migration pattern adeptly reveals the microscale mechanisms of the internal erosion phenomena observed at different stages. The inflow rate is independent of the suffusion critical hydraulic gradient but impacts the suffosion critical hydraulic gradient and internal erosion behavior following suffusion. Because hydraulic shear stress is a comprehensive indicator that considers both hydraulic gradient and initial porosity, it is more appropriate to use it to evaluate the internal stability potential of WGLS.

BackgroundLimited and inconclusive data from observational studies and randomized controlled trials exist on the levels of circulating micronutrients in the blood and their association with respiratory infections.MethodsA Mendelian randomization (MR) analysis was conducted to assess the impact of 12 micronutrients on the risk of three types of infections [upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), and pneumonia] and their 14 subtypes. This study utilized a bidirectional MR approach to evaluate causal relationships and included a range of sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. The threshold for statistical significance was set at p

The effects of black bean supplemented with wheat bran sourdough fermented by phytase and β-glucosidase producing Pediococcus acidilactici (L19) and Pediococcus pentosaceus (J28), respectively, on baking quality and staling characteristics of wheat composite bread were investigated. Compared to controls (12.21-15.33 mg/g), phytate content decreased (p < 0.05) in sourdoughs (higher decline in L19 than J28 sourdoughs). Also, relative to controls, the lactic acid (26.87-48.82 mg/g) and acetic acid (2.62-12.33 mg/g) increased (p < 0.05), while the total dietary fiber (TDF) decreased by 22.73 to 38.83 % and soluble dietary fiber (SDF) increased by 22.29 to 78.02 % in sourdoughs. In bread, phytate content decreased (p < 0.05) from 8.68-11.15 mg/g in controls to 0.95-3.21 mg/g in bread prepared with sourdoughs: greater decline in L19 than J28 sourdoughs with wheat bran and black bean. Compared to controls, SDF increased from 0.78-1.63 to 1.17-2.82 mg/g in breads prepared with sourdoughs: higher increase in J28 than L19 sourdoughs with wheat bran in black bean. Subsequently, specific volume increased, crumb firmness and chewiness reduced, staling rate during storage declined and overall sensory acceptance increased in breads prepared with sourdoughs than controls. Particularly, use of J28 than L19 starters and supplementation of wheat bran in black bean sourdough led to better outcomes. Therefore, sourdough acidification, the additive effect of wheat bran in black bean enhanced TDF in sourdough: this increased enzyme activity and synthesis of metabolites which were responsible for the improved baking quality, sensory acceptance and staling properties of breads prepared with sourdough. In conclusion, the use of carefully selected lactic acid bacteria starters, wheat bran supplementation in black bean flour sourdough improved the baking quality, shelf-life and staling properties of bread.

Objective: This study aimed to delineate the clear cell renal cell carcinoma (ccRCC) intrinsic subtypes through unsupervised clustering of radiomics and transcriptomics data and to evaluate their associations with clinicopathological features, prognosis, and molecular characteristics. Methods: Using a retrospective dual-center approach, we gathered transcriptomic and clinical data from ccRCC patients registered in The Cancer Genome Atlas and contrast-enhanced computed tomography images from The Cancer Imaging Archive and local databases. Following the segmentation of images, radiomics feature extraction, and feature preprocessing, we performed unsupervised clustering based on the “CancerSubtypes” package to identify distinct radiotranscriptomic subtypes, which were then correlated with clinical-pathological, prognostic, immune, and molecular characteristics. Results: Clustering identified three subtypes, C1, C2, and C3, each of which displayed unique clinicopathological, prognostic, immune, and molecular distinctions. Notably, subtypes C1 and C3 were associated with poorer survival outcomes than subtype C2. Pathway analysis highlighted immune pathway activation in C1 and metabolic pathway prominence in C2. Gene mutation analysis identified VHL and PBRM1 as the most commonly mutated genes, with more mutated genes observed in the C3 subtype. Despite similar tumor mutation burdens, microsatellite instability, and RNA interference across subtypes, C1 and C3 demonstrated greater tumor immune dysfunction and rejection. In the validation cohort, the various subtypes showed comparable results in terms of clinicopathological features and prognosis to those observed in the training cohort, thus confirming the efficacy of our algorithm. Conclusion: Unsupervised clustering based on radiotranscriptomics can identify the intrinsic subtypes of ccRCC, and radiotranscriptomic subtypes can characterize the prognosis and molecular features of tumors, enabling noninvasive tumor risk stratification.

