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Abstract Moyamoya disease (MMD) suffers from impaired cerebrovascular hemodynamics and high perioperative complications occurrence. This study aims to propose and evaluate the relationship between intraoperative hemodynamics and perioperative complications, and propose a potential compensatory self-recirculation network in MMD. We prospectively enrolled 63 MMD patients undergone combined revascularization, and patients were divided into decreased and increased group according to decreased and increased microvascular transit time (MVTT), respectively. Mean age of all patients was 45.9 ± 9.4 years. The post-bypass hyperperfusion syndrome occurrence was significantly higher in the decreased MVTT group, and the cerebral infarction occurrence was significantly higher in the increased MVTT group. For the hemodynamics of the recipient artery around anastomosis, the parameters of distal site demonstrated a significant higher intensity and shorter time in the decreased MVTT group, while the parameters of the proximal site demonstrated a significant higher intensity and shorter time in the increased MVTT group. Pre-bypass and post-bypass collision of blood flow in artery and vein were firstly observed and illustrated. Intraoperative hemodynamics showed close relationship with perioperative complications. The blood flow of MMD seems to develop a unique compensatory self-recirculation system and contribute to the clinical complications, providing a new insight to the clinical management the pathology of the disease.

177Lu- prostate specific membrane antigen (PSMA) radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China. Based on domestic clinical practice and experimental data and referred to international experience and viewpoints, the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Abstract Fine-grained management of rice fields can enhance the yield and quality of rice crops. Challenges in achieving fine classification include interference from similar vegetation, the irregularity of natural field shapes, and complex scale variations. This paper introduces Rice Attention Cascade Network (RACNet), for the fine classification of rice fields in high-resolution satellite remote sensing imagery. The network employs the Hybrid Task Cascade network as the base framework and uses spectral and indices mixed multimodal data as input to reinforce the feature differentiation of similar vegetation. Initially, a Channel Attention Deformable-ResNet (CAD-ResNet) was designed to enhance the feature representation of rice on different channels. Deformable convolution improves the ability of CAD-ResNet to capture irregular field shapes. Then, to address the issue of complex scale changes, the multi-scale features extracted by the CAD-ResNet are progressively fused using an Asymptotic Feature Pyramid, reducing the loss of scale information between non-adjacent layers. Experiments on the Meishan rice dataset show that the proposed method is capable of accurate instance segmentation for fragmented or irregularly shaped rice fields. The evaluation metric AP50 of RACNet reaches 50.8%.

Abstract Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

Significant technical challenges exist when measuring synaptic connections between neurons in living brain tissue. The patch clamping technique, when used to probe for synaptic connections, is manually laborious and time-consuming. To improve its efficiency, we pursued another approach: instead of retracting all patch clamping electrodes after each recording attempt, we cleaned just one of them and reused it to obtain another recording while maintaining the others. With one new patch clamp recording attempt, many new connections can be probed. By placing one pipette in front of the others in this way, one can ‘walk’ across the mouse brain slice, termed ‘patch-walking.’ We performed 136 patch clamp attempts for two pipettes, achieving 71 successful whole cell recordings (52.2%). Of these, we probed 29 pairs (i.e. 58 bidirectional probed connections) averaging 91 μm intersomatic distance, finding three connections. Patch-walking yields 80–92% more probed connections, for experiments with 10–100 cells than the traditional synaptic connection searching method.

ABSTRACT Objectives: Osteoarthritis (OA) is a degenerative disease associated with chondrocyte injury. This study investigated the dysregulation of microRNA-650 (miR-650) in cartilage tissues of patients with OA. Its function and mechanism were also investigated in OA cell models. Methods: miR-650 levels were examined in 15 OA cartilage tissues and ten healthy cartilage tissues. SW1353 cells were used for cell function experiments and IL-1β was applied to the cells to mimic OA conditions in vitro. Cell functions such as proliferation, apoptosis, and inflammation were detected. The downstream target gene of miR-650 was identified and confirmed by bioinformatic analysis and luciferase activity assay. Rescue experiments were performed to verify the mechanism. Results: Suppressed expression of miR-650 was tested in patients with OA and cell models. Overexpression of miR-650 increased cell proliferation but suppressed apoptosis and inflammation of SW1353. As the target gene of miR-650, WNT1 overexpression counteracted the role of miR-650 in the function of SW1353. Conclusion: miR-650 can protect against articular cartilage injury in OA by targeting WNT1. Level of Evidence I, Experimental Study.

Abstract Background Analyzing distance-dependent functional connectivity density (FCD) yields valuable insights into patterns of brain activity. Nevertheless, whether alterations of FCD in non-acute stroke patients are associated with the anatomical distance between brain regions remains unclear. This study aimed to explore the distance-related functional reorganization in non-acute stroke patients following left and right hemisphere subcortical lesions, and its relationship with clinical assessments. Methods In this study, we used resting-state fMRI to calculate distance-dependent (i.e., short- and long-range) FCD in 25 left subcortical stroke (LSS) patients, 22 right subcortical stroke (RSS) patients, and 39 well-matched healthy controls (HCs). Then, we compared FCD differences among the three groups and assessed the correlation between FCD alterations and paralyzed motor function using linear regression analysis. Results Our findings demonstrated that the left inferior frontal gyrus displayed distance-independent FCD changes, while the bilateral supplementary motor area, cerebellum, and left middle occipital gyrus exhibited distance-dependent FCD alterations in two patient subgroups compared with HCs. Furthermore, we observed a positive correlation between increased FCD in the bilateral supplementary motor area and the motor function of lower limbs, and a negative correlation between increased FCD in the left inferior frontal gyrus and the motor function of both upper and lower limbs across all stroke patients. These associations were validated by using a longitudinal dataset. Conclusions The FCD in the cerebral and cerebellar cortices shows distance-related changes in non-acute stroke patients with motor dysfunction, which may serve as potential biomarkers for predicting motor outcomes after stroke. These findings enhance our comprehension of the neurobiological mechanisms driving non-acute stroke. Trial registration All data used in the present study were obtained from a research trial registered with the ClinicalTrials.gov database (NCT05648552, registered 05 December 2022, starting from 01 January 2022).

