Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Rheumatoid arthritis (RA) represents a persistent autoimmune condition distinguished by a multifaceted etiology that encompasses both genetic and environmental factors. Recent progress in understanding the mechanisms behind RA pathogenesis has delved into the critical role of epigenetic regulatory processes, including DNA methylation, histone modifications, and the regulation by microRNAs (miRNAs). These findings provide new insights into the intricate nature of RA and pave the way for innovative therapeutic strategies. This review consolidates the latest developments in the epigenetic regulation of RA, concentrating on how these mechanisms affect the dysregulated signaling pathways associated with the disease. We analyze the roles of specific proteins that function as 'writers', 'erasers', and 'readers' in epigenetic modifications, highlighting their potential as targets for therapeutic intervention. Additionally, in view of the significance of miRNAs in the pathogenesis of RA, we deliberate on their involvement in disease progression and explore miRNA-based treatment strategies. By integrating these diverse epigenetic dimensions, this review offers a comprehensive epigenetic perspective on RA pathogenesis and identifies promising avenues for future research and therapeutic interventions.

OBJECTIVES: To investigate the protective effects of dexmedetomidine (DEX) against heat stress (HS)-induced oncosis in human skeletal muscle cells (HSKMCs) and its underlying mechanisms. METHODS: A HSKMC model of HS-induced oncosis were established by 43 ℃ water bath for 4 h, and the effects of treatments with 30 μmol/L DEX, ML385 (a Nrf2 inhibitor) +DEX, si-Nrf2+HS, and si-Nrf2+DEX prior to modeling on cell viability was assessed using CCK-8 assay. Oncosis characteristics were evaluated using transmission electron microscopy and Annexin V-FITC/PI flow cytometry. The oxidative stress markers (GSH, GSH-Px, MDA, SOD and ROS), mitochondrial membrane potential, energy metabolism, and inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the cells were quantified using standard kits, and the expressions of porimin, caspase-3 and Nrf2 pathway proteins were analyzed using Western blotting and qRT-PCR. RESULTS: HS induced typical oncotic features in HSKMCs including organelle swelling and cytoplasmic vacuolization. DEX pretreatment significantly attenuated these changes, reduced Annexin V⁺/PI⁺ cell ratio and cellular porimin expression, and lowered the levels of ROS and MDA while restoring GSH and SOD levels. DEX pretreatment also significantly increased the mitochondrial membrane potential and ATP level, upregulated the expressions of Nrf2, p-Nrf2, HO-1 and NQO1, and suppressed the expressions of TNF-α, IL-6 and IL-1β. The protective effects of DEX were obviously attenuated by interventions with ML385 or si-Nrf2. CONCLUSIONS DEX mitigates HS-induced HSKMC oncosis by activating the Nrf2/HO-1 pathway to relieve oxidative stress, mitochondrial dysfunction, and inflammatory responses.
Humans ; Dexmedetomidine/pharmacology* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects* ; Heat-Shock Response/drug effects* ; Signal Transduction/drug effects* ; Membrane Potential, Mitochondrial ; Muscle, Skeletal/cytology* ; Heme Oxygenase-1/metabolism* ; Apoptosis/drug effects*