Ultra wideband (UWB) indoor positioning technology is attracting significant attention in the present realm of indoor wireless positioning technology due to its numerous advantages, including low energy consumption, exceptional wireless transmission rates, remarkable resolution, and powerful anti-interference capabilities.This paper applies the time of arrival (TOA) location technique, derived from the research on UWB location method, to calculate the distance between the base station and the tag using the signal flight time. By incorporating the bilateral two-way ranging algorithm, the system has been fine-tuned to lower the precision demands on the hardware.A novel positioning algorithm is introduced, utilizing both C-Taylor and adaptive robust Kalman filter, which is based on the Time of Arrival (TOA) method. This algorithm aims to address the limitations of Chan and Taylor algorithms and minimize the non-line-of-sight (NLOS) error. This algorithm has excellent theoretical research value and practical application value.

Abstract Purpose To compare the safety and efficacy of CPG in the rectus abdominis and intercostal regions. Materials and methods This retrospective study included 226 patients who underwent CPG at a single center, with the stoma placed in the rectus abdominis or intercostal region. Surgical outcomes and complications, such as pain and infection within 6 months postoperatively, were recorded. Results The surgical success rate was 100%, and the all-cause mortality rate within 1 month was 0%. An intercostal stoma was placed in 56 patients; a rectus abdominis stoma was placed in 170 patients. The duration of surgery was longer for intercostal stoma placement (37.66 ± 14.63 min) than for rectus abdominis stoma placement (30.26 ± 12.40 min) (P = 0.000). At 1 month postsurgery, the rate of stoma infection was greater in the intercostal group (32.1%) than in the rectus abdominis group (20.6%), but the difference was not significant (P = 0.077). No significant difference was observed in the infection rate between the two groups at 3 or 6 months postsurgery (P > 0.05). Intercostal stoma patients reported higher pain scores during the perioperative period and at 1 month postsurgery (P = 0.000), but pain scores were similar between the two groups at 3 and 6 months postsurgery. The perioperative complication rates for intercostal and rectus abdominis surgery were 1.8% and 5.3%, respectively (P = 0.464), with no significant difference in the incidence of tube dislodgement (P = 0.514). Patient weight improved significantly at 3 and 6 months postoperatively compared to preoperatively (P

Abstract Background The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. Methods Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. Results Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα+ TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα+ TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression. Conclusions Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

Abstract Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc’s cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.

Among the existing prediction methods for strata behaviors law in working faces, the methods based on numerical simulation and statistical regression cannot achieve real-time and precise prediction of strata behaviors law in working faces. Deep learning methods have problems such as a large number of hyperparameters that are difficult to set and slow model training speed. In order to solve the above problems, based on the time-series data of internal stress changes in the coal body monitored during the mining process of the 402102 working face in Hujiahe Coal Mine, the particle swarm optimization based gate recurrent unit (PSO-GRU) is applied to predict the strata behaviors law in the working face. The PSO algorithm is used to optimize GRU. The PSO-GRU model is constructed to achieve automatic optimization of hyperparameters, thereby improving the training speed and prediction precision of GRU. Based on the prediction results, the analytic hierarchy process (AHP) is used to establish the evaluation index system of the main control factors of the strata behaviors of the 402102 mining face. The roof conditions, mining technology, coal seam occurrence, and geological structure are identified as the first level indicators affecting the strata behaviors of the working face. The 14 representative second level indicators are further subdivided. The test results show the following points. ① Compared with the unoptimized GRU model, the mean square error (MSE) of the PSO-GRU model is reduced by 83.9%, the root mean square error (RMSE) is reduced by 59.8%, the mean absolute error (MAE) is reduced by 59.0%, and the coefficient of determination R2 is increased by 28.9%. ② The PSO-GRU model has a fitting degree of over 0.980 for predicting strata behaviors data, demonstrating good nonlinear fitting and generalization capabilities. ③ The occurrence factors of coal seams in geological conditions have the greatest impact on the strata behaviors of the mining face, with a weight of 0.47. Among the factors that can be intervened by humans, the impact of advancing speed on the strata behaviors of the working face is the greatest, with a weight of 0.13.

Osteoarthritis (OA) etiology is multifactorial, and its prevalence is growing globally. The Gut microbiota shapes our immune system and impacts all aspects of health and disease. The idea of utilizing probiotics to treat different conditions prevails. Concerning musculoskeletal illness and health, current data lack the link to understand the interactions between the host and microbiome. We report that S. thermophilus, L. pentosus (as probiotics), and γ-aminobutyric acid (GABA) harbour against osteoarthritis in vivo and alleviate IL-1β induced changes in chondrocytes in vitro. We examined the increased GABA concentration in mice's serum and small intestine content followed by bacterial treatment. The treatment inhibited the catabolism of cartilage and rescued mice joints from degradation. Furthermore, the anabolic markers upregulated and decreased inflammatory markers in mice knee joints and chondrocytes. This study is the first to represent GABA's chondrogenic and chondroprotective effects on joints and human chondrocytes. This data provides a foundation for future studies to elucidate the role of GABA in regulating chondrocyte cell proliferation. These findings opened future horizons to understanding the gut-joint axis and OA treatment. Thus, probiotic/GABA therapy shields OA joints in mice and could at least serve as adjuvant therapy to treat osteoarthritis.