Abstract Background Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. Methods FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. Results The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. Conclusion In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials. Graphical Abstract. FPHA was successfully prepared through the chemical and thermal process. The immunomodulatory effects of FPHA were investigated through in vitro and in vivo studies, revealing its ability to induce a metabolic shift in macrophages from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This metabolic remodeling resulted in a notable suppression of M1 macrophage polarization and promotion of M2 macrophage polarization. Furthermore, FPHA was found to enhance osteogenic differentiation and facilitate bone repair. These findings underscore the promising potential of FPHA as a biomaterial for bone regenerative applications, providing valuable insights for the development of bioactive materials with metabolic-immunoregulatory properties Graphical Abstract

Abstract. Caloric restriction (CR) is a well-established dietary intervention known to extend healthy lifespan and exert positive effects on aging-related diseases, including cardiovascular conditions. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, have emerged as key regulators of cellular metabolism, stress responses, and the aging process, serving as energy status sensors in response to CR. However, the mechanism through which CR regulates Sirtuin function to ameliorate cardiovascular disease remains unclear. This review not only provided an overview of recent research investigating the interplay between Sirtuins and CR, specifically focusing on their potential implications for cardiovascular health, but also provided a comprehensive summary of the benefits of CR for the cardiovascular system mediated directly via Sirtuins. CR has also been shown to have considerable impact on specific metabolic organs, leading to the production of small molecules that enter systemic circulation and subsequently regulate Sirtuin activity within the cardiovascular system. The direct and indirect effects of CR offer a potential mechanism for Sirtuin modulation and subsequent cardiovascular protection. Understanding the interplay between CR and Sirtuins will provide new insights for the development of interventions to prevent and treat cardiovascular diseases.

BackgroundThe management of patients with initially mild acute ischemic stroke (AIS), defined by the National Institutes of Health Stroke Scale (NIHSS) scores 0–5, remains ambiguous despite advances in stroke treatment. The early identification of patients likely to deteriorate is critical in preventing lasting disability.AimsWe investigated the frequency and early predictors of poor functional outcomes in AIS patients with large-vessel occlusion (LVO) and initial mild deficits.MethodsWe performed a retrospective observational study of consecutive AIS patients admitted to a single comprehensive stroke center between 2018 and 2021. The inclusion criteria were a diagnosis of AIS, an arrival NIHSS score of 0–5, imaging-confirmed LVO, and arrival within 24 h of the last-known-well time. The primary outcome was the change in the discharge-modified Rankin Score (ΔmRS) from baseline, categorized as 0–1 (stable outcome) or >1 (poor outcome). Early neurological deterioration was defined as a mean NIHSS score increase of >1 in the first 24-h period. Univariate and multivariable regression analyses were performed. The mean daily NIHSS scores were compared between groups using an analysis of variance (ANOVA).ResultsOf 4,410 stroke admissions, 120 patients met the study inclusion criteria, with 71 (59.2%) patients having a ΔmRS of 0–1 and 49 (40.8%) patients having a ΔmRS of > 1. The mean arrival NIHSS score was similar between groups. However, the mean first-24-h NIHSS score was significantly higher in the poor outcome group vs. the stable outcome group (2.13 vs. 0.95, p < 0.001). A demographic-adjusted multivariable logistic regression revealed that a higher mean first-24-h NIHSS score was the sole early predictor of poor outcome (odds ratio [OR] of 1.65 and a 95% confidence interval [CI] of [1.18, 2.48]). The only association with early neurological deterioration was vertebral artery occlusion, with an OR of 0.35 and a 95% CI of [0.14, 0.81]. The trending mean daily NIHSS scores revealed that patients with poor outcomes deteriorate within 24 h, a significant difference from the stable group (p < 0.001).ConclusionPoor outcomes occurred in a significant proportion of LVO patients with initial mild deficits. The only association was early neurological deterioration. To prevent poor outcomes, rapid identification of any clinical deterioration should prompt consideration of thrombectomy.

Abstract Type 2 diabetic kidney disease (T2DKD) is a common microvascular complication of type 2 diabetes mellitus (T2DM), and its incidence is significantly increasing. Microinflammation plays an important role in the development of T2DKD. Based on this, this study investigated the value of inflammatory markers including neutrophil–lymphocyte ratio (NLR), high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1) in the prediction of T2DKD. This was a cross-sectional survey study. A total of 90 patients with T2DM, who were hospitalized in the nephrology and endocrinology departments of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from June 2021 to January 2022, were included and divided into three groups (A1, A2, A3) according to the urinary albumin-to-creatinine ratio (UACR). Observe and compare the basic information, clinical and laboratory data, and the inflammatory markers NLR, hs-CRP, MCP-1. Results revealed that high levels of NLR (OR = 6.562, 95% CI 2.060–20.902, P = 0.001) and MCP-1 (OR = 1.060, 95% CI 1.026–1.095, P

Abstract Some plants do not grow due to the high pH levels of ecological concrete pore solutions. In this paper, we design and build an integrated device featuring a combined microbial film and a transverse/U-shaped grouting film. We have applied to the China Intellectual Property Office for an invention patent on this device. The device overcomes the blockage of the grouting port caused by microbial and vertical grouting. The vertical grouting tube leaves holes inside a specimen, reducing the compressive strength, while the integrated device optimizes and decreases variation in the recycling of microbial bacteria. The reduction in the pore alkalinity of porous ecological concrete resulting from the microbial grouting film of this device is larger than that resulting from a microbial sprayed film. The pH values of porous ecological concrete with microbial grouting films and microbial sprayed films are obtained by the pure slurry soaking method and solid–liquid extraction method, respectively. The pH value is lower for the film obtained by the pure slurry soaking method than for that obtained by the solid–liquid extraction method. Conversely, the pH value of porous ecological concrete with a microbial grouting film is reduced to approximately 8 at an age of 56 days. The compressive strengths of the porous ecological concrete specimens with the two films are almost the same. The results of this study provide the necessary theoretical basis for developing alkali reduction technology for porous ecological concrete with environmental and economic benefits.

