G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Objective To study the effects of the intelligent hearing-assistive system incorporated in Nuro-tron cochlear implants(CI),including the autonomic acoustic scene recognition(ASR),intelligent strategy config-uration as well as the objective and subjective hearing improvements on recipients.Methods ① To evaluate the per-formance of the ASR matule,in a sound-proof room,the preset five kinds of test audios,including speech,noise,speech in noise,pure music(without human voice)and non-pure Music(with human voice)were played.Each type of scenes included 6 to 9 5 min test files.The prediction accuracy and scene switching times were calculated.② In order to evaluate the noise-reduction performance of the ABeam technology in the speech enhancement module,13 Nurotron? CI recipients were recruited and their speech recognition rate when ABeam was"ON"and"OFF"with noise coming from 90°,180°or 270°were tested,individually.Also,their subjective hearing feedback was evaluated through visual analogue scale(VAS)evaluation.Results The ASR module achieved high prediction performance,with prediction accuracy 99％±4％,96％±9％,94％±12％,94％±15％,92％±13％for speech,noise,noisy speech,pure music and non-pure music,respectively.The scene transation times for each individual scene were 1.1 ±0.3,1.4±0.7,1.3±0.5,1.4±0.8 and 1.3±0.5,indicating that the prediction was also stable.When noise came from the sides and behind of recipients and speech signal from the front,the adaptive dual microphone noise re-duction algorithm ABeam significantly increased the speech recognition score(SRS)in 5 dB signal-to-noise(SNR)environment(P＜0.001),with an average increase of 15.92％.Especially when the noise came from 180 degree backward,the SRS increased 28.68％when ABeam was"0N",which was significantly higher than when ABeam was"OFF"(P＜0.01).Conclusion The intelligent hearing-assistive system can help CI recipients automatically configure appropriate SPSs under different environments,improving the speech intelligibility and hearing comfort.

The protection of open abdomen (OA) wound is a significant subject in the field of trauma surgery. The key technical challenge in the early stage of OA wound management involves promoting granulation tissue filling between intestinal segments, reducing intestinal wall abrasion, and preventing the development of enteroatmospheric fistulas (EAF). Hydrogels, characterized by their high water content and exceptional biocompatibility, serve as extracellular matrix-mimicking materials, and are extensively employed in various medical and healthcare applications. In this review, we discuss the application of hydrogel developed by natural biomaterials in OA wounds protection, taking into consideration the unique pathophysiological characteristics of the OA wounds. This review aims to provide valuable insights for the development of hydrogel materials for early-stage OA wound protection in future research.

The protection of open abdomen (OA) wound is a significant subject in the field of trauma surgery. The key technical challenge in the early stage of OA wound management involves promoting granulation tissue filling between intestinal segments, reducing intestinal wall abrasion, and preventing the development of enteroatmospheric fistulas (EAF). Hydrogels, characterized by their high water content and exceptional biocompatibility, serve as extracellular matrix-mimicking materials, and are extensively employed in various medical and healthcare applications. In this review, we discuss the application of hydrogel developed by natural biomaterials in OA wounds protection, taking into consideration the unique pathophysiological characteristics of the OA wounds. This review aims to provide valuable insights for the development of hydrogel materials for early-stage OA wound protection in future research.