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes, in which the Indian hedgehog (IHH) and parathyroid hormone-related protein-parathyroid hormone-1 receptor (PTHrP-PTH1R) feedback loop is crucial. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) branch of the unfolded protein response (UPR) is essential for normal cartilage development. However, the precise role of ER stress effector IRE1α, encoded by endoplasmic reticulum to nucleus signaling 1 (ERN1), in skeletal development remains unknown. Herein, we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth. ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates. Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation. XBP1s, produced by p-IRE1α-mediated splicing, binds and up-regulates PTH1R and IHH, which coordinate cartilage development. Meanwhile, ER stress cannot be activated normally in ERN1-deficient chondrocytes. In conclusion, ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress. ERN1 may have a potential role as a new target for cartilage growth and maturation.

Objective: To explore the differential expression profiles of DNA methylation sites/regions and potential molecular mechanisms in the peripheral blood of coronary heart disease (CHD)-induced unstable angina pectoris patients with or without Qi deficiency and blood stasis syndrome, and to provide scientific evidence for the conbination of disease and syndrome. Methods: According to the pre-determined inclusion and exclusion criteria, the study subjects were enrolled and divided into two groups namely CHD-induced unstable angina group (G group) and healthy control group (J group) to conduct “disease” analysis, while G group was further divided into Qi deficiency and blood stasis syndrome group (case group) and non-Qi deficiency blood stasis syndrome group (control group) to perform “syndrome” analysis. The general data and clinical information of the study subjects were collected. The peripheral venous blood was extracted on an empty stomach, and the Illumina Infinium MethylationEPIC BeadChip (850K methylation chip) was used to detect the differential expression profiles of DNA methylation in each group, ChAMP software (V 2.14.0) was used for the differential methylation data analysis, with a threshold of the adjusted P value (adj.P.val) < 0.01. Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) were employed for the functional and pathway enrichment analyses of related mapped genes. Results: A total of 263 differentially methylated CpG positions (DMPs) were screened out between G and J groups, including 191 hypermethylated positions such as cg05845204 and cg08906898, and 72 hypomethylated positions such as cg26919182 and cg13149459. These positions were mainly mapped to 148 genes encompassing RNA binding motif protein 39 (RBM39), acetyl-CoA acyltransferase 2 (ACAA2), protein phosphatase 1 regulatory subunit 12B (PPP1R12B), and the dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2). GO functional enrichment analysis revealed that the genes of the DMPs were primarily enriched in protein localization to chromosomes, regulation of cell morphogenesis, negative regulation of calcium-mediated signals, etc. KEGG pathway analysis suggested that the genes were mainly enriched in fatty acid metabolism and endocytosis pathways. In addition, a total of 23 differential methylation regions (DMRs) were identified, with overlapping genes such as transmembrane protein 232 (TMEM232), ribosomal protein large P1 (RPLP1), peroxisomal biogenesis factor 10 (PEX10), and forkhead box N3 (FOXN3) recognized. It was found that GO functions were mainly enriched in the negative regulation of Ras protein signal transduction, small GTPase-mediated signal transduction, negative regulation, etc. A total of 1 703 differential methylation sites were screened out between case and control groups, including 444 increased methylation positions such as cg05573767 and 1 259 decreased methylationpositions such as cg19938535, and cg03893872. These positions were mapped to 1108 genes such as ribosomal protein S6 kinase A2 (RPS6KA2), leucine rich repeat containing 16A (LRRC16A), and hedgehog acyltransferase (HHAT). According to the GO functional enrichment analysis, the genes relating to the DMPs were mainly enriched in biological functions such as transmembrane receptor protein serine/threonine kinase signaling pathway and axonogenesis. The KEGG pathway enrichment analysis suggested the involvement of Rap1 signaling pathway, adenosine 5’-monophosphate-activated protein kinase (AMPK) signaling pathway, etc. A total of 21 DMRs were identified, including 22 overlapping genes such as mucin 4 (MUC4), three prime repair exonuclease 1 (TREX1), and LIM homeobox 6 (LHX6). GO analysis demonstrated that the genes primarily participated in molecular functions such as positive regulation of transmembrane transport, regulation of fatty acid metabolism, and copper ion binding. Conclusion: This study reveals the methylation patterns of DMPs and DMRs in patients with Qi deficiency and blood stasis syndrome caused by CHD-induced unstable angina pectoris. Potential epigenetic regulation of fatty acid metabolism, Rap1 signaling, and other molecular functions are involved in the development of CHD between the ''disease'' and ''syndrome''.