Objective:To investigate the application of time series models in forecasting pre-hospital emergency ambulance trips in Handan City and develop the LPro ensemble model for improved prediction accuracy to support emergency resource allocation.Methods:Pre-hospital emergency data from Handan Emergency Medical Command Center (2019-2023) were retrospectively analyzed. From 324 799 original records, 289 949 valid records were included after cleaning. The training set (2019-2022: 215 918 records) included 35 527 records in 2019, 52 015 in 2020, 61 836 in 2021, and 66 540 in 2022. The validation set (2023) contained 74 031 records. ARIMA, linear trend seasonal, exponential smoothing, and Prophet models were fitted to the training set. The LPro ensemble model was constructed using MAPE-based weighting (linear trend seasonal model: 0.38, Prophet: 0.62). Performance metrics included MAPE, RMSE, MAE, and R 2. Results:Data showed annual growth (compound annual growth rate 23.27%) and seasonal patterns (October peaks, February troughs). Ambulance dispatches increased annually with monthly cyclical patterns. For 2023 validation predictions: ARIMA (MAPE 8.76%, RMSE 619, MAE 491, R 2 0.4563), linear trend seasonal (MAPE 9.83%, RMSE 671, MAE 545, R 2 0.3608), Prophet (MAPE 8.43%, RMSE 562, MAE 503, R 2 0.5513), exponential smoothing (MAPE 8.08%, RMSE 643, MAE 410, R 2 0.4124). LPro model showed superior performance (MAPE 7.05%, RMSE 491, MAE 393, R 2 0.6570), with 16.37% lower MAPE, 12.63% lower RMSE, 21.87% lower MAE, and 19.17% higher R 2 versus Prophet. Conclusion:The LPro ensemble model substantially enhances prediction accuracy and reliability, offering scientific support for emergency resource optimization and dispatch scheduling in Handan City.

Resectable non-small cell lung cancer (NSCLC) is prone to recurrence and metastasis after simple surgery. Although patients can benefit from preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy, the 5-year survival rate is not significantly improved. In recent years, with the rise of immunotherapy, NSCLC immunotherapy has gradually received attention. Many explorations have been made on resectable NSCLC immunotherapy, and satisfactory results have been obtained. With the release of multiple phase 3 research results, a new chapter in resectable NSCLC immunotherapy has officially opened. However, there are still many problems in the immunotherapy of resectable NSCLC. This article reviews the current relevant research and provides reference for clinical application.

Microglia, originating from primitive macrophages in the yolk sac, serves as both immune system defenders and regulators of homeostasis. These cells exhibit two primary polarization states: conventionally activated(M1)and alternatively activated(M2). The polarization of microglia plays a crucial role in influencing inflammatory disorders, metabolic imbalances, and neural degeneration. This process is implicated in various aspects of ocular diseases, especially age-related macular degeneration(AMD), including inflammation, oxidative stress and pathological angiogenesis. The distinct functional phenotypes of microglia impact disease progression and prognosis. Thus, regulating the polarization or functional phenotype of microglia at different stages of AMD holds promise for personalized therapeutic approaches. This comprehensive review outlines the involvement of microglia polarization in both physiological and pathological conditions, emphasizing its relevance in AMD. The discussion underscores the potential of polarization as a foundation for personalized treatment strategies for AMD.

Objective To investigate the correlation between MEX3A and differentiation characteristics of gastric cancer and intestinal metaplasia,and its combination with caudal-related homeobox transcription factor 2(CDX2)and mucin 2(MUC2)and mucin 5AC(MUC5AC)to determine the role of carcinogenic intestinal metaplasia.Methods From January 2010 to December 2014,a total of 410 cases of gastric cancer and paracarcinoma paraffin-embedded tissue samples were selected from the Central Hospital Affiliated to Shenyang Medical College and the Second Hospital Affiliated to Shenyang Medical College.According to pathological diagnosis,they were divided into control group(mild superficial gastritis,79 cases),intestinal metaplasia group(149 cases)and gastric cancer group(182 cases).The expressions of MEX3A,CDX2,MUC2 and MUC5AC were detected by immunohistochemistry.Results MEX3A was highly expressed in gastric cancer group and intestinal metaplasia group,especially diffuse gastric cancer,poorly differentiated gastric cancer and type Ⅲ intestinal metaplasia(P<0.05).CDX2 and MUC2 were highly expressed in gastric cancer group and intestinal metaplasia group,especially intestinal type gastric cancer,highly and moderately differentiated gastric cancer,type Ⅰ and type Ⅱ intestinal metaplasia(P<0.05).The expression of MUC5AC was high in control group and low in gastric cancer group and intestinal metaplasia group,especially in intestinal type gastric cancer,type Ⅰ and type Ⅲ intestinal metaplasia(P<0.05).Gastric cancer and intestinal metaplasia differentiation were negatively correlated with MEX3A and MUC5AC expression,but positively correlated with CDX2 and MUC2 expression(P<0.05).MEX3A was negatively correlated with the expression of CDX2 and MUC2,and positively correlated with the expression of MUC5AC in gastric cancer(P<0.05).MEX3A was negatively correlated with the expression of CDX2 and MUC2 in intestinal metaplasia(P<0.05),while CDX2 was positively correlated with the expression of MUC2(P<0.05).Conclusion MEX3A is negatively correlated with gastric cancer and intestinal metaplasia differentiation.Gastric cancer is characterized by high MEX3A expression and low CDX2 and MUC2 expression.

