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Oral administration of resveratrol is able to ameliorate the progression of diabetic nephropathy (DN); however, its mechanisms of action remain unclear. Recent evidence suggested that the gut microbiota is involved in the metabolism therapeutics. In the current study, we sought to determine whether the anti-DN effects of resveratrol are mediated through modulation of the gut microbiota using the genetic db/db mouse model of DN. We demonstrate that resveratrol treatment of db/db mice relieves a series of clinical indicators of DN. We then show that resveratrol improves intestinal barrier function and ameliorates intestinal permeability and inflammation. The composition of the gut microbiome was significantly altered in db/db mice compared to control db/m mice. Dysbiosis in db/db mice characterized by low abundance levels of Bacteroides , Alistipes , Rikenella , Odoribacter , Parabacteroides , and Alloprevotella genera were reversed by resveratrol treatment, suggesting a potential role for the microbiome in DN progression. Furthermore, fecal microbiota transplantation, derived from healthy resveratrol-treated db/m mice, was sufficient to antagonize the renal dysfunction, rebalance the gut microbiome and improve intestinal permeability and inflammation in recipient db/db mice. These results indicate that resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol, which provides supporting evidence for the gut–kidney axis in DN.

Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.

Stimulator of interferon genes (STING), a major adaptor protein in antiviral innate immune signaling, is considered as one of the most important regulators of antiviral and antitumor immunity. Although STING agonists are now intensively studied in clinical trials as a new class of adjuvants to boost cancer immunotherapy, the tumor-intrinsic role of the STING pathway in shaping the tumor microenvironment remains controversial. Here, we discovered that STING plays a vital role in regulation of myeloid-derived suppressor cell (MDSC) differentiation and antitumor immunity in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). Mechanistic analyses reveal that STING represses NPC-derived MDSC induction by enhancing SOCS1 expression in both tumor cells and MDSCs. SOCS1 physically interacts with STAT3 through its SH2 domain to prevent STAT3 phosphorylation and dimerization, resulting in reduced MDSC induction via inhibition of GM-CSF and IL-6 production. Notably, reduced tumoral STING expression was found to be significantly associated with a poor prognosis for NPC patients. Our findings reveal a novel mechanism linking STING to tumor microenvironmental cytokine production and MDSC induction.

Background To compare the efficacy of combining posterior superior alveolar (PSA) block, anterior middle superior alveolar (AMSA) block, and labial infiltration of the maxillary central incisor versus PSA + AMSA alone for pain control during minimally invasive nonsurgical periodontal therapy (MINST). Methods Twenty-four patients with stage II-III periodontitis were enrolled in the single-center, single-blind, split-mouth randomized controlled trial. The maxillary right and left quadrants were randomized to receive either PSA + AMSA blocks and labial infiltration (test group) or PSA + AMSA alone (control group) during subgingival instrumentation. Pain levels during injection and treatment were assessed using a 100 mm visual analog scale (VAS). Primary outcomes included intraoperative and injection-related pain scores, while secondary outcomes comprised treatment duration, injection time, patient satisfaction, and adverse events. Data were analyzed using GraphPad Prism 9. Results Twenty-one subjects completed the study. No significant difference in injection pain was observed between groups (test: 22.74 ± 14.10 mm vs. control: 20.21 ± 12.27 mm; P  = 0.248). However, the test group exhibited a statistically significant reduction in intraoperative pain (test: 11.07 ± 10.36 mm vs. control: 16.43 ± 11.55 mm; P  = 0.021). Patient satisfaction was significantly higher in the test group [test: 90 (IQR 90–100) vs. control: 90 (80–90); P  = 0.004]. No clinically meaningful differences were detected in treatment duration or adverse event rates ( P  > 0.05). Conclusions The combined PSA + AMSA blocks and labial infiltration protocol reduced intraoperative pain and improved satisfaction versus PSA + AMSA blocks, without prolonging treatment. Despite clinical promise, the small sample size limits generalizability, necessitating multicenter trials to validate efficacy and broader applicability. Trial registration The trial protocol was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2400086566) on 05-07-2024.

Objective. The mechanism of steroidogenesis and spermatogenesis impairment in men with type 2 diabetes remains unclear. We aimed to explore the local changes of steroidogenesis and spermatogenesis in the testis of db/db mice. Research Design and Methods. We performed single-cell RNA sequencing analysis in the testis of db/db and C57BL/6J mice. The differentially expressed genes were then confirmed by real-time PCR. The histopathological characteristics of testis in db/db mice and C57BL/6J control were also performed. Results. The 20-week-old db/db mice had significantly higher blood glucose and body weight (both p<0.001). The serum testosterone levels (4.4 ± 0.8 vs. 9.8 ± 0.7 ng/ml, p=0.001) and weight of the testis (0.16 ± 0.01 vs. 0.24 ± 0.01 g, p<0.001) were significantly lower in db/db mice than that in C57BL/6J controls. db/db mice had a lower cross-sectional area of seminiferous tubules and thickness of the cell layer (both p<0.05). The numbers of Sertoli cells and Leydig cells decreased in db/db mice (both p<0.01). Single-cell RNA sequencing analysis showed that compared with the control group, the percentage of spermatogonia was significantly higher in the db/db mouse (p<0.001), while the proportions of spermatocytes, round and elongating spermatids, and sperms were all lower in the db/db mouse (p all<0.001). The most differentially expressed genes were found in round spermatids (n = 86), which were not found in spermatogonia, spermatocyte, and sperm. Igfbp5 was the most significantly decreased gene in Leydig cells of the db/db mouse, while the expression of Cd74, H2-Aa, and H2-Eb1 was elevated. Ccl7 and Ptgds were the most significantly increased and decreased genes in Sertoli cells of the db/db mouse. Conclusions. The present study indicates spermiogenesis and steroidogenesis defects in db/db mice. The mechanism of steroidogenesis impairment in the testis of db/db mice deserves further investigation.

In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy. PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.

Introduction. Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. Methods. In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n=19), dulaglutide group (n=19), insulin glargine group (n=10), and placebo (n=17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. Results. Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11±0.24% vs. 7.40±0.16%, P=0.007), dulaglutide (8.77±0.37% vs. 7.06±0.28%, P<0.001), and insulin glargine (8.57±0.24% vs. 7.23±0.25%, P<0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P=0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P<0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P<0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P<0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P=0.001). Conclusions. Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

The impact failure response characteristics of rock specimens and bolted rock specimens under different impact dynamic loads were studied by Split Hopkinson pressure bar (SHPB). By comparing the time history laws of incident energy, reflection energy, transmission energy and dissipation energy in the process of rock impact failure in combination with the dynamic strain characteristics of bolts and rock, the energy dissipation mechanism of bolted rock under impact loading was obtained. The design idea of surrounding rock bolt support in a dynamic loading roadway was proposed. The results show that ① When the impact velocity of the bullet is 7.1 m/s, 8.1 m/s and 8.9 m/s, the “EPRD” (effectiveness for a given period to resistance dynamic load) of bolted rock are 158 μs, 139 μs and 121 μs, respectively. The increase in impact velocity shortens the “EPRD” of bolted rock and accelerates the failure of bolted rock. ② The impact dynamic load energy of bolted rock is stored in the form of strain energy in the \"cooperative deformation stage\". The impact dynamic load energy of the \"non-cooperative deformation stage\" is dissipated by the pore initiation and development of the rock matrix, new surface, new crack and shear slip deformation between the bolt and rock. The impact dynamic load energy of the “failure stage” primarily acts on the broken rock. ③ The dissipation energy is an inherent property of bolted rock and has nothing to do with the impact dynamic load. The influence of the impact dynamic load on the deformation of the roadway surrounding rock can be reduced by increasing the \"anti-energy\" coefficient of the surrounding rock.

Accurate and rapid response in complex driving scenarios is a challenging problem in autonomous driving. If a target is detected, the vehicle will not be able to react in time, resulting in fatal safety accidents. Therefore, the application of driver assistance systems requires a model that can accurately detect targets in complex scenes and respond quickly. In this paper, a lightweight feature extraction model, ShuffDet, is proposed to replace the CSPDark53 model used by YOLOX by improving the YOLOX algorithm. At the same time, an attention mechanism is introduced into the path aggregation feature pyramid network (PAFPN) to make the network focus more on important information in the network, thereby improving the accuracy of the model. This model, which combines two methods, is called ShuffYOLOX, and it can improve the accuracy of the model while keeping it lightweight. The performance of the ShuffYOLOX model on the KITTI dataset is tested in this paper, and the experimental results show that compared to the original network, the mean average precision (mAP) of the ShuffYOLOX model on the KITTI dataset reaches 92.20%. In addition, the number of parameters of the ShuffYOLOX model is reduced by 34.57%, the Gflops are reduced by 42.19%, and the FPS is increased by 65%. Therefore, the ShuffYOLOX model is very suitable for autonomous driving applications.

In the quark-diagram scheme, we study the charmed baryon decays of B c → B ∗ M , where B c is Λ c + or Ξ c + ( 0 ) , together with B ∗ ( M ) the decuplet baryon (pseudoscalar meson). It is found that only two W -exchange processes are allowed to contribute to B c → B ∗ M . Particularly, we predict B ( Λ c + → Σ ∗ 0 ( + ) π + ( 0 ) ) = ( 2.8 ± 0.4 ) × 10 - 3 , which respects the isospin symmetry. Besides, we take into account the SU (3) flavor symmetry breaking, in order to explain the observation of B ( Λ c + → Σ ∗ + η ) . For the decays involving Δ + + ( u u u ) , we predict B ( Λ c + → Δ + + π - , Ξ c + → Δ + + K - ) = ( 7.0 ± 1.4 , 13.5 ± 2.7 ) × 10 - 4 as the largest branching fractions in the singly Cabibbo-suppressed Λ c + , Ξ c + → B ∗ M decay channels, respectively, which are accessible to the LHCb, BELLEII and BESIII experiments.