Abstract Cognition and behavior could reciprocally impact each other and together determine mental health amid large-scale disasters such as COVID-19. This study reports a six-month cohort study of a population-representative sample of Hong Kong residents (N = 906) from March–August 2021 (T1) to September 2021–February 2022 (T2). Cross-lagged panel analyses reveal that T1 poor behavioral functioning as indicated by high daily routine disruptions is inversely associated with T2 cognitive adaptation as indicated by self-efficacy and meaning-making but not vice versa. T1 routine disruptions but not cognitive adaptation are positively associated with T2 probable depression/anxiety. The positive link between T1 routine disruptions and T2 probable disorders is mediated by poor cognitive adaptation at T2. The present findings suggest that upholding daily behavioral functioning relative to positive states of mind could have a more pivotal role in mental health amid large-scale disasters. Future studies can test interventions that enhance the sustainment of regular daily routines.

European Union (EU) has long attached importance to innovation strategies, from the Lisbon strategy to the EU 2020 strategy. The evaluation of sustainable innovation efficiency (SIE) of EU countries aids in defining institutional and policy actions to enhance environmentally friendly innovation in the EU, and is essential and appropriate. Through the data envelopment analysis (DEA) approach, this paper measures the SIE in 27 EU countries, from 2000 to 2017, considering industrial waste and total energy consumption. The results show that the sustainable innovation efficiency among countries differs significantly. Only eight countries consistently have an efficient value of 1 during this period. The EU as a whole has a high efficiency value of 0.7403, but there are obvious differences among the five regions. Efficiency values in the north and south are consistently higher than the EU’s average efficiency value. The results also show that undesirable outputs lead to the reduction of innovation efficiency in most regions. The findings also provide policy makers with useful decision support insights for regional sustainable innovation, energy conservation and emission reduction policies. In addition, sustainable innovation governance should continue to be strengthened to promote and support the improvement of SIE.

The co-ensiling technique is widely used to improve silage quality; however, it remains unclear as to what high-quality silages can be made by co-ensiling Napier grass (NG) with Sugarcane top (ST). The aim of this study was to evaluate the fermentation characteristics, chemical composition, and microbiological profile of silage produced from mixtures of NG and ST in varying ratios. Silage was prepared using a small-scale fermentation system, and treatments were designed as control silage (NG ensiled alone) or with 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100%ST on a fresh matter basis with six replicates, respectively. Increasing ST in the silage reduced the contents of crude protein, ash, acetic acid, butyric acid, ammonia-N, as well as pH, but increased the contents of dry matter, ether extract, neutral detergent fiber, acid detergent fiber, water-soluble carbohydrate, lactic acid, and lactic acid bacteria. Lactobacillales and Enterobacterales were the dominant orders, with Lactiplantibacillus and Weissella as the dominant genera. Co-ensiling NG with ST enhanced microbial diversity and richness. ST, as a local by-product, is a viable additive to improve NG silage quality and nutrition. This study suggests that good-quality silages can be produced with NG: ST ratios of 40:60 to 20:80 and that these silages offer an opportunity to optimize the nutrient supply for ruminants.

Sinapine is a natural polyphenol from the cruciferous plant family that has anti-aging effects but is low in bioavailability. To improve the bioavailability and therapeutic effect of sinapine, sinapine-crosslinked dual-protein-based hydrogels were prepared using soy protein isolate as a cross-linking agent. The preparation conditions were optimized by single-factor experiments, and the optimal ratios were obtained as follows: the concentration of sinapine was 300 μg/mL; the water–oil ratio was 1:3. The encapsulation rate was greater than 95%, and the drug loading capacity was 3.5 mg/g. In vitro, digestion experiments showed that the dual-protein-based hydrogels as a drug carrier stabilized the release of sinapine and improved the bioavailability of sinapine by 19.3%. The IC50 of DPPH antioxidants was 25 μg/mL as determined by in vitro digestion, and the antioxidant capacity of ABTS was about 20% higher than that of glutaraldehyde control. This is due to the addition of sinapine to enhance the antioxidant properties of the system. It can be seen that the developed hydrogels have potential applications in related fields, such as food nutrition fortification and drug delivery.

mRNA vaccines have shown great potential in responding to emerging infectious diseases, with their efficacy and stability largely dependent on the delivery vehicles—lipid nanoparticles (LNPs). This study aims to explore the mechanisms by which LNPs encapsulate mRNA, as well as the effects of different N/P ratios and acid types in nucleic acid solutions on the structure and properties of LNPs, using the ethanol solvent injection method as the encapsulation technique. Six systems were designed, based on the composition and proportions of the existing mRNA vaccine mRNA-1273, and molecular dynamics (MD) simulations were employed to investigate the self-assembly process of LNPs. Ethanol was used as a solvent instead of pure water to better mimic experimental conditions. The results indicate that lipid components self-assemble into nanoparticles under neutral conditions, with the ionizable lipid SM-102 predominantly concentrating in the core of the particles. Upon mixing with nucleic acids in acidic conditions, LNPs undergo disassembly, during which protonated SM-102 encapsulates mRNA through electrostatic interactions, forming stable hydrogen bonds. Cluster structure analysis revealed that the four lipid components of LNPs are distributed sequentially from the outside inwards as DMG-PEG 2000, DSPC, cholesterol, and protonated SM-102. Moreover, LNPs constructed under low pH or low N/P ratios using citric acid exhibited larger volumes and more uniform distribution. These findings provide a scientific basis for further designing and optimizing LNP components to enhance the efficacy of mRNA vaccine encapsulation.