β-glucosidase has important applications in food, pharmaceutics, biomass conversion and other fields, exploring β-glucosidase with strong adaptability and excellent properties thus has received extensive interest. In this study, a novel glucosidase from the GH1 family derived from Cuniculiplasma divulgatum was cloned, expressed, and characterized, aiming to find a better β-glucosidase. The amino acid sequences of GH1 family glucosidase derived from C. divulgatum were obtained from the NCBI database, and a recombinant plasmid pET-30a(+)-CdBglA was constructed. The recombinant protein was induced to express in Escherichia coli BL21(DE3). The enzymatic properties of the purified CdBglA were studied. The molecular weight of the recombinant CdBglA was 56.0 kDa. The optimum pH and temperature were 5.5 and 55 ℃, respectively. The enzyme showed good pH stability, 92.33% of the initial activity could be retained when treated under pH 5.5-11.0 for 1 h. When pNPG was used as a substrate, the kinetic parameters K_m, V_max and K_cat/K_m were 0.81 mmol, 291.99 μmol/(mg·min), and 387.50 s^-1 mmol^-1, respectively. 90.33% of the initial enzyme activity could be retained when CdBglA was placed with various heavy metal ions at a final concentration of 5 mmol/L. The enzyme activity was increased by 28.67% under 15% ethanol solution, remained unchanged under 20% ethanol, and 43.68% of the enzyme activity could still be retained under 30% ethanol. The enzyme has an obvious activation effect at 0-1.5 mol/L NaCl and can tolerate 0.8 mol/L glucose. In conclusion, CdBglA is an acidic and mesophilic enzyme with broad pH stability and strong tolerance to most metal ions, organic solvents, NaCl and glucose. These characteristics may facilitate future theoretical research and industrial production.
beta-Glucosidase ; Sodium Chloride ; Temperature ; Glucose ; Ethanol/chemistry* ; Ions ; Hydrogen-Ion Concentration ; Enzyme Stability ; Substrate Specificity

Objective:To investigate the clinicopathological characteristics, treatment methods and prognosis of renal primary neuroendocrine neoplasms.Methods:The clinical data of 42 patients with renal neuroendocrine neoplasms admitted to the First Affiliated Hospital of Zhengzhou University from October 2011 to June 2021 were retrospectively analyzed.There were 17 males and 25 females. The median age was 60.0 (50.0, 67.0) years old.The CT enhancement scan lesion was slightly intensified with less intensification than normal renal parenchyma.The clinic manifestation included lumbar abdominal pain in 7 cases, hematuria in 3 cases, abdominal distension in 1 cases, and asymptomatic in 8 cases. The average diameter of tumor was 8.0 (4.0, 10.0) cm. The tumor of 13 cases was in the left, and 6 cases was in the right. 6 cases were in T 1 stage, 11 cases were in T 2, 11 cases were in T 3, and 14 cases were in T 4.17 cases had lymph node metastasis, 11 cases had distant metastasis.The surgical method was radical nephrectomy in 27 cases, nephrectomy in 5 cases and interventional embolization in 4 case, and no operation in 6 cases, including 5 with chemotherapy alone and 1 with supportive care.Patients were classified by WHO Classification of renal tumors of the urinary system and the male reproductive organs (2016) into high-differentiated renal neuroendocrine tumors (NET, including carcinoid and atypical carcinoids) and high-grade renal neuroendocrine carcinoma (NEC, including small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma). The clinicopathological characteristics and prognosis of the 2 groups were compared, and the Cox proportional regression risk model was used to analyze the clinical factors affecting the prognosis. Results:In the NET group, 12 cases were carcinoids and 7 cases were atypical carcinoids. In the NEC group, 23 cases were small cell carcinomas.The mean Ki-67 index of 42 cases was 35% (4.5%, 62.5%). The proportion of positive expression of the neuroendocrine markers CD56, chromogranin A (CgA), and synapsin (Syn) were (37/42), (15/42), and (38/42), respectively. A total of 42 patients were followed up, and the median follow-up time was 60 (35, 99) months, and the median survival time was 25 (15, 60) months. The 3-year and 5-year overall survival rates were 40.0% and 21.2%. The 3-year and 5-year overall survival rates in the NET group were 72.6% and 42.3%.The 3-year and 5-year overall survival rates in the NEC groups were 6.3% and 0, respectively. The mean Ki-67 index was 3% (2%, 10%) in the NET group, 2 patients received postoperative chemotherapy and 3 patients had early progression after initial treatment.The mean Ki-67 index in the NEC group was 60% (40%, 80%), 15 patients received postoperative chemotherapy, and 13 patients had early progression of initial treatment.There were statistically differences in treatment method, postoperative chemotherapy, Ki-67 index, and early disease progression (all P <0.05) between the two groups.The results of univariate analysis showed that sex, age, early progression, treatment method, tumor differentiation, and Ki-67 index were all factors influencing patient prognosis (all P <0.05). Cox multivariate analysis showed that poorly differentiated NEC ( HR=13.964, P=0.003) and early progression ( HR=3.626, P=0.018) were independent risk factors for patient survival, and renal radical surgery ( HR=0.197, P=0.033) was independent protective factors for patient survival. Further subgroup analysis showed that the median survival time of the NEC patients with adjuvant chemotherapy after surgery was significantly longer compared with the patients without adjuvant chemotherapy (21 and 9 months, P=0.012). Conclusions:Primary renal neuroendocrine tumors are clinically rare, often manifested as lumbar and abdominal pain, and radical renal surgical treatment is preferred.The NET has a better prognosis and NEC prognosis is extremely poor, but NEC patients can have survival benefit from chemotherapy. NEC and early progression of the disease are independent prognostic risk factors, and radical renal surgical treatment is an independent protective factor for prognosis.

