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Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.

Phytohormone signalling pathways have an important role in defence against pathogens mediated by cell-surface pattern recognition receptors and intracellular nucleotide-binding leucine-rich repeat class immune receptors

Easy-to-use, fast, and accurate virus detection method is essential for patient management and epidemic surveillance, especially during severe pandemics. Loop-mediated isothermal amplification (LAMP) on a microfluidic platform is suitable for detecting infectious viruses, regardless of the availability of medical resources. The purpose of this review is to introduce LAMP-based microfluidic devices for virus detection, including their detection principles, methods, and application.Facing the uncontrolled spread of viruses, the large-scale deployment of LAMP-based microfluidic platforms at the grassroots level can help expand the coverage of nucleic acid testing and shorten the time to obtain test reports. Microfluidic chip technology is highly integrated and miniaturized, enabling precise fluid control for effective virus detection. Performing LAMP on miniaturized systems can reduce analysis time, reagent consumption and risk of sample contamination, and improve analytical performance.Compared to traditional benchtop protocols, LAMP-based microfluidic devices reduce the testing time, reagent consumption, and the risk of sample contamination. In addition to simultaneous detection of multiple target genes by special channel design, microfluidic chips can also integrate digital LAMP to achieve absolute quantification of target genes.

Knowledge of dasatinib-induced nephrotic syndrome is largely based on case reports. The clinical features of dasatinib-induced nephrotic syndrome are unknown. We collected case reports of 25 patients with nephrotic syndrome and analyzed their clinical characteristics. Overall, the onset of nephrotic syndrome ranged from 10 days to 5 years after dasatinib administration. Nine patients (36.0%) had clinical symptoms, mainly periorbital edema and lower-extremity edema. Serum albumin ranged from 1.2 g/dL to 3.7 g/dL in 10 patients (38.5%). The 24-h urine protein values ranged from 3.54 g/day to 118 g/day. Kidney biopsy of 13 patients (52.0%) mainly showed focal foot process effacement, mesangial hyperplasia, endothelial cell damage and focal segmental glomerulosclerosis. Proteinuria resolved or recovered after dasatinib discontinuation or dose reduction or switching to other tyrosine kinase inhibitors (TKIs).

Objectives Comparing the long-term tumor control results of partial cystectomy(PC)and radical cystectomy(RC)in the treatment of muscle-invasive bladder cancer, and to explore the feasible method of bladder preservation therapy (BPT)in patients with MIBC. Methods We retrospectively analyzed the clinical data of 102 patients with muscle-invasive bladder cancer in our hospital between January 2012 and December 2018, of whom 32 cases in the partial cystectomy group and 70 cases in the radical cystectomy group. We performed a comparative analysis of patient general information, perioperative-related indicators and postoperative follow-up data, comparing OS, PFS, and DSS at 1, 2, 3, 4, and 5 years in both groups, and comparing tumour recurrence and metastasis in postoperative patients. Results All the 102 cases in this study were successfully completed. Partial cystectomy group and Radical cystectomy group median operating time (169.50(130.00 ~ 225.25) min and 420.00(343.75 ~ 483.75) min, p 0.05). Conclusion In patients with limited solitary T2N0M0 and T3N0M0 muscle-invasive bladder cancer, partial cystectomy plus bladder instillations treatment can achieve comparable tumour control to radical cystectomy. However, patients in the PC group have significant advantages in terms of operative time, intraoperative bleeding, intraoperative and postoperative blood transfusion, preoperative preparation time, total hospital stay, postoperative recovery time, operative costs and operative complications. This option may be considered for such patients with a need for bladder preservation.

In craniomaxillofacial (CMF) surgery planning, a preoperative reconstruction of the CMF reference model is crucial for surgical restoration, especially the reconstruction of bilateral defects. Current reconstruction algorithms mainly generate reference models from the image analysis aspect, however, clinical indicators of the CMF reference model mostly consider the distribution of anatomical landmarks. Generating a reference model with optimal clinical evaluation helps promote the feasibility of an algorithm.We first build a dataset with 100 normal skull models and then calculate a statistical shape model (SSM) and the distribution of normal cephalometric values, which indicate the statistical features of a population. To further generate personalized reference models, we apply non-rigid registration to align the SSM with the defect skull model. An evaluation standard to select the optimal reference model considers both global performance and anatomical evaluation. Moreover, we develop a landmark detection network to improve the automatic level of the algorithm.The proposed method performs better than methods including Iterative Closest Point and SSM. From a global evaluation aspect, the results show that the RMSE between the reference model and the ground truth is [Formula: see text] mm, the percentage of vertices with error below 2 mm is [Formula: see text]% and the average faces distance is [Formula: see text] mm (better than the state-of-the-art method). From the anatomical evaluation aspect, the target registration error between the landmark pairs is [Formula: see text] mm. In addition, the clinical application confirms that the reference model can meet clinical requirements.To the best of our knowledge, we propose the first CMF reconstruction method considering the global performance of reconstruction and anatomically local evaluation from clinical experience. Simulated experiments and clinical cases prove the general applicability and strength of the method.

Immune and inflammatory responses have an important function in the pathophysiology of pulmonary hypertension (PH). However, little is known about the immune landscape in peripheral circulation in patients with high-altitude pulmonary hypertension (HAPH). We apply single-cell transcriptomics to characterize the monocytes that are significantly enriched in the peripheral blood mononuclear cells (PBMC) of HAPH patients. We discover an increase in C1 (non-classical) and C2 (intermediate) monocytes in PBMCs and a decrease in hypoxia-inducible transcription factor-1α (HIF-1α) in all monocyte subsets associated with HAPH. In addition, we demonstrate that similar immune adaptations may exist in HAPH and PH. Overall, we characterize an immune cell atlas of the peripheral blood in HAPH patients. Our data provide evidence that specific monocyte subsets and HIF-1α downregulation might be implicated in the pathogenesis of HAPH.

Background Chimeric antigen receptor macrophage (CAR-M) therapy is a novel cancer immunotherapy approach that integrates CAR structure and macrophage functions. CAR-M therapy has shown unique and impressive antitumor effects in immunotherapy for solid tumors. However, the polarization state of macrophages can affect the antitumor effect of CAR-M. We hypothesized that the antitumor activity of CAR-Ms may be further improved after inducing M1-type polarization. Methods In this report, we constructed a novel HER2-targeting CAR-M, which was composed of humanized anti-HER2 scFv, CD28 hinge region and FcγRI transmembrane domain and intracellular domain. Phagocytosis, tumor-killing capacities, and cytokine release of CAR-Ms were detected with or without M1-polarization pretreatment. Several syngeneic tumor models were used to monitor the in vivo antitumor activity of M1-polarized CAR-Ms. Results After polarization with LPS combined with interferon-γ in vitro, we found that the phagocytic and tumor-killing capacities of CAR-Ms against target cells were significantly enhanced. The expression of costimulatory molecules and proinflammatory cytokines was also significantly increased after polarization. By establishing several syngeneic tumor models in vivo, we also demonstrated that infusing polarized M1-type CAR-Ms could effectively suppress tumor progression and prolong the survival of tumor-bearing mice with enhanced cytotoxicity. Conclusions We demonstrated that our novel CAR-M can effectively eliminate HER2-positive tumor cells both in vitro and in vivo, and M1 polarization significantly enhanced the antitumor ability of CAR-M, resulting in a stronger therapeutic effect in solid cancer immunotherapy.

Transitioning from holistic analysis to a fine-grained level analysis may provide further understanding of psychopathology. This study aimed to explore dimension-level relationships between suicidal ideation, meaning in life, and affect in a joint framework using network analysis and to identify potential prevention and intervention targets to address suicidal ideation. A total of 852 healthy adults aged 18–35 years completed self-report scales to assess suicidal ideation, meaning in life, and affect. A regularized partial correlation network was then built to examine the links between these dimensions. Expected influence and bridge expected influence values were calculated for each node. The prevalence of suicidal ideation was 4.2%. The search for and presence of meaning in life and positive and negative affect exhibited distinct and complex links to the three dimensions of suicidal ideation (pessimism, sleep, and despair). The important central nodes were search for meaning in life, sleep, despair, and positive affect, while the critical bridge nodes were positive affect, negative affect, and presence of meaning in life. These findings provide further understanding of the specific roles of meaning in life and affect in suicidal ideation. The identified nodes may be promising targets for prevention and intervention for suicidal ideation.

Background During the eleven years from 2010 to 2021, preliminary statistics have shown that Fuwai Hospital completed 23,571 mechanical valve replacements for various types of valves, and 1139 mechanical valve replacements were performed in Guangyuan First People's Hospital. Only two patients developed valve leaflet escape, so valve leaflet escape is a rare postoperative complication. Case presentation In 2010 and 2021, two patients were selected after they had unilateral leaflet escape after having mechanical valve replacements in Fuwai Hospital of Chinese Academy of Medical Sciences and Guangyuan First People's Hospital. Both patients underwent reoperations with the classic operation and the new bileaflet mechanical prosthetic heart valve was sutured. The treatment of detached single lobe and distal vessel was comprehensively determined, and the condition was treated according to the patient's symptoms, CT results, ultrasound results and other test results, as well as whether this detached lobe caused any abnormal hemodynamics of the distal vessel. The patient with mechanical aortic valve escape completed the 10-year follow-up, and patient with mechanical mitral valve escape completed the 3-month follow-up. there was no thrombosis or hematoma at the embolic site; the patient had no lower limb symptoms. Conclusions The reason for the leaflet escape may be related to the valve design and the leaflet material. If the detached leaflets are damaged and if the distal blood vessels are affected, simultaneous surgical treatment is required. Those patients whose vessels were not damaged by the valve lobe should be carefully monitored.

Background Medication-related osteonecrosis of the jaw (MRONJ) is a serious debilitating disease caused by anti-resorption and anti-angiogenesis drugs, significantly affecting patients' quality of life. Recent studies suggested that primary gingival wound healing may effectively prevent the development of MRONJ. This study aimed to evaluate the effects of low-level light therapy (LLLT) on promoting gingival wound healing in extraction sockets of MRONJ-like mice and preventing the occurrence of MRONJ. Furthermore, we explored underlying mechanisms. Methods Mice were randomly divided into the Ctrl, Zol, and Zol + LLLT groups. Administration of zoledronate and tooth extraction of bilateral maxillary second molars were used to build the MRONJ model, and LLLT was locally administered into the tooth sockets to examine the effect of LLLT. Next, to explore the function of IL-1RA, we performed LLLT with interleukin-1 receptor antagonist (IL-1RA) neutralizing antibody (named Zol + LLLT + IL-1RA NAb group) or negative control antibodies for tooth extraction in subsequent rescue animal experiments. Stereoscope observations, micro-computed tomography, and histological examination were conducted to evaluate gingival wound healing and bone regeneration in tooth sockets. The effects of LLLT on the migration capacities of zoledronate-treated epithelial cells were assessed in vitro. Results LLLT promoted primary gingival wound healing without exposed necrotic bone. Micro-computed tomography results showed higher bone volume and mineral density of the tooth sockets after LLLT. Histology analysis showed complete gingival coverage, obvious bone regeneration, and reduced soft tissue inflammation, with down-regulated pro-inflammation cytokines, like interleukin-1 beta (IL-1β) and tumor necrosis factor-α (TNF-α), and up-regulated IL-1RA expression in the gingival tissue in the LLLT group. The rescue assay further showed that the effects of LLLT promoting gingival wound healing and preventing MRONJ might be partially abolished by IL-1RA neutralizing antibodies. In vitro studies demonstrated that LLLT accelerated zoledronate-treated epithelial cell migration. Conclusions LLLT might promote primary gingival wound healing and contribute to subsequent bone regeneration of the tooth extractions in MRONJ-like lesions via IL-1RA-mediated pro-inflammation signaling suppression.

The Martian atmospheric waves perturbation Datasets (MAWPD) version 2.0 is the first observation-based climatology dataset of Martian atmospheric waves. It contains climatology-gridded temperature, gravity waves, and tides spanning the whole Martian year. MAWPD uses the Data INterpolating Empirical Orthogonal Functions method (DINEOF) reconstruction method for data assimilation with the observational data from the Mars Global Surveyor (MGS), Mars Reconnaissance Orbiter (MRO), Mars Atmosphere and Volatile EvolutioN (MAVEN), Mars Pathfinder (MP), Mars Phoenix Lander (MPL), Mars Exploration Rover (MER) and Mars Express (MEX) temperature retrievals. The dataset includes gridded fields of temperature (Level 1 data) as well as the physical quantities of GWs (Level 2 data, amplitude, and potential energies), SPWs and tides (Level 2 data, amplitude, and phase). The MAWPD, based entirely on multiple reliable observations, provides climatological background atmospheric information of temperature and wave disturbances on Mars. The dataset is not only useful for observation-based scientific studies concerning Martian atmospheric waves, e.g., circulation, dust storms, and wave excitation mechanism, but also for cross-validating with model-based datasets or model results.

Objective To investigate the role of microRNA-155-5p on apoptosis and inflammatory response in human renal glomerular endothelial cells (HRGEC) cultured with high glucose. Methods The primary HRGEC were mainly studied, light microscopy was used to detect changes in cell morphology. Quantitative Real Time-Polymerase Chain Reaction, Western Blot, immunofluorescence were aimed to observe the mRNA and protein expression levels of target gene ETS-1, downstream factors VCAM-1, MCP-1 and cleaved caspase-3 in each group after high glucose treatment as well as transfection with miR-155 mimics or inhibitor. Results The expression of inflammatory factors and apoptosis of HRGEC cells increased under high glucose treatment. Compared with normal-glucose treatment, the expression of microRNA-155 markedly increased in HRGECs treated with high-glucose, as well as the mRNA and protein levels of ETS-1, VCAM-1, MCP-1 and cleaved caspase-3. Overexpression of microRNA-155 remarkably downregulated mRNA and protein levels of ETS-1, VCAM-1, MCP-1 and cleaved caspase-3, whereas miRNA-155 knockdown upregulated their levels. In addition, HRGEC cells were transfected with miR-155 mimics and ETS-1 siRNA with high glucose stimulation. The expression of ETS-1 was positively correlated with the expression of downstream factors VCAM-1 and MCP-1. These results suggest that ETS-1 can mediate endothelial cell inflammation by regulating VCAM-1 and MCP-1. Conclusion MiR-155 can negatively regulate the expression of target gene ETS-1 and its downstream factors VCAM-1, MCP-1 and cleaved caspase-3, thus mediating the inflammatory response and apoptosis of HRGEC.

Through multi-order structure function analysis and singularity measurement, the Hurst index and intermittent parameter are obtained to quantitatively describe the characteristics of atmospheric disturbance based on the round-trip intelligent sounding system (RTISS) in the lower-middle stratosphere. According to the third-order structure function, small-scale gravity waves are classified into three states: stable, unstable, and accompanied by turbulence. The evolution of gravity waves is reflected by the variation of the third-order structure function over time, and the generation of turbulence is also observed. The atmospheric disturbance intensity parameter RT is defined in this paper and contains both wave disturbance ( \begin{document}$ {H}_{1} $\end{document} ) and random intermittency ( \begin{document}$ {C}_{1} $\end{document} ). RT is considered to reflect the characteristics of atmospheric disturbance more reasonably than either of the above two alone. In addition, by obtaining the horizontal wavenumber spectrum from the flat-floating stage and the vertical wavenumber spectrum from the ascending and descending stages at the height range of 18–24 km, we found that when the gravity wave activity is significantly enhanced in the horizontal direction, the amplitude of the vertical wavenumber spectrum below is significantly larger, which shows a significant impact of gravity wave activity on the atmospheric environment below.