Abstract Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs’ contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment.

Objective To investigate the HBV infection markers detection and demographic characteristics of first-time blood donors, so as to provide evidence for blood donor recruitment. Methods HBsAg was detected by ELISA, HBsAg negative samples were tested for HBV DNA, and chemiluminescence method was used to detect HBsAg, HBsAb, HBcAb, HBeAg and HBeAb in first-time blood donor HBsAg-/HBV DNA+ samples. Demographic information of HBsAg positive first-time donors was analyzed. Results From 2018 to 2022, a total of 502 739 people participated in voluntary blood donation, and first-time blood donors accounted for 33.79%. The HBsAg positive rate of first-time donors(28.37/10 000, 482/169 897)was higher than that of repeated blood donors(3.46/10 000, 115/332 842) (OR=8.23, 95%CI: 6.72~10.09), and the HBV DNA positive rate of first-time blood donors(4.83/10 000, 82/169 897)was lower than that of repeated blood donors(6.52/10 000, 217/332 842)(OR=0.74, 95%CI: 0.57~0.95). The positive rate of HBcAb in HBsAg-/HBV DNA+ samples of first-time blood donors was 73.17%. Significant differences were noticed in HBsAg-/HBV DNA+ and HBsAg positive rate among first-time blood donors among gender, age, education background and occupation (all P

Abstract Skin cutaneous melanoma (SKCM) constitutes a malignant cutaneous neoplasm characterized by an exceedingly unfavorable prognosis. Over the past years, necroptosis, a manifestation of inflammatory programmed cell demise, has gained substantial traction in its application. However, a conclusive correlation between the expression of necroptosis-related genes (NRGs) and SKCM patient's prognosis remains elusive. In this endeavor, we have undertaken an integrative analysis of genomic data, aiming to provide an exhaustive evaluation of the intricate interplay between melanoma necroptosis and immune-infiltration nuances within the tumor microenvironment. Through meticulous scrutiny, we have endeavored to discern the prognostic potency harbored by individual necroptosis-associated genes. Our efforts culminated in the establishment of a risk stratification framework, allowing for the appraisal of necroptosis irregularities within each afflicted cutaneous melanoma patient. Notably, those SKCM patients classified within the low-risk cohort exhibited a markedly elevated survival quotient, in stark contrast to their high-risk counterparts (p

Objectives: To address the poor efficacy and percutaneous penetration of grape seed oil, ionic liquids and nanotechnology were combined to prepare a grape seed oil emulsion. Methods: A novel Menthol-CoQ10 ionic liquid and ionic liquid based grapeseed oil emulsion were prepared and confirmed. Results: The average size of the grapeseed oil emulsion was 218 nm, and its zeta potential was −33.5 mV. The ionic liquid-based grape seed oil emulsion exhibited a transdermal penetration effect 4.63-fold higher than that of ordinary grape seed oil emulsion. Ionic liquid also displayed enhanced efficiency both in vitro and in vivo. It significantly inhibited the production of DPPH free radicals and tyrosinase, inhibited melanin and matrix metalloproteinase-1 (MMP-1) produced by cells, and promoted type I collagen expression in fibroblasts. After 28 days of continuous use, the grapeseed oil emulsion improved the water content of the stratum corneum and the rate of transepidermal water loss, enhanced the firmness and elasticity of the skin, and significantly improved the total number and length of under-eye lines, tail lines, nasolabial folds, and marionette lines on the face. Conclusions: Menthol-CoQ10 ionic liquid is a promising functional excipient for both transdermal delivery increase and efficient enhancement. Ionic liquid and nanotechnology for grape seed oil facial mask displayed significantly enhanced efficacy and permeability.

Monitoring the effectiveness of COVID-19 vaccination is critical for understanding if the vaccinated population, especially the elderly, is adequately protected from the emergence of new SARS-CoV-2 variants. This study aimed to investigate the effects of COVID-19 vaccination on the severity of symptoms and mortality in hospitalized geriatric patients during the Omicron BF.7 surge in Macao. Data from electronic health records and vaccination registry of inpatients aged 60 years or above admitted to Kiang Wu Hospital from 12 December 2022 to 12 March 2023 were retrospectively analyzed. The study involved 848 people, including 426 vaccinated and 422 unvaccinated individuals. The mean CXR scores (8.95 ± 9.49 vs. 11.41 ± 10.81, p < 0.001) and the mean MEWS scores (0.96 ± 2.01 vs. 1.49 ± 2.45, p < 0.001) were lower in the vaccinated group. By comparing the dose counts, no significant difference was seen in the odds of death. Based on the time of the last vaccination, 128 people were categorized as complete and 298 as incomplete vaccination. The complete vaccination group showed a 54% (95% CI 0.23–0.91) reduction in mortality risk (p = 0.026). The study findings not only reconfirm the effectiveness of COVID-19 vaccination but, more importantly, highlight the importance of vaccination timing to maximize vaccines’ protective effect.

Abstract Giardia duodenalis is a gastrointestinal protozoan ubiquitous in nature. It is a confirmed zoonotic pathogen, and cattle are considered a source of giardiasis outbreaks in humans. This study aimed to evaluate the prevalence and multilocus genotype (MLG) of G. duodenalis in dairy cattle in Central Inner Mongolia. This study was based on the small subunit ribosomal RNA (SSU rRNA), glutamate dehydrogenase (gdh), triosephosphate isomerase (tpi), and beta-giardin (bg) genes of G. duodenalis. DNA extraction, polymerase chain reaction (PCR), and sequence analysis were performed on 505 dairy cattle fecal samples collected in 2021 from six sampling sites and four age groups in Central Inner Mongolia to determine the prevalence and MLG distribution of G. duodenalis. The PCR results of SSU rRNA revealed that the overall prevalence of G. duodenalis was 29.5% (149/505) and that the overall prevalence of the diarrhea and nondiarrhea samples was 31.5% (46/146) and 28.5% (103/359), respectively; the difference was not significant (p > 0.05). SSU rRNA sequence analysis revealed that G. duodenalis assemblage E (91.1%, 133/146) was primarily detected and that assemblage A (8.9%, 13/146) was detected in 13 samples. The G. duodenalis—positive samples were PCR amplified and sequenced for gdh, tpi, and bg, from which 38, 47, and 70 amplified sequences were obtained, respectively. A combination of G. duodenalis assemblages A and E were detected in seven samples. Multilocus genotyping yielded 25 different assemblage E MLGs, which formed six subgroups. To the best of our knowledge, this is the first report regarding G. duodenalis infection in dairy cattle in Inner Mongolia, China. This study revealed that Inner Mongolian cattle pose a risk of giardiasis transmission to humans and that the distribution of local cattle G. duodenalis assemblage E MLGs is diverse. The findings of this study can bridge the knowledge gap in the molecular epidemiological investigation of giardiasis in Central Inner Mongolia.