The effects of single- (Lactobacillus fermentum) or mixed-strain (Lactobacillus fermentum, Kluyveromyces marxianus) fermentation of red bean with or without wheat bran on sourdough bread quality and nutritional aspects were investigated. The results showed that, compared to unfermented controls, the tannins, phytic acid, and trypsin inhibitor levels were significantly reduced, whereas the phytochemical (TPC, TFC, and gallic acid) and soluble dietary fiber were increased in sourdough. Meanwhile, more outstanding changes were obtained in sourdough following a mixed-strain than single-strain fermentation, which might be associated with its corresponding β-glucosidase, feruloyl esterase, and phytase activities. An increased specific volume, reduced crumb firmness, and greater sensory evaluation of bread was achieved after mixed-strain fermentation. Moreover, diets containing sourdough, especially those prepared with mixed-strain-fermented red bean with wheat bran, significantly decreased serum pro-inflammatory cytokines levels, and improved the lipid profile, HDL/LDL ratio, glucose tolerance, and insulin sensitivity of mice. Moreover, gut microbiota diversity increased towards beneficial genera (e.g., Bifidobacterium), accompanied with a greater increase in short-chain fatty acid production in mice fed on sourdough-based bread diets compared to their controls and white bread. In conclusion, mixed-strain fermentation’s synergistic effect on high fiber-legume substrate improved the baking, sensory quality, and prebiotic effect of bread, leading to potential health benefits in mice.

Abstract Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

Abstract Water engineering facilities are a crucial component of the Beijing-Hangzhou Grand Canal during the Ming and Qing dynasties, and their distribution is closely related to the hydrological and topographical characteristics of the area. In this study, we reconstructed the canal network distribution map and water engineering facilities database of the Ming and Qing periods using ArcGIS (Geographical information systems software) 10.8 software. We employed Amos (Analyze of Moment Structures) 26.0 software to investigate the influence of various natural environmental factors on the selection of water engineering facility sites. The results revealed a significant correlation between the spatial distribution of water engineering facilities and the main channel slope and slope direction, which had a direct impact. The estimated coefficient for the main channel slope was -0.166, showing a negative correlation with the spatial distribution of water engineering facilities, while the estimated coefficient for the main channel slope direction was − 0.112, also indicating a negative correlation. Moreover, the estimated coefficient for the watershed area where water engineering facilities were located was -0.096, demonstrating a negative correlation. In contrast, the effects of tributary slope and slope direction on the spatial distribution of water engineering facilities were indirect, mediated by the watershed area where these facilities were situated. The effect size for tributary slope was -0.017, showing a negative correlation, while the effect size for tributary slope direction was 0.010, indicating a positive correlation with the spatial distribution of water engineering facilities.The study achieves the integration of the heritage of water engineering facilities along the canal from point to line, provides data support for the construction of the cultural heritage corridor of the canal, and facilitates the promotion of heritage protection and rational layout, which is of great significance to the understanding of the canal culture.

Abstract Clinical immunity against Plasmodium falciparum infection develops in residents of malaria endemic regions, manifesting in reduced clinical symptoms during infection and in protection against severe disease but the mechanisms are not fully understood. Here, we compare the cellular and humoral immune response of clinically immune (0-1 episode over 18 months) and susceptible (at least 3 episodes) during a mild episode of Pf malaria infection in a malaria endemic region of Malawi, by analysing peripheral blood samples using high dimensional mass cytometry (CyTOF), spectral flow cytometry and single-cell transcriptomic analyses. In the clinically immune, we find increased proportions of circulating follicular helper T cells and classical monocytes, while the humoral immune response shows characteristic age-related differences in the protected. Presence of memory CD4+ T cell clones with a strong cytolytic ZEB2+ T helper 1 effector signature, sharing identical T cell receptor clonotypes and recognizing the Pf-derived circumsporozoite protein (CSP) antigen are found in the blood of the Pf-infected participants gaining protection. Moreover, in clinically protected participants, ZEB2+ memory CD4+ T cells express lower level of inhibitory and chemotactic receptors. We thus propose that clonally expanded ZEB2+ CSP-specific cytolytic memory CD4+ Th1 cells may contribute to clinical immunity against the sporozoite and liver-stage Pf malaria.

