Single Living Cell "Observation-Analysis" Integrated Platform Decodes Cell Migration Plasticity Orchestrated by Nucleocytoplasmic STAT3.

Cell migration requires the interplay among diverse migration patterns. The molecular basis of distinct migration programs is undoubtedly vital but not fully explored. Meanwhile, the lack of tools for investigating spontaneous migratory plasticity in a single living cell also adds to the hindrance. Here, we developed a micro/nanotechnology-enabled single-cell analytical platform to achieve coherent monitoring of spontaneous migratory pattern and signaling molecules. Via the platform, we unveiled a previously unappreciated STAT3 regionalization on the multifunctional regulations of migration. Specifically, nuclear STAT3 is associated with amoeboid migration, while cytoplasmic STAT3 promotes mesenchymal movement. Opposing effects of JAK2 multisite phosphorylation shape its response to STAT3 distribution in a dynamic and antagonistic manner, eventually triggering a reversible amoeboid-mesenchymal transition. Based on the above results, bioinformatics further revealed a possible downstream regulator of nucleocytoplasmic STAT3. Thus, our platform, as an exciting technological advance in single-cell migration research, can provide in-depth mechanism interpretations of tumor metastasis and progression.

Association between nutritional risk and fatigue in frailty conditions for older adult patients: a multicentre cross-sectional survey study.

BACKGROUND AND AIMS: Frailty is widespread in the elderly, while there is a bi-directional relationship between frailty and malnutrition. The objectives of this study were to investigate the prevalence and correlation of frailty and nutritional risk in older adult patients and to analyse the factors associated with fatigue which is one indicator of frailty. METHODS: This cross-sectional multicentre survey study was conducted in five hospitals in the same city from 01 January 2021 to 01 December 2021. We collected information on gender, age, diseases, medication and dietary status. Frailty status was diagnosed using the FRAIL scale, and Nutritional Risk Screening-2002 was used to screen the nutritional risk. Spearman rank correlation was used to analyse the correlation between frailty and nutritional risk. Univariate and multivariate logistic regression analyses were used to analyse the risk factors related to fatigue in all patients and inpatients. RESULTS: Among 2016 older adult patients, the prevalence of frailty was 15.1% (305/2016), the prevalence of nutritional risk was 16.2% (327/2016) and the overlap prevalence of frailty and nutritional risk was 7.3% (147/2016). Multivariate analysis showed that nutritional risk (OR 3.109, 95% CI 2.384 to 4.056, p<0.001) was an independent risk factor for fatigue in all patients; similar results were found for nutritional risk (OR 2.717, 95% CI 2.068 to 3.571, p<0.001) in hospitalised patients. CONCLUSIONS: Frailty and nutritional risk are prevalent among older adult patients, and nutritional risk is associated with the occurrence of fatigue in older adult patients and older adult inpatients. TRIAL REGISTRATION NUMBER: China Clinical Trial Registry (Registered No. ChiCTR-EPC-14005253).

Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression.

BACKGROUND: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. METHODS: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. RESULTS: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. CONCLUSIONS: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.

Flexible Strain Sensor Based on Nickel Microparticles/Carbon Black Microspheres/Polydimethylsiloxane Conductive Composites for Human Motion Detection.

Herein, we report a dual-functional flexible sensor (DFFS) using a magnetic conductive polymer composed of nickel (Ni), carbon black (CB), and polydimethylsiloxane (PDMS). The material selection for the DFFS utilizes the excellent elasticity of the PDMS matrix and the synergistic interaction between Ni and CB. The DFFS has a wide strain range of 0-170%, a high sensitivity of 74.13 (140-170%), and a low detection limit of 0.3% strain. The DFFS based on superior performance can accurately detect microstrain/microvibration, oncoming/contacting objects, and bicycle riding speed. Additionally, the DFFS can be used for comprehensive monitoring of human movements. Therefore, the DFFS of this work shows significant value for implementation in intelligent wearable devices and noncontact intelligent control.

An Interference Mitigation Method for FMCW Radar Based on Time-Frequency Distribution and Dual-Domain Fusion Filtering.

Radio frequency interference (RFI) significantly hampers the target detection performance of frequency-modulated continuous-wave radar. To address the problem and maintain the target echo signal, this paper proposes a priori assumption on the interference component nature in the radar received signal, as well as a method for interference estimation and mitigation via time-frequency analysis. The solution employs Fourier synchrosqueezed transform to implement the radar's beat signal transformation from time domain to time-frequency domain, thus converting the interference mitigation to the task of time-frequency distribution image restoration. The solution proposes the use of image processing based on the dual-tree complex wavelet transform and combines it with the spatial domain-based approach, thereby establishing a dual-domain fusion interference filter for time-frequency distribution images. This paper also presents a convolutional neural network model of structurally improved UNet++, which serves as the interference estimator. The proposed solution demonstrated its capability against various forms of RFI through the simulation experiment and showed a superior interference mitigation performance over other CNN model-based approaches.

Old woman with Sheehan's syndrome suffered severe hyponatremia following percutaneous coronary intervention: a case report and review of literature.

Glucocorticoid deficiency can lead to hypoglycemia, hypotension, and electrolyte disorders. Acute glucocorticoid deficiency under stress is very dangerous. Here, we present a case study of an elderly patient diagnosed with Sheehan's syndrome, manifesting secondary adrenal insufficiency and secondary hypothyroidism, managed with daily prednisone and levothyroxine therapy. She was admitted to our hospital due to acute non-ST segment elevation myocardial infarction. The patient developed nausea and limb twitching post-percutaneous coronary intervention, with subsequent diagnosis of hyponatremia. Despite initial intravenous sodium supplementation failed to rectify the condition, and consciousness disturbances ensued. However, administration of 50 mg hydrocortisone alongside 6.25 mg sodium chloride rapidly ameliorated symptoms and elevated blood sodium levels. Glucocorticoid deficiency emerged as the primary etiology of hyponatremia in this context, exacerbated by procedural stress during percutaneous coronary intervention. Contrast agent contributed to blood sodium dilution. Consequently, glucocorticoid supplementation emerges as imperative, emphasizing the necessity of stress-dose administration of glucocorticoid before the procedure. Consideration of shorter intervention durations and reduced contrast agent dosages may mitigate severe hyponatremia risks. Moreover, it is crucial for this patient to receive interdisciplinary endocrinologist management. In addition, Sheehan's syndrome may pose a risk for coronary atherosclerotic disease.

Survival Predictive Nomograms for Non-Surgical Brain Metastases Patients From Non-Small Cell Lung Cancer Receiving Radiotherapy: A Population-Based Study.

OBJECTIVE: A high number of Non-Small Cell Lung Cancer (NSCLC) patients with brain metastasis who have not had surgery often have a negative outlook. Radiotherapy remains a most common and effective method. Nomograms were developed to forecast the cancer-specific survival (CSS) and overall survival (OS) in NSCLC individuals with nonoperative brain metastases who underwent radiotherapy. METHODS: Information was gathered from the Surveillance, Epidemiology, and End Results (SEER) database about patients diagnosed with NSCLC who had brain metastases not suitable for surgery. Nomograms were created and tested using multivariate Cox regression models to forecast CSS and OS at intervals of 1, 2, and 3 years. RESULTS: The research involved 3413 individuals diagnosed with NSCLC brain metastases who had undergone radiotherapy but had not experienced surgery. These participants were randomly divided into two categories. The analysis revealed that gender, age, ethnicity, marital status, tumor location, tumor laterality, tumor grade, histology, T stage, N stage, chemotherapy, tumor size, lung metastasis, bone metastasis, and liver metastasis were significant independent predictors for OS and CSS. The C-index for the training set for predicting OS was .709 (95% CI, .697-.721), and for the validation set, it was .705 (95% CI, .686-.723), respectively. The C-index for predicting CSS was .710 (95% CI, .697-.722) in the training set and .703 (95% CI, .684-.722) in the validation set, respectively. The nomograms model, as suggested by the impressive C-index, exhibits outstanding differentiation ability. Moreover, the ROC and calibration curves reveal its commendable precision and distinguishing potential. CONCLUSIONS: For the first time, highly accurate and reliable nomograms were developed to predict OS and CSS in NSCLC patients with non-surgical brain metastases, who have undergone radiotherapy treatment. The nomograms may assist in tailoring counseling strategies and choosing the most effective treatment method.

Post-failure analysis of model resin-composite restorations subjected to different chemomechanical challenges.

OBJECTIVE: The current study aimed to evaluate the effects of different combinations of chemical and mechanical challenges on the failure load, failure mode and composition of the resulting fracture surfaces of resin-composite restorations. METHODS: Three resin composites were used to fill dentin disks (2 mm inner diameter, 5 mm outer diameter, and 2 mm thick) made from bovine incisor roots. The model restorations, half of which were preconditioned with a low-pH buffer (48 h under pH 4.5), were subjected to diametral compression with either a monotonically increasing load (fast fracture) or a cyclic load with a continuously increasing amplitude (accelerated fatigue). The load or number of cycles to failure was noted. SEM was performed on the fracture surfaces to determine the proportions of dentin, adhesive, and resin composite. RESULTS: Both cyclic fatigue and acid preconditioning significantly reduced the failure load and increased the proportion of interfacial failure in almost all the cases, with cyclic fatigue having a more pronounced effect. Cyclic fatigue also increased the amount of adhesive/hybrid layer present on the fracture surfaces, but the effect of acid preconditioning on the composition of the fracture surfaces varied among the resin composites. SIGNIFICANCE: The adhesive or hybrid layer was found to be the least resistant against the chemomechanical challenges among the components forming the model restoration. Increasing such resistance of the tooth-restoration interface, or its ability to combat the bacterial actions that lead to secondary caries following interfacial debonding, can enhance the longevity of resin-composite restorations.

Tunneling Proton Grotthuss Transfer Channels by Hydrophilic-Zincophobic Heterointerface Shielding for High-Performance Zn-MnO2 Batteries.

Hollandite-type manganese dioxide (α-MnO2) is recognized as a promising cathode material upon high-performance aqueous zinc-ion batteries (ZIBs) owing to the high theoretical capacities, high working potentials, unique Zn2+/H+ co-insertion chemistry, and environmental friendliness. However, its practical applications limited by Zn2+ accommodation, where the strong coulombic interaction and sluggish kinetics cause significant lattice deformation, fast capacity degradation, insufficient rate capability, and undesired interface degradation. It remains challenging to accurately modulate H+ intercalation while suppressing Zn2+ insertion for better lattice stability and electrochemical kinetics. Herein, proton Grotthuss transfer channels are first tunneled by shielding MnO2 with hydrophilic-zincophobic heterointerface, fulfilling the H+-dominating diffusion with the state-of-the-art ZIBs performance. Local atomic structure and theoretical simulation confirm that surface-engineered α-MnO2 affords to the synergy of Mn electron t2g-eg activation, oxygen vacancy enrichment, selective H+ Grotthuss transfer, and accelerated desolvation kinetics. Consequently, fortified α-MnO2 achieves prominent low current density cycle stability (≈100% capacity retention at 1 C after 400 cycles), remarkable long-lifespan cycling performance (98% capacity retention at 20 C after 12 000 cycles), and ultrafast rate performance (up to 30 C). The study exemplifies a new approach of heterointerface engineering for regulation of H+-dominating Grotthuss transfer and lattice stabilization in α-MnO2 toward reliable ZIBs.

Discovery and structural mechanism of DNA endonucleases guided by RAGATH-18-derived RNAs.

CRISPR-Cas systems and IS200/IS605 transposon-associated TnpBs have been utilized for the development of genome editing technologies. Using bioinformatics analysis and biochemical experiments, here we present a new family of RNA-guided DNA endonucleases. Our bioinformatics analysis initially identifies the stable co-occurrence of conserved RAGATH-18-derived RNAs (reRNAs) and their upstream IS607 TnpBs with an average length of 390 amino acids. IS607 TnpBs form programmable DNases through interaction with reRNAs. We discover the robust dsDNA interference activity of IS607 TnpB systems in bacteria and human cells. Further characterization of the Firmicutes bacteria IS607 TnpB system (ISFba1 TnpB) reveals that its dsDNA cleavage activity is remarkably sensitive to single mismatches between the guide and target sequences in human cells. Our findings demonstrate that a length of 20 nt in the guide sequence of reRNA achieves the highest DNA cleavage activity for ISFba1 TnpB. A cryo-EM structure of the ISFba1 TnpB effector protein bound by its cognate RAGATH-18 motif-containing reRNA and a dsDNA target reveals the mechanisms underlying reRNA recognition by ISFba1 TnpB, reRNA-guided dsDNA targeting, and the sensitivity of the ISFba1 TnpB system to base mismatches between the guide and target DNA. Collectively, this study identifies the IS607 TnpB family of compact and specific RNA-guided DNases with great potential for application in gene editing.

The significant contribution of comammox bacteria to nitrification in a constructed wetland revealed by DNA-based stable isotope probing.

The discovery of Comammox bacteria (CMX) has changed our traditional concept towards nitrification, yet its role in constructed wetlands (CWs) remains unclear. This study investigated the contributions of CMX and two canonical ammonia-oxidizing microorganisms, ammonia-oxidizing bacteria (AOB) and archaea to nitrification in four regions (sediment, shoreside, adjacent soil, and water) of a typical CW using DNA-based stable isotope probing. The results revealed that CMX not only widely occurred in sediment and shoreside zones with high abundance (5.08 × 104 and 6.57 × 104 copies g-1 soil, respectively), but also actively participated in ammonia oxidation, achieving ammonia oxidation rates of 1.43 and 2.00 times that of AOB in sediment and shoreside, respectively. Phylogenetic analysis indicated that N. nitrosa was the dominant and active CMX species. These findings uncovered the crucial role of CMX in nitrification of sediment and shoreside, providing a new insight into nitrogen cycle of constructed wetlands.

Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor.

The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

Predictors and influence of postoperative moderate-to-severe pain of PACU in the patients with malignancy.

BACKGROUND: This study was identified the risk factors for and designed to investigate influence of postoperative moderate-to-severe pain of post anaesthesia care unit (PACU) in patients with malignancy. METHODS: A retrospective study was performed on 22,600 cancer patients with malignancy who underwent elective radical surgery in the new hospital of First Affiliated Hospital of Wenzhou Medical University, between January 2016 and June 2021. All patients were transferred to the PACU after tracheal extubation. Patients were divided into two groups according to a visual analogue scale (VAS) score of > 3: the no-moderate-severe-pain group and moderate-to-severe-pain group. Data pertaining to demographic, surgical, anaesthetic, and other factors were recorded. Lasso and logistic regression analysis was performed to explore the risk factors, then a nomogram was constructed to predict the moderate-severe-pain in the PACU. Validation was performed by using another 662 cancer patients in old hospital. The ROC curves and calibration curve were used to evaluate the accuracy and predictive ability of the nomogram. RESULTS: The incidence of postoperative moderate-to-severe pain of PACU in patients with malignancy was 1.42%. Gender, type of surgery, postoperative use of PCA, intraoperative adjuvant opioid agonists, NSAIDS, epidural analgesia, duration of anaesthesia, intraoperative massive haemorrhage, PACU vomiting were independent predictors for postoperative moderate-to-severe pain of PACU in the patients with malignancy. The area under the ROC curve of the predictive models in the primary and validation groups were 0.817 and 0.786, respectively. Moderate-to-severe pain in the PACU correlated with hypertension, hyperglycaemia, agitation, and hypoxemia (P < 0.05). CONCLUSIONS: The prediction model for postoperative moderate-to-severe pain of PACU in patients with malignancy has good predictive ability and high accuracy, which is helpful for PACU medical staff to identify and prevent postoperative moderate-to-severe pain in advance. TRIAL REGISTRATION: The study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (No.KY2021-097) and registered in the Chictr.org.cn registration system on 06/12/2021 (ChiCTR2100054013).

Analysis of depression incidence and influence factors among middle-aged and elderly diabetic patients in China: based on CHARLS data.

BACKGROUND: To investigate the incidence of depression in middle-aged and elderly patients with diabetes in China and the influencing factors to provide a theoretical basis to improve the mental health of middle-aged and elderly patients with diabetes and formulate prevention, control, and intervention strategies. METHODS: The sample of this study was obtained from the China Health and Aging Tracking Survey (CHARLS) 2018 survey data, and middle-aged and older patients with diabetes(responding "Yes" to the questionnaire: "Have you ever been told by a doctor that you have diabetes or elevated blood glucose [including abnormal glucose tolerance and elevated fasting glucose]?") aged ≥ 45 years were selected as study subjects (n = 2,613 ). Depressive symptoms of the study subjects were determined using the simplified version of the Depression Scale for Epidemiological Surveys scores(a score ≥ 10 was defined as depression), influence factors were analyzed using binary logistic regression, and proportion of depressive symptoms was standardized using the sex ratio of the seventh census. RESULTS: Among the 2,613 middle-aged and elderly patients with diabetes, 1782 (68.2%) had depressive symptoms and 831 (31.8%) had no depressive symptoms. There were 481 (27.0%) patients aged 45-59 years, 978 (54.9%) aged 60-74 years, and 323 (18.1%) aged ≥ 75 years. The depression rate among middle-aged and elderly Chinese patients with diabetes after standardization correction was 67.5%. Binary logistic regression results showed that age, education level, life satisfaction, marital satisfaction, self-rated health grade, somatic pain, visual impairment, physical disability, and the presence of comorbid chronic diseases were factors that influenced the onset of depression in middle-aged and elderly Chinese patients with diabetes (P < 0.05). CONCLUSION: According to a survey analysis of the CHARLS 2018 data, depression is influenced by a combination of factors among middle-aged and elderly patients with diabetes in China. Therefore, for this population, targeted prevention and control should be carried out for key populations, such as middle-aged and elderly people, poor physical health, and low life satisfaction and marital satisfaction, from various dimensions (e.g., demographic and sociological factors, physical health status, and life satisfaction and marital satisfaction).

G-CSF improving combined whole brain radiotherapy and immunotherapy prognosis of non-small cell lung cancer brain metastases.

OBJECTIVE: To evaluate the therapeutic advantage of G-CSF to whole brain radiotherapy (WBRT) in combination with immunotherapy as a first-line treatment for non-small cell lung cancer (NSCLC) brain metastases (BMs). METHODS: In this retrospective study, 117 patients (37 in G-CSF group and 80 in no G-CSF group) who underwent first-line WBRT combined with immunotherapy were enrolled. Their survival, intracranial response, BM-related symptoms and toxicity were evaluated. RESULTS: The overall survival (OS) of patients in G-CSF group was significantly improved compared to patients no G-CSF group (median time: 14.8 vs 10.2 months; HR: 0.61, 95 % CI: 0.38-0.97, p = 0.035). However, there were no significant differences in intracranial responses between the two groups (p > 0.05). The G-CSF group exhibited a significantly higher rate of relief from BM-related symptoms compared to the no G-CSF group (91.7 % vs 59.5 %, p = 0.037). Cox proportional hazards regression analyses indicated that after-treatment ALC > 0.9 × 10^9/L (HR 0.57, 95 % CI 0.32-0.99, p = 0.046) and Hb > 110 g/dL (HR 0.41, 95 % CI 0.24-0.71, p = 0.001) were significant potential factors associated with extended OS. The addition of G-CSF was well tolerated and effectively reduced the incidence of neutropenia (0 % vs 5.0 %, p = 0.17). CONCLUSION: Integrating G-CSF with WBRT and immunotherapy as a first-line treatment for NSCLC-BMs has exhibited significant efficacy and favorable tolerability.

Tactile corpuscle-inspired piezoresistive sensors based on (3-aminopropyl) triethoxysilane-enhanced CNPs/carboxylated MWCNTs/cellulosic fiber composites for textile electronics.

Recently, wearable electronic products and gadgets have developed quickly with the aim of catching up to or perhaps surpassing the ability of human skin to perceive information from the external world, such as pressure and strain. In this study, by first treating the cellulosic fiber (modal textile) substrate with (3-aminopropyl) triethoxysilane (APTES) and then covering it with conductive nanocomposites, a bionic corpuscle layer is produced. The sandwich structure of tactile corpuscle-inspired bionic (TCB) piezoresistive sensors created with the layer-by-layer (LBL) technology consists of a pressure-sensitive module (a bionic corpuscle), interdigital electrodes (a bionic sensory nerve), and a PU membrane (a bionic epidermis). The synergistic mechanism of hydrogen bond and coupling agent helps to improve the adhesive properties of conductive materials, and thus improve the pressure sensitive properties. The TCB sensor possesses favorable sensitivity (1.0005 kPa-1), a wide linear sensing range (1700 kPa), and a rapid response time (40 ms). The sensor is expected to be applied in a wide range of possible applications including human movement tracking, wearable detection system, and textile electronics.

Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.

Extraction and characterization of polysaccharides from Schisandra sphenanthera fruit by Lactobacillus plantarum CICC 23121-assisted fermentation.

Improving the yield of polysaccharides extracted from Schisandra sphenanthera is a major challenge in traditional Chinese medicinal plants. In this study, we investigated the potential of Lactobacillus plantarum CICC 23121-assisted fermentation as an extraction tool for S. sphenanthera polysaccharides (SSP). We observed that 11.12 ± 0.28 % of polysaccharides were extracted from S. sphenanthera using strain CICC 23121 -assisted fermentation (F-SSP), which was 53.38 % higher than that using hot water extraction (NF-SSP). The optimized parameters were a fermentation time of 15.5 h, substrate concentration of 4 %, and inoculum size of 3 %. Lactic acid produced by strain CICC 23121 increased the release of intracellular polysaccharides by breaking down cell walls. Compared to NF-SSP, F-SSP contained higher and lower total carbohydrate and protein contents, respectively, and its monosaccharide composition was the same as that of NF-SSP; however, their distributions were different. F-SSP had a higher molecular weight, better aqueous stability, and looser surface morphology, and strain CICC 23121-assisted fermentation did not change the molecular structure of SSP. Both NF-SSP and F-SSP showed the potential to regulate human intestinal microflora. Our findings revealed that strain CICC 23121-assisted fermentation is an efficient method for extracting S. sphenanthera polysaccharides without affecting their physicochemical and bioactive properties.

Identification of oleic acid as an endogenous ligand of GPR3.

Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream Gs signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating Gs/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a "born to be activated and cold to enhance" model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.