Abstract Background Lipid metabolism plays an important role in liver regeneration, but its regulation still requires further research. In this study, lipid metabolites involved in mouse liver regeneration at different time points were sequenced and analyzed to study their influence on liver regeneration and its mechanism. Methods Our experiment was divided into two parts. The first part examined lipid metabolites during liver regeneration in mice. In this part, lipid metabolites were sequentially analyzed in the livers of 70% mouse hepatectomy models at 0, 1, 3and 7 days after operation to find the changes of lipid metabolites in the process of liver regeneration. We screened L-carnitine as our research object through metabolite detection. Therefore, in the second part, we analyzed the effects of carnitine on mouse liver regeneration and lipid metabolism during liver regeneration. We divided the mouse into four groups: control group (70% hepatectomy group); L-carnitine group (before operation) (L-carnitine were given before operation); L-carnitine group (after operation)(L-carnitine were given after operation) and L-carnitine + perhexiline maleate (before operation) group. Weighing was performed at 24 h, 36 and 48 h in each group, and oil red staining, HE staining and MPO staining were performed. Tunnel fluorescence staining, Ki67 staining and serological examination. Results Sequencing analysis of lipid metabolites in 70% of mouse livers at different time points after hepatectomy showed significant changes in carnitine metabolites. The results showed that, compared with the control group the mouse in L-carnitine group (before operation) at 3 time points, the number of fat drops in oil red staining was decreased, the number of Ki67 positive cells was increased, the number of MPO positive cells was decreased, the number of Tunnel fluorescence positive cells was decreased, and the liver weight was increased. Serum enzymes were decreased. Compared with control group, L-carnitine group (after operation) showed similar trends in all indexes at 36 and 48 h as L-carnitine group (before operation). L-carnitine + perhexiline maleate (before operation) group compared with control group, the number of fat drops increased, the number of Ki67 positive cells decreased, and the number of MPO positive cells increased at 3 time points. The number of Tunnel fluorescent positive cells increased and serum enzyme increased. However, both liver weights increased. Conclusion L-carnitine can promote liver cell regeneration by promoting lipid metabolism and reduce aseptic inflammation caused by excessive lipid accumulation.

This meta-analysis aims to assess the success rate of pulpotomy in the treatment of permanent teeth with carious pulp exposure and to compare the efficacy of different capping materials. Randomized controlled trials were searched in PubMed, EMBASE, Web of Science, Clinicaltrial.gov, and Cochrane Library until August 31, 2023. The pooled success rate was estimated in the overall population and in subgroups. Additional analyses comparing different capping materials using odds ratio (OR) and 95% confidence interval (95%CI) were performed. The certainty of evidence was graded using the GRADE approach. A total of 25 randomized trials with an average follow-up duration ≥ 12 months were finally included. The overall success rate of pulpotomy was 86.7% (95%CI: 82.0-90.7%). The success rate was not significantly affected by root development, pulpotomy type, and follow-up duration. Teeth with irreversible pulpitis had a relatively lower success rate than teeth with normal pulp or reversible pulpitis (82.4% [95%CI: 74.6-89.0%] vs 92.0% [95%CI: 87.9-95.4%], P = 0.013). Directly compared to conventional calcium hydroxide, mineral trioxide aggregate (88.2% vs 79.1%, OR = 2.41, 95%CI: 1.28-4.51, P = 0.006) and Biodentine (97.5% vs 82.9%, OR = 6.03, 95%CI: 0.97-37.6, P = 0.054) had higher successful rates. No significant difference between MTA and other biomaterials was found. The results were graded as very low to low certainty of evidence. In conclusion, pulpotomy is an effective treatment of permanent teeth with carious pulp exposure. Mineral trioxide aggregate and Biodentine can be recommended with more favorable outcomes as capping materials.

PurposeThe anterior flange height of the current femoral component increases with an increasing distal femoral anteroposterior dimension. During total knee arthroplasty (TKA), we have observed that a large femur may have a thinner anterior condyle, whereas a small femur may have a thicker anterior condyle. The first purpose of this study was to examine whether the femoral anterior condyle height decreases as the distal femoral anteroposterior size increases and whether gender differences exist in anterior condyle height.MethodsA total of 1218 knees undergoing TKA intraoperative and computed tomography scans from 303 healthy knees were used to measure the anterior lateral condylar height (ALCH), anterior medial condylar height (AMCH), and the lateral anteroposterior (LAP) and medial anteroposterior (MAP) dimensions of distal femurs. The LAP and MAP measurements were used for adjustments to determine whether gender differences exist in anterior condyle heights. Linear regression analysis was performed to determine correlations between ALCH and LAP or between AMCH and MAP.ResultsThere were significant differences between males and females in ALCH in both the CT and TKA groups and AMCH in the CT group (all PConclusionsThe results demonstrate that femoral anterior condylar height decreased with increasing anteroposterior dimension in both the medial and lateral condyle. In addition, this study also showed that anterior condylar heights are highly variable, with gender differences. The data may provide an important reference for designing femoral anterior flange thickness to precisely match the natural anterior condylar anatomy.