Abstract Background Clinical significance of various subtypes of epidermal growth factor receptor (EGFR) exon 19 deletion (ex19del) mutation in non‐small cell lung cancer (NSCLC) remains unclear. Methods We analyzed EGFR ex19del subtypes in NSCLC patients receiving first‐line tyrosine kinase inhibitor (TKI) therapy at our center (January 2018–June 2022) and correlated them with median progression‐free survival (mPFS) and median overall survival (mOS). Results We identified 17 different EGFR ex19del variants in 101 patients. Between the classic (E746_A750del, 64.4%) and nonclassic groups (the rest variants), no significant difference was observed in mPFS (13.5 vs. 19.3 months, p = 0.18) or mOS (44.1 vs. 77.0 months, p = 0.06). mPFS showed no significant difference between ex19del subgroups classified based on the presence of insertion (ex19delins), starting position or length of deletion. However, patients with ex19delins starting at E746 showed longer mPFS than the others (29.7 vs. 12.5 months, p = 0.04), and patients with ex19del of 15 nucleotides had shorter mOS than the others (44.1 vs. 77.0 months, p = 0.03). In multivariate analysis, ex19delins independently predicted a better PFS (HR = 0.311, p = 0.03); however, 15 nucleotide deletion was no longer associated with OS (HR = 0.181, p = 0.11). Secondary T790M mutation incidence was significantly higher in the ex19del subgroup starting at E746 than the others (64.7% vs. 30.8%, p = 0.04). Conclusions Our study revealed potential differences in TKI efficacy, resistance mechanism, and prognosis of various EGFR ex19del subtypes in NSCLC, underscoring the need for precise selection of first‐line therapy.

A crack-free high-Mn TWIP steel welding joint with comparable strength and superplastic was obtained via vacuum electron beam welding (VEBW) where the microstructural evolution, mechanical behaviors and strengthening mechanism of welding joint were investigated. The results indicated that the welding joint with a typical nail-shaped welding cross-section was divided into three zones including the base metal (BM), heat-affected zone (HAZ) and fusion zone (FZ). Massive fine AlN-type precipitates with the hexagonal crystal structure were observed in welding join. The orientation relationship between the γ-austenite matrix and AlN precipitates was determined as [001]γ//[2110]AlN. In FZ, small-sized cellular grains or columnar grains with consistent growth directions were combined into large-sized columnar grains with obvious preferential orientation. Compared with the base mantal, the yield strength, ultimate strength and elongation of the VEBWed specimen were slightly reduced by 6.03%, 4.7% and 13.23%, respectively. However, the impact toughness was obviously decreased from the 87.90 J–68.97 J after the VEBW process, which was mainly attributed to the brittle AlN precipitates, inhomogeneous microstructure and back stress induced by the plastic mismatch between gradient grains. The strength contributions of different regions to overall strength including of BM, HAZ and FZ in welding joint were calculated. Here, the dislocation strengthening and precipitation strengthening were the dominant strengthening mechanisms of FZ, which was attributed to the high level of density and massive fine AlN precipitates induced by micro-elements segregations during the VEBW process.

Objective To investigate the effects of microRNA-21 (miR-21) on proliferation, apoptosis and aerobic clycolysis of pancreatic cancer cells and its possible mechanism. Methods Human pancreatic cancer cell SW1990 and normal pancreatic duct epithelial cell HPDE were taken as research objects. SW1990 cells were transfected and divided into miR-NC group (transfected with miR-NC) and miR-21-minic group (transfected with miR-21-minic). MTT and clone formation assay were used to detect cell proliferation ability. Flow cytometry was used to detect cell apoptosis. RT-qPCR was used to detect the mRNA expression levels of miR-21 and pyruvate kinase M2 (PKM2) in cells. Western blot was used to detect PKM2 protein level. The luciferase reporter assay was used to detect the targeting relationship between miR-21 and PKM2. Results The expression level of miR-21 in SW1990 cells was higher than that in HPDE cells (0.79±0.02 vs 0.23±0.02, t =34.290, P＜0.01), while the expression levels of PKM2 protein (0.41±0.03) and mRNA (0.62±0.02) in SW1990 cells were lower than those in HPDE cells (0.95±0.02, 1.13±0.03, t =25.940, 24.500, P＜0.01). At 72 and 96 hours, the cell proliferation ability and number of clones cell in the miR-21-minic group were significantly higher than those in the miR-NC group, while the number of apoptotic cells was lower than that in the miR-NC group (P＜0.05). The glucose consumption, and the content of lactate, hexokinase (HK) and lactate dehydrogenase (LDH) in miR-21-mimic group were significantly higher than those in miR-NC group ( t =5.992, 21.340, 5.643, 4.008, P＜0.05). The level of PKM2 protein in the miR-21 mic group was lower than that in the miR-NC group ( t =10.070, P＜0.01). There were a certain number of complementary base pairs between miR-21 and WT-3′ UTR-PKM2, and the cell luciferase activity of miR-21-minic+WT-PKM2 group was lower than that of the transfected miR-NC+WT-PKM2 group ( t =15.680, P＜0.01). Conclusion The overexpression of miR-21 in pancreatic cancer cells may promote the proliferation, aerobic glycolysis, and inhibit apoptosis of pancreatic cancer cells. The mechanism may be related to targeting PKM2.