Purpose To establish and evaluate a high-speed fragment-induced penetrating liver injury model in pigs assisted by portable ultrasound.Materials and Methods With the aid of portable ultrasound,the lower edge of the liver at the end of expiration and the lower edge of the right chest at the end of inspiration of 10 Landrace pigs were positioned on the body surface.Then the sighting line was traced to determine the direction of projection and the sighting point.High-speed(about 627 m/s)fragments were projected through an experimental ballistic gun to induce penetrating liver injury.Blood pressure,heart rate,respiratory rate,pulse oxygen saturation and other physiological indexes were measured 15 minutes before shooting and 20 minutes after shooting.20 minutes after injury,the liver injury and the degree of injury were examined by ultrasound.After injury,the liver injury and abdominal fluid accumulation were observed by on-site portable ultrasound,and the size of liver trauma,liver injury grade,abdominal fluid accumulation location and maximum depth were recorded.The degree of liver injury was evaluated by comparison with the gross pathological results.Results Nine out of ten pigs were successfully modeled.The success rate of penetrating liver injury induced by fragments was 90%(9/10),other organ injury in abdominal cavity was 22.22%(2/9),and diaphragm penetrating injury was 22.22%(2/9),which did not occur obvious hemopneumothorax.After injury,the systolic blood pressure,diastolic blood pressure,and pulse oxygen saturation of the pigs decreased[(132.44±12.65)mmHg vs.(103.33±33.43)mmHg,(96.44±12.27)mmHg vs.(70.89±24.21)mmHg,(89.44±8.49)%vs.(76.00±13.41)%;t=2.440,2.651,4.084,all P<0.05],and the heart rate increased[(94.00±17.39)times/min vs.(139.89±37.21)times/min;t=3.534,P<0.05].Within 20 minutes after modeling,portable ultrasound images showed that the liver injury was a patchy,heterogeneous,slightly strong echo area with clear and irregular boundary,and the continuity of the local liver capsule was interrupted.The ascites appeared in the abdominal cavity with the maximum depth of(4.16±1.35)cm.The American association for the surgery of trauma(AAST)liver injury grading of gross pathology after the animals were killed showed that there were 6 cases of grade Ⅱ and 3 cases of grade Ⅲ.Along the fragment projection direction,the short diameter measured by ultrasound was positively correlated with the depth of gross pathological laceration(r=0.945,P<0.001).Compared with the gross specimen,the accuracy rate of ultrasonic AAST grading of liver injury was 88.89%(8/9).Conclusion The model of high-speed fragment-induced liver injury in pigs assisted by portable ultrasound is accurate and stable,and portable ultrasound can effectively evaluate the penetrating liver injury,which provides a basis for the treatment of liver firearm injury.

Objective To investigate the dietary patterns of rural residents in the high-incidence areas of esophageal cancer (EC), and to explore the clustering and influencing factors of risk factors associated with high-incidence characteristics. Methods A special structured questionnaire was applied to conduct a face-to-face survey on the dietary patterns of rural residents in Yanting county of Sichuan Province from July to August 2021. Univariate and multivariate logistic regression models were used to analyze the influencing factors of risk factor clustering for EC. Results There were 838 