Abstract Wilson's disease (WD) is an autosomal recessive disorder with a genetic basis. The predominant non-motor symptom of WD is cognitive dysfunction, although the specific genetic regulatory mechanism remains unclear. Tx-J mice, with an 82% sequence homology of the ATP7B gene to the human gene, are considered the most suitable model for WD. This study employs deep sequencing to investigate the differences in RNA transcript profiles, both coding and non-coding, as well as the functional characteristics of the regulatory network involved in WD cognitive impairment. The cognitive function of tx-J mice was evaluated using the Water Maze Test (WMT). Long non-coding RNA (lncRNA), circular RNA (circRNA), and messenger RNA (mRNA) profiles were analyzed in the hippocampal tissue of tx-J mice to identify differentially expressed RNAs (DE-RNAs). Subsequently, the DE-RNAs were used to construct protein–protein interaction (PPI) networks, as well as DE-circRNAs and lncRNAs-associated competing endogenous RNA (ceRNA) expression networks, and coding-noncoding co-expression (CNC) networks. To elucidate their biological functions and pathways, the PPI and ceRNA networks were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A total of 361 differentially expressed mRNAs (DE-mRNAs), comprising 193 up-regulated and 168 down-regulated mRNAs, 2627 differentially expressed long non-coding RNAs (DE-lncRNAs), consisting of 1270 up-regulated and 1357 down-regulated lncRNAs, and 99 differentially expressed circular RNAs (DE-circRNAs), consisting of 68 up-regulated and 31 down-regulated circRNAs, were observed in the tx-J mice group when compared to the control mice group. Gene Ontology (GO) and pathway analyses revealed that DE-mRNAs were enriched in cellular processes, calcium signaling pathways, and mRNA surveillance pathways. In contrast, the DE-circRNAs-associated competing endogenous RNA (ceRNA) network was enriched for covalent chromatin modification, histone modification, and axon guidance, whereas the DE-lncRNAs-associated ceRNA network was enriched for dendritic spine, regulation of cell morphogenesis involved in differentiation, and mRNA surveillance pathway. The study presented the expression profiles of lncRNA, circRNA, and mRNA in the hippocampal tissue of tx-J mice. Furthermore, the study constructed PPI, ceRNA, and CNC expression networks. The findings are significant in comprehending the function of regulatory genes in WD associated with cognitive impairment. These results also offer valuable information for the diagnosis and treatment of WD.

Abstract Predicting the origin-destination (OD) probability distribution of agent transfer is an important problem for managing complex systems. However, prediction accuracy of associated statistical estimators suffer from underdetermination. While specific techniques have been proposed to overcome this deficiency, there still lacks a general approach. Here, we propose a deep neural network framework with gated recurrent units (DNNGRU) to address this gap. Our DNNGRU is network-free, as it is trained by supervised learning with time-series data on the volume of agents passing through edges. We use it to investigate how network topologies affect OD prediction accuracy, where performance enhancement is observed to depend on the degree of overlap between paths taken by different ODs. By comparing against methods that give exact results, we demonstrate the near-optimal performance of our DNNGRU, which we found to consistently outperform existing methods and alternative neural network architectures, under diverse data generation scenarios.

Abstract Background Patients with malignant tumors are more likely to have psychological problems due to their worries about their life expectancy. To understand the psychological status of elderly patients with malignant liver tumor undergoing hepatectomy better, the study was designed to investigate the current situation of anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy and to analyze its related factors. Methods A total of 126 elderly patients with malignant liver tumor undergoing hepatectomy were selected as the research objects. The anxiety and depression of all subjects were evaluated by HADS (Hosptial Anxiety and Depression Scale). The correlation factors affecting the psychological state of elderly patients with malignant liver tumor undergoing hepatectomy were analyzed by linear regression method. Results The HADS-A score of elderly patients with malignant liver tumor undergoing hepatectomy was 8.79 ± 2.56, among which 37 patients were asymptomatic, 60 patients with suspicious symptoms, and 29 patients with definite symptoms. The HADS-D score was 8.40 ± 2.97, among which 61 patients were asymptomatic, 39 patients with suspicious symptoms, and 26 patients with definite symptoms. Multivariate analysis using linear regression method showed that FRAIL score, residence, and complication were significantly associated with anxiety and depression of elderly patients with malignant liver tumor undergoing hepatectomy. Conclusions Anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy were obvious. FRAIL score, regional differences, and the complication were the risk factors for anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy. Improving frailty, reducing regional differences, and preventing complications is beneficial to alleviate the adverse mood of elderly patients with malignant liver tumor undergoing hepatectomy.

Abstract Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease that can be treated with revascularization. Surgery increases the risk of poor wound healing (PWH) due to the impact on the blood supply to the flap. We aimed to analyze risk factors for PWH in MMD with a complete Y-shaped incision. A total of 125 patients with MMD were enrolled in this prospective observational study. The wounds were assessed and measured on the third and seventh days after surgery. The mean age of these patients was 43.3 ± 10.0 years. The ratio of male to female was 1:1.3. 15 (12.0%) patients had incision complications. 5 patients (4.0%) had redness; 2 patients (1.6%) had swelling; 2 patients (1.6%) had fat necrosis; 3 patients (2.4%) had incision infection; and 3 patients (2.4%) had flap necrosis. Student’s t test showed significant differences in BMI (P = 0.040) and fever time (P = 0.050). The standard chi-squared test showed significant differences in incision infection (P = 0.010), suture mode (P = 0.047), and cutting off large branch vessels in the flap (P

Abstract To compare the clinical efficacy of an innovative modified single-incision technique without special extraperitoneal PORT with that of transperitoneal multi-incision robot-assisted laparoscopic radical prostatectomy and to explore the feasibility and safety of the former. A retrospective analysis was performed on 259 patients who received robot-assisted laparoscopic radical prostatectomy in the Robot Minimally Invasive Center of Sichuan Provincial People's Hospital between September 2018 and August 2021. Among them were 147 cases involving extraperitoneal single incision with no special PORT (Group A) and 112 cases involving multiple incisions by the transperitoneal method (Group B). Differences in age, PSA level, Gleason score, prostate volume, body mass index, clinical stage, lower abdominal operation history, and lymph node dissection ratio between the two groups were not statistically significant (P > 0.05). All operations were performed by the same operator. In this study, all 259 operations were completed successfully, and there was no conversion. There was no significant difference in transperitoneal blood loss, postoperative hospital stay, positive rate of incision margin, indwelling time of urinary catheter, satisfaction rate of immediate urine control, satisfaction rate of urine control 3 months after operation, positive rate of postoperative lymph node pathology or postoperative pathological stage between the two groups (P > 0.05). There were significant differences in operation time, postoperative exhaust time and incision length (P