With its unique properties and potential applications, nanoparticle-based delivery platforms for messenger RNA (mRNA) vaccines have gained significant attention in recent years. Nanoparticles have the advantages of enhancing immunogenicity, targeting delivery, and improving stability, providing a new solution for drug and vaccine delivery. In some clinical studies, a variety of nanoparticle delivery platforms have been gradually applied to a wide range of vaccine applications. Current research priorities are exploring various types of nanoparticles as vaccine delivery systems to enhance vaccine stability and immunogenicity. Lipid nanoparticles (LNPs) have shown promising potential in preclinical and clinical studies on the efficient delivery of antigens to immune cells. Moreover, lipid nanoparticles and other nanoparticles for nucleic acids, especially for mRNA delivery systems, have shown vast potential for vaccine development. In this review, we present various vaccine platforms with an emphasis on nanoparticles as mRNA vaccine delivery vehicles. We describe several novel nanoparticle delivery platforms for mRNA vaccines, such as lipid-, polymer-, and protein-based nanoparticles. In addition, we provide an overview of the anti-tumor immunity of nanovaccines against different tumors in cancer immunotherapy. Finally, we outline future perspectives and remaining challenges for this promising technology of nanoparticle-based delivery platforms for vaccines.

Semantic scene completion is a crucial outdoor scene understanding task that has direct implications for technologies like autonomous driving and robotics. It compensates for unavoidable occlusions and partial measurements in LiDAR scans, which may otherwise cause catastrophic failures. Due to the inherent complexity of this task, existing methods generally rely on complex and computationally demanding scene completion models, which limits their practicality in downstream applications. Addressing this, we propose a novel integrated network that combines the strengths of 3D and 2D semantic scene completion techniques for efficient LiDAR point cloud scene completion. Our network leverages a newly devised lightweight multi-scale convolutional block (MSB) to efficiently aggregate multi-scale features, thereby improving the identification of small and distant objects. It further utilizes a layout-aware semantic block (LSB), developed to grasp the overall layout of the scene to precisely guide the reconstruction and recognition of features. Moreover, we also develop a feature fusion module (FFM) for effective interaction between the data derived from two disparate streams in our network, ensuring a robust and cohesive scene completion process. Extensive experiments with the popular SemanticKITTI dataset demonstrate that our method achieves highly competitive performance, with an mIoU of 35.7 and an IoU of 51.4. Notably, the proposed method achieves an mIoU improvement of 2.6 % compared to previous methods.

Background and Purpose: In urological surgery, accurate localization of the ureteral orifice is crucial for procedures such as ureteral stent insertion, assessment of ureteral orifice lesions, and prostate tumor resection. Consequently, we have developed and validated a computer-assisted ureteral orifice detection system that combines the YOLO deep convolutional neural network and the attention mechanism. Data: The cases were partitioned into a training set and a validation set at a 4:1 ratio, with 84 cases comprising 820 images in the training set and 20 cases containing 223 images in the validation set. Method: We improved the YOLO network structure to accomplish the detection task. Based on the one-stage strategy, we replaced the backbone of YOLOv5 with a structure composed of ConvNeXt blocks. Additionally, we introduced GRN (Global Response Normalization) modules and SE blocks into the blocks to enhance deep feature diversity. In the feature enhancement section, we incorporated the BiFormer attention structure, which provides long-distance context dependencies without adding excessive computational costs. Finally, we improved the prediction box loss function to WIoU (Wise-IoU), enhancing the accuracy of the prediction boxes. Results: Testing on 223 cystoscopy images demonstrated a precision of 0.928 and recall of 0.756 for our proposed ureteral orifice detection network. With an overlap threshold of 0.5, the mAP of our proposed image detection system reached 0.896. The entire model achieved a single-frame detection speed of 5.7 ms on the platform, with a frame rate of 175FPS. Conclusion: We have enhanced a deep learning framework based on the one-stage YOLO strategy, suitable for real-time detection of the ureteral orifice in endoscopic scenarios. The system simultaneously maintains high accuracy and good real-time performance. This method holds substantial potential as an excellent learning and feedback system for trainees and new urologists in clinical settings.