Objective:To explore new methods of treating Graves′ disease (GD) by targeting thyroid stimulating hormone receptor (TSHR) and intercellular adhesion molecule-1 (ICAM-1).Methods:The small interfering RNA (siRNA) targeting TSHR and the ICAM-1 monoclonal antibody (mAb) were designed and synthesized. Thirty GD model mice were randomly divided into siRNA treatment group, ICAM-1 mAb treatment group, and untreated GD group (10 mice in each group), and 10 normal mice were taken as blank control. Serum thyroxine (T 4), thyroid stimulating hormone (TSH), TSH receptor-stimulating antibody (TSAb) and TSH-stimulation blocking antibody (TSBAb) were measured before and after treatment. At the end of the treatment, body mass and heart rate of mice in each group were measured, and thyroid uptake of 99Tc mO 4-, thyroid size and pathological changes were evaluated. Independent-sample t test, paired t test and one-way analysis of variance were used to analyze data. Results:After three treatments, the body mass of mice in siRNA group and ICAM-1 mAb group were significantly lower than that of normal mice ( F=3.50, P=0.025); the heart rates of the mice in two groups were significantly lower than that of untreated GD mice ( F=24.73, P<0.001). Heart rate of mice treated with siRNA decreased significantly, close to that of normal mice. After treatment, the serum T 4((27.58±1.94) vs (65.71±6.89) μg/L, (27.24±3.50) vs (70.84±8.46) μg/L), TSAb ((331.44±43.38) vs (457.33±45.85) mU/L, (275.16±45.80) vs (443.91±42.32) mU/L) and TSBAb ((13.94±1.11) vs (15.83±5.92) mU/L, (14.59±1.02) vs (17.05±6.16) mU/L) levels of mice in both siRNA group and ICAM-1 mAb group significantly decreased ( t values: 4.45-10.87, all P<0.05), while the serum TSH levels of mice in two groups significantly increased ((0.13±0.05) vs (0.04±0.05) mU/L, (1.46±0.34) vs (0.06±0.03) mU/L; t values: -2.22, -5.87, P values: 0.007, <0.001). The elevated TSH level and decreased TSAb level of mice treated with ICAM-1 mAb were significantly different from those treated with siRNA ( t values: 1.03, -1.63, P values: 0.002, 0.031). After treatment, the uptake of 99Tc mO 4- in part of the thyroid lobes of mice was decreased, and the enlargement degree of the corresponding lobes was reduced. The thyroid pathology of mice in the treated groups showed that the absorption vacuoles of thyroid follicles were reduced, and the phenomenon of thinner colloids was improved. No obvious damage was observed in the heart, liver and kidneys of the mice. Conclusions:Both the siRNA targeting TSHR and ICAM-1 mAb have therapeutic effects on GD model mice. The siRNA is better at controlling heart rate, and ICAM-1 mAb is better at increasing TSH and decreasing TSAb. Each of the above treatment methods is safe and effective, which can provide new ideas for GD targeted therapy.