Abstract Background Previous studies have shown that depression is often accompanied by an increase in mtDNA copy number and a decrease in ATP levels; however, the exact regulatory mechanisms remain unclear. Methods In the present study, Western blot, cell knockdown, immunofluorescence, immunoprecipitation and ChIP-qPCR assays were used to detect changes in the Ahi1/GR-TFAM-mtDNA pathway in the brains of neuronal Abelson helper integration site-1 (Ahi1) KO mice and dexamethasone (Dex)-induced mice to elucidate the pathogenesis of depression. In addition, a rescue experiment was performed to determine the effects of regular exercise on the Ahi1/GR-TFAM-mtDNA-ATP pathway and depression-like behavior in Dex-induced mice and Ahi1 KO mice under stress. Results In this study, we found that ATP levels decreased and mitochondrial DNA (mtDNA) copy numbers increased in depression-related brain regions in Dex-induced depressive mice and Ahi1 knockout (KO) mice. In addition, Ahi1 and glucocorticoid receptor (GR), two important proteins related to stress and depressive behaviors, were significantly decreased in the mitochondria under stress. Intriguingly, GR can bind to the D-loop control region of mitochondria and regulate mitochondrial replication and transcription. Importantly, regular exercise significantly increased mitochondrial Ahi1/GR levels and ATP levels and thus improved depression-like behaviors in Dex-induced depressive mice but not in Ahi1 KO mice under stress. Conclusions In summary, our findings demonstrated that the mitochondrial Ahi1/GR complex and TFAM coordinately regulate mtDNA copy numbers and brain ATP levels by binding to the D-loop region of mtDNA Regular exercise increases the levels of the mitochondrial Ahi1/GR complex and improves depressive behaviors. Video Abstract

Abstract Background Hepatic resection is a potentially curative treatment for patients with hepatocellular carcinoma (HCC). The treatment of elderly patients with HCC has always been difficult. With the development of geriatrics and geriatric surgery, the number of elderly patients with HCC undergoing hepatectomy has gradually increased. To further improve the long-term prognosis of elderly patients with hepatocellular carcinoma undergoing surgery, it is necessary to study the related perioperative factors. Our aim was to study the impact of preoperative and intraoperative factors on the long-term survival of elderly patients with HCC who underwent hepatectomy. Methods A total of 151 elderly patients with HCC who underwent hepatectomy were retrospectively studied. Univariate and multivariate Cox regression analyses were performed for preoperative- and intraoperative-related prognostic factors. Results The 1-, 3-, 5- and 10-year overall survival rates of elderly patients with HCC who underwent resection were 79.5%, 60.8%, 46.6%, and 25.4%, respectively. Multivariate analyses identified four independent predictors of long-term prognosis: Child–Pugh grade (B/C versus A: HR[hazard ratio] = 2.318, P = 0.019), alpha-fetoprotein value (> 20 ng/ml versus ≤ 20 ng/ml: HR = 1.972, P = 0.005), resection style (anatomical versus no anatomical: HR = 1.976, P = 0.006), and intraoperative blood loss (> 400 ml versus ≤ 400 ml: HR = 2.008, P = 0.003). Conclusions Poor survival of elderly patients with HCC who underwent hepatectomy was correlated with the preoperative and intraoperative factors of Child–Pugh grade, Alpha-fetoprotein value, resection style, and intraoperative blood loss.

Abstract People more accurately remember faces of their own racial group compared to faces of other racial groups; this phenomenon is called the other-race effect. To date, numerous researchers have devoted themselves to exploring the reasons for this other-race effect, and they have posited several theoretical explanations. One integrated explanation is the categorization-individuation model, which addresses two primary ways (categorization and individuation) of racial face processing and emphasizes the emergence of these two ways during the encoding stage. Learning-recognition and racial categorization tasks are two classical tasks used to explore racial face processing. Event-related potentials can facilitate investigation of the encoding differences of own- and other-race faces under these two typical task demands. Unfortunately, to date, results have been mixed. In the current study, we investigated whether categorization and individuation differ for own- and other-race faces during the encoding stage by using racial categorization and learning-recognition tasks. We found that task demands not only influence the encoding of racial faces, but also have a more profound effect in the encoding stage of recognition tasks for other-race faces. More specifically, own-race faces demonstrate deeper structural encoding than other-race faces, with less attentional involvement. Moreover, recognitions tasks might ask for more individual-level encoding, requiring more attentional resources in the early stage that may be maintained until relatively late stages. Our results provide some evidence concerning task selection for future racial face studies and establish a groundwork for a unified interpretation of racial face encoding.

Precision medicine will be the direction of future medical development, especially in cancer diagnosis and treatment. With the deepening of breast cancer-related research, new factors related to diagnosis, treatment and prognosis are constantly being discovered. Researchers combine different factors to form a multigene panel testing, guiding clinicians' decision-making. The application scope of multigene panel detection is constantly expanding. At present, it has been tried in the prognosis evaluation of lymph node-positive and human epidermal growth factor receptor 2-positive breast cancer patients and the early screening of breast cancer. With continuous technological advancement, there will be broader application prospects in the future. The current narrative review was planned to evaluate the recent advances in applying multigene panel testing in breast cancer cases. Key Words: Multigene panel testing, Breast cancer, Oncotype Dx, MammaPrint, Endopredict, PAM50, BCI, CancerSeek.

Highlights 1. Circulating exosomal RNA sequencing identified novel potential biomarkers of clear cell renal cell carcinoma (ccRCC). 2. The early diagnostic signature comprising KMT2D and PREX2 showed high accuracy in distinguishing ccRCCs from healthy individuals. 3. The differential diagnostic signature comprising CUL9, KMT2D, and PREX2 showed great performance in distinguishing ccRCCs from benign renal masses. 4. These signatures could be promising and noninvasive biomarkers for ccRCC detection.

Summary: Background: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown. Methods: In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler's dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins. Findings: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders. Interpretation: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC. Funding: This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].

Abstract The co-pyrolysis of oily sludge with biomass to prepare carbon materials is not only an effective way to mitigate oily sludge pollution, but it is also a method of obtaining carbon materials. In this study, a carbon material (OS-CS AC) was obtained by the direct co-pyrolysis of oily sludge (OS) and corn stalks (CS) and then applied to Cr(VI) removal. According to the hydroxy and carboxy masking experiments and the characterization of OS-CS AC by FT-IR, SEM, XPS, XRD, and N2 physical adsorption–desorption, Cr(VI) can be adsorbed efficiently through pore filling, the surface oxygen-containing functional groups can promote the reduction of Cr(VI) to Cr(III) through electron donors, and the greater the electrostatic attraction between the electron-donating functional groups of OS-CS AC and the Cr(VI) is, the stronger the ability to remove Cr(VI). In addition, the removal process was discussed, and the results indicated that the McKay kinetic model, Langmuir isotherm model and Van't Hoff thermodynamic model were the most suitable models for removal. The main factors affecting the removal of Cr(VI) were discussed, and the removal of Cr(VI) reached 99.14%, which gives a comprehensive utilization way of oily sludge and corn stalks.

JNK3, a member of the MAPK family, plays a pivotal role in mediating cellular responses to stress signals, with its activation implicated in a myriad of inflammatory conditions. While JNK3 holds promise as a therapeutic target for neurodegenerative disorders such as Huntington’s, Parkinson’s, and Alzheimer’s diseases, there remains a gap in the market for effective JNK3 inhibitors. Despite some pan-JNK inhibitors reaching clinical trials, no JNK-targeted therapies have achieved market approval. To bridge this gap, our study introduces a sophisticated virtual screening approach. We begin with an energy-based screening, subsequently integrating a variety of rescoring techniques. These encompass glide docking scores, MM/GBSA, and artificial scoring mechanisms such as DeepDock and advanced Graph Neural Networks. This virtual screening workflow is designed to evaluate and identify potential small-molecule inhibitors with high binding affinity. We have implemented a virtual screening workflow to identify potential candidate molecules. This process has resulted in the selection of ten molecules. Subsequently, these ten molecules have undergone biological activity evaluation to assess their potential efficacy. Impressively, molecule compound 6 surfaced as the most promising, exhibiting a potent kinase inhibitory activity marked by an IC50 of 130.1 nM and a notable reduction in TNF-α release within macrophages. This suggests that compound 6 could potentially serve as an effective inhibitor for the treatment of neuroinflammation and neurodegenerative diseases. The prospect of further medicinal modifications to optimize compound 6 presents a promising avenue for future research and development in this field. Utilizing binding pose metadynamics coupled with molecular dynamics simulations, we delved into the explicit binding mode of compound 6 to JNK3. Such insights pave the way for refined drug development strategies. Collectively, our results underscore the efficacy of the hybrid virtual screening workflow in the identification of robust JNK3 inhibitors, holding promise for innovative treatments against neuroinflammation and neurodegenerative disorders.

BackgroundEarly triage of patients with mushroom poisoning is essential for administering precise treatment and reducing mortality. To our knowledge, there has been no established method to triage patients with mushroom poisoning based on clinical data. ObjectiveThe purpose of this work was to construct a triage system to identify patients with mushroom poisoning based on clinical indicators using several machine learning approaches and to assess the prediction accuracy of these strategies. MethodsIn all, 567 patients were collected from 5 primary care hospitals and facilities in Enshi, Hubei Province, China, and divided into 2 groups; 322 patients from 2 hospitals were used as the training cohort, and 245 patients from 3 hospitals were used as the test cohort. Four machine learning algorithms were used to construct the triage model for patients with mushroom poisoning. Performance was assessed using the area under the receiver operating characteristic curve (AUC), decision curve, sensitivity, specificity, and other representative statistics. Feature contributions were evaluated using Shapley additive explanations. ResultsAmong several machine learning algorithms, extreme gradient boosting (XGBoost) showed the best discriminative ability in 5-fold cross-validation (AUC=0.83, 95% CI 0.77-0.90) and the test set (AUC=0.90, 95% CI 0.83-0.96). In the test set, the XGBoost model had a sensitivity of 0.93 (95% CI 0.81-0.99) and a specificity of 0.79 (95% CI 0.73-0.85), whereas the physicians’ assessment had a sensitivity of 0.86 (95% CI 0.72-0.95) and a specificity of 0.66 (95% CI 0.59-0.73). ConclusionsThe 14-factor XGBoost model for the early triage of mushroom poisoning can rapidly and accurately identify critically ill patients and will possibly serve as an important basis for the selection of treatment options and referral of patients, potentially reducing patient mortality and improving clinical outcomes.

Abstract Common hepatic artery pseudoaneurysm is a rare and potentially life‐threatening complication after pancreaticoduodenectomy, and the possible cause is unclear. We report a case of intraperitoneal hemorrhage after pancreaticoduodenectomy who was discharged after embolization under digital subtraction angiography. We conside that this complication may be related to iatrogenic injury.

Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell–mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression — to a level equal to the PD-1 mAb — which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb–treated patients with non–small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.

IntroductionRopivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects.MethodsThe abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block.ResultsSingle-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 μg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h.ConclusionsRODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe.Trial registrationChictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.

Summary: Background: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. Methods: A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. Findings: In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5–81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. Interpretation: In our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. Funding: None.

Objectives To examine the association between housing types and COVID-19 infection (or mental health) during the early stages of the pandemic by using the large-scale individual-level All of Us Research Program COVID-19 Participant Experience (COPE) survey data. We hypothesise that housing types with a shared component are associated with elevated COVID-19 infection and subsequent mental health conditions.Design A retrospective case–control study.Setting Secondary analysis of online surveys conducted in the USA.Participants 62 664 participant responses to COPE from May to July 2020.Primary and secondary outcome measures Primary outcome measure is the self-reported COVID-19 status, and the secondary outcome measures are anxiety or stress. Both measures were applied for matched cases and controls of the same race, sex, age group and survey version.Results A multiple logistic regression analysis revealed that housing types with a shared component are significantly associated with COVID-19 infection (OR=1.19, 95% CI 1.1 to 1.3; p=2×10−4), anxiety (OR=1.26, 95% CI 1.1 to 1.4; p=1.1×10−6) and stress (OR=1.29, 95% CI 1.2 to 1.4; p=4.3×10−10) as compared with free-standing houses, after adjusting for confounding factors. Further, frequent optional shopping or outing trips, another indicator of the built environment, are also associated with COVID-19 infection (OR=1.36, 95% CI 1.1 to 1.8; p=0.02), but not associated with elevated mental health conditions. Confounding factors are controlled in the analysis such as ethnicity, age, social distancing behaviour and house occupancy.Conclusion Our study demonstrates that houses with a shared component tend to have an increased risk of COVID-19 transmission, which consequently leads to high levels of anxiety and stress for their dwellers. The study also suggests the necessity to improve the quality of the built environment such as residential housing and its surroundings through planning, design and management, ensuring a more resilient society that can cope with future pandemics.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II– (Ang II–) and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-κB target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA.

Abstract Almond is one of the most featured nut crops owing to its high nutritional value. However, due to three different waves of flower and fruitlet drop, fruit drop is a major concern for growers. In this study, we carried out a time-course transcriptome analysis to investigate gene expression differences between normal and abnormal fruitlet development. By de novo assembly analysis, we identified 33,577 unigenes and provided their functional annotations. In total, we identified 7,469 differentially expressed genes and observed the most apparent difference between normal and abnormal fruits at 12 and 17 days after flowering. Their biological functions were enriched in carbon metabolism, carbon fixation in photosynthetic organisms and plant hormone signal transduction. RT-qPCR validated the expression pattern of 14 representative genes, including glycosyltransferase like family 2, MYB39, IAA13, gibberellin-regulated protein 11-like and POD44, which confirmed the reliability of our transcriptome data. This study provides an insight into the association between abnormal fruit development and carbohydrate signaling from the early developmental stages and could be served as useful information for understanding the regulatory mechanisms related to almond fruit drop.

AbstractObjective Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism.Methods Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure.Results Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43).Conclusion We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

Abstract Mercury (Hg) exposure poses serious health risks to humans, resulting in extensive investigations examining Hg accumulation, biotransformation and uptake in crops. In this investigation, Hg accumulation in potato tubers due to bioaccumulation processes was determined and bioconcentration factors affecting bioaccumulation were identified using a greenhouse experiment. Our results showed that the percentage of available Hg concentrations from total Hg in soil samples were less than 1.2%, indicating that soils used in our experiment exhibited a high binding strength for Hg, with alkaline soil recording the lowest available Hg/total Hg ratio. Results indicated that soil type and Hg treatment, as well as their interactions, significantly affected Hg accumulation in potato tubers (P

Based on the morphological comparisons and molecular results, three new species of Homatula, i.e., H. geminusclathratus sp. nov., H. microcephala sp. nov., and H. longibarbatus sp. nov., have been described and named from the Lancang-jiang (the upper Mekong River) and the Chuan-he (the upper Black River, a tributary of the Red River) basins. The loaches of Homatula from the Lancang-jiang and the Chuan-he can be distinguished via morphology, genetics, and geographic distribution. All of the 10 recorded species distributed in the Nu-jiang (the upper Salween River), the Lancang-jiang, and the upper Black River share the following combination of character states: whole body, except head, densely scaled; lateral line complete; and a short adipose crest along the dorsal midline of the caudal peduncle, anteriorly not reaching vertically through the anal-fin origin. Species with these characters are called the densely-scaled group of Homatula. The three newly described species belong to the densely-scaled group of Homatula. Based on molecular phylogenetics, these Homatula species form a monophyletic group that can be divided into two clades, the densely-scaled group and the non-densely-scaled group. The densely-scaled group of Homatula includes 13 species occurring between the Nu-jiang and the upper Black River. The non-densely-scaled group is non-monophyletic and includes 14 species that are distributed in the Red, Pearl, Yangtze, and Yellow River basins. Species of the non-densely-scaled group are clustered into four sub-clades that are constrained to the four river basins. Homatula exclusively inhabits mountain streams with rapid or gentle currents, vauclusian springs, underground rivers connected to streams, and ditches near villages and farmland. No specimens of Homatula were collected from the main streams of Lixian-jiang, Lancang-jiang, and Nu-jiang as well as their large tributaries. Small environmental changes in the habitat of Homatula, such as water pollution or extensive human use, can lead to species/population extinction. Effective conservation of rare and endemic fishes, like loaches of Homatula, entails systematic observations and more targeted protection.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world, caused millions of deaths and a severe illness which poses a serious threat to human health. Objective: To develop an antigen detection kit that can identify Omicron novel coronavirus mutants. Methods: BALB/c mice were immunized with the nucleocapsid protein of SARS-CoV-2 Omicron mutant treated with β-propiolactone. After fusion of myeloma cells with immune cells, Elisa was used to screen the cell lines capable of producing monoclonal antibodies. The detection kit was prepared by colloidal gold immunochromatography. Finally, the sensitivity, specificity and anti-interference of the kit were evaluated by simulating positive samples. Results: The sensitivity of the SARS-CoV-2 antigen detection kit can reach 62.5 TCID50/mL, and it has good inclusiveness for different SARS-CoV-2 strains. The kit had no cross-reaction with common respiratory pathogens, and its sensitivity was still not affected under the action of different concentrations of interferences, indicating that it had good specificity and stability. Conclusion: In this study, monoclonal antibodies with high specificity to the N protein of the Omicron mutant strain were obtained by monoclonal antibody screening technology. Colloidal gold immunochromatography technology was used to prepare an antigen detection kit with high sensitivity to detect and identify the mutant Omicron strain.