In this study, changes in abiotic environmental factors were analyzed based on measured data from Dawangtan Reservoir in Nanning City during 2021–2022. The Carlson Integrated Trophic State Index method was applied to evaluate water quality and eutrophication in the reservoir, considering both exogenous inputs and internal water quality conditions. Additionally, by investigating water quality and biological factors (zooplankton and fish) in the reservoir, this study identified the main drivers influencing phytoplankton outbreaks in Dawangtan Reservoir through redundancy analysis (RDA) and Pearson correlation analysis. The results showed that the combined trophic state index of the reservoir varied between 29.2 and 56.5 throughout the year, with each water quality indicator performing worse during the summer months when temperatures were higher. There was a positive correlation between zooplankton biomass and phytoplankton biomass, and the increase in the proportion of phytophagous fish contributed to the reduction in phytoplankton. The redundancy analysis revealed that the distribution of phytoplankton species was significantly correlated with total phosphorus (TP), pH, dissolved oxygen (DO), and chlorophyll a (Chl-a), with different phytoplankton species responding variably to these environmental factors. Finally, a multiple stepwise regression analysis was used to construct the optimal response equation between Chl-a concentration and environmental factors. The results indicated that pH, Secchi disk (SD), DO, and biological oxygen demand (BOD) were the main factors affecting Chl-a concentration. Therefore, the outcomes of abiotic environmental factors and lake biological resources should be considered in the restoration of eutrophic lakes to achieve the desired restoration effect.

Objective To introduce the Hr gene of spontaneously mutated SHJHhr mice into BALB/cAShjh inbred mice with clear genetic background,and provide a basis for study on the molecular mechanism of Hr gene mutation-induced abnormal phenotype and the application of this model. Methods Using a backcross-intercross breeding method guided by phenotypic monitoring, mutant genes from SHJHhr mice bred by spontaneous mutation were introduced into inbred BALB/cAShjh mice by homozygous mutation introgression, and the mice were bred into BALB/cA.Cg.SHJHhr (abbreviated as C.Cg.SHJHhr) mice after 10 generations. The genotypes of 90 single nucleotide polymorphism (SNP) detection sites were analyzed in C.Cg.SHJHhr mice by multiplex PCR library construction followed by next generation sequencing. Then 14 biochemical locus marker genes were detected in C.Cg.SHJHhr mice according to the method of GB/T 14927.1-2008. Finally, whole genome exon sequencing was utilized to detect the mutated genes in this mouse.Results From May 2018 to March 2022, a total of 10 generations of backcross-intercross were conducted to complete the construction of the C.Cg.SHJHhr mouse line. Among the 90 SNPs loci detected, except for rs13484115 and rs13484116, all the other loci had the same genotype as the recipient mice BALB/cAShjh. The results of biochemical marker gene detection showed that all the 14 loci of the mouse were the same as those of the recipient mouse. Whole genome exon sequencing found that the mouse had 109 site mutations compared with the recipient mouse strain, including 71 synonymous mutations, 1 stopgain, 37 missense mutations, and 20 genes involved in protein sequence alterations (including the reported Hr gene).Conclusion C.Cg.SHJHhr mice were created. Through exon sequencing and genetic analysis, three Hr mutated genes and associated mutated genes that mainly cause phenotypic variations were identified, which provides a basis for expanding the application of C.Cg.SHJHhr mice in biomedical research.

Abstract Topologically protected photonic edge states offer unprecedented robust propagation of photons that are promising for waveguiding, lasing, and quantum information processing. Here, we report on the discovery of a class of hybrid topological photonic crystals that host simultaneously quantum anomalous Hall and valley Hall phases in different photonic band gaps. The underlying hybrid topology manifests itself in the edge channels as the coexistence of the dual-band chiral edge states and unbalanced valley Hall edge states. We experimentally realize the hybrid topological photonic crystal, unveil its unique topological transitions, and verify its unconventional dual-band gap topological edge states using pump-probe techniques. Furthermore, we demonstrate that the dual-band photonic topological edge channels can serve as frequency-multiplexing devices that function as both beam splitters and combiners. Our study unveils hybrid topological insulators as an exotic topological state of photons as well as a promising route toward future applications in topological photonics.

Progranulin (PGRN) is a multifunctional growth factor involved in many physiological processes and disease states. The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis (OA) led us to investigate the role of PGRN in the regulation of chondrocyte autophagy. PGRN knockout chondrocytes exhibited a deficient autophagic response with limited induction following rapamycin, serum starvation, and IL-1β-induced autophagy. PGRN-mediated anabolism and suppression of IL-1β-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor. Mechanistically, during the process of OA, PGRN and the ATG5–ATG12 conjugate form a protein complex; PGRN regulates autophagy in chondrocytes and OA through, at least partially, the interactions between PGRN and the ATG5–ATG12 conjugate. Furthermore, the ATG5–ATG12 conjugate is critical for cell proliferation and apoptosis. Knockdown or knockout of ATG5 reduces the expression of ATG5–ATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism. Overexpression of PGRN partially reversed this effect. In brief, the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA. Such studies provide new insights into the pathogenesis of OA and PGRN-associated autophagy in chondrocyte homeostasis.