Objective: To explore clustering and risk factors of Staphylococcus aureus (S. aureus) carriage among kindergarten children in Liuzhou. Methods: Two sided nasal swabs were collected from 1 702 children in Liuzhou from April to June 2018. Parents of all the children were investigated by questionnaires. The random effect Logistic regression was used to analyze the clustering and risk factors of S. aureus carriage. Results: The carriage rate of S. aureus among kindergarten children was 16.3%. The randomeffect Logistic regression model indicated that the class-level random effect of S. aureus carriage among children was statistically significant(Z=2.12, P<0.01). Children aged 6 to 7 years (OR=2.18, 95%CI=1.45-3.27) and 5 years (OR=1.65, 95%CI=1.08-2.50) had higher carriage rates of S. aureus than those aged 3-4 years. The history of antibiotic using (OR=1.45, 95%CI=1.05-2.01) and skin and soft tissue infections (OR=1.36, 95%CI=1.04-1.79) in the previous year were risk factors of S. aureus carriage among children. Conclusion The class level clustering of S. aureus carriage is observed in healthy children. Age, history of antibiotic usage and history of skin and soft tissue infections are associated with risk of S. aureus carriage among preschool children.

Objective:To explore the clinical features and prognosis of urachal carcinoma.Methods:The clinical data of 35 patients with urachal carcinoma admitted to the First Affiliated Hospital of Zhengzhou University from August 2011 to November 2019 were analyzed retrospectively. There were 23 males and 12 females, with a male to female ratio of 1.92∶1. The average age was (52.1±13.9) years old, and the median age was 55 years old. There were 8 patients with a history of smoking and 3 patients with a history of drinking. There were 5 cases of hypertension, 5 cases of diabetes, 2 cases of coronary heart disease, and 1 case of cerebral infarction. The first symptoms were hematuria in 25 cases, lower abdominal pain in 4 cases, abdominal mass in 2 cases, umbilical discharge in 1 case, and asymptomatic in 4 cases.Preoperative CT examination showed that the tumor was located on the top wall of the bladder in 24 cases and the front wall of the bladder in 11 cases. There were 25 solid tumors and 10 cystic tumors. The maximum diameter of the tumor was 1.5 to 11.0 cm, and the median maximum diameter of the tumor was 4.0 cm. Preoperative cystoscopy detected masses on the anterior or top wall of the bladder and urachal carcinoma was suspected in 35 cases. All 35 cases underwent enlarged partial cystectomy (conventional resection of the umbilical part), and 3 cases underwent pelvic lymph node dissection at the same time. Among them, 19 cases underwent open surgery, 14 cases underwent laparoscopic surgery, and 2 cases underwent Da Vinci robot assisted laparoscopic surgery.Results:According to Mayo staging, there were 10 cases of stage Ⅰ, 18 cases of stage Ⅱ, 1 case of stage Ⅲ, and 6 cases of stage Ⅳ. The overall follow-up rate was 91.4% (32/35), and the median follow-up time was 41 (3-103) months. The 1-year survival rate was 82.5%, the 3-year survival rate was 59.3%, and the 5-year survival rate was 53.9%. Univariate analysis showed that age ( P=0.033), maximum tumor diameter ( P=0.011), lymph node metastasis ( P=0.002), distant metastasis ( P=0.011), pathological grade ( P=0.001), Mayo staging ( P=0.026) were ralated prognostic factors (all P<0.05). Cox multivariate analysis showed that the pathologically poor differentiation ( HR=1.640, 95% CI 1.112-2.418, P=0.013), and the largest tumor diameter ≥4cm were ( HR=5.000, 95% CI 1.099-22.755, P=0.037). Independent factors affecting patient prognosis. Conclusions:Urachal carcinoma is a malignant bladder tumor with insidient onset. Most of the first diagnosis symptoms are hematuria. When diagnosed, most patients are in the middle and late stages of clinical grading, and the prognosis is poor.Pathological grade and maximum tumor diameter are independent factors that affect the prognosis of patients with urachal carcinoma. The higher was the pathological grade, and the larger was the maximum tumor diameter, the worse was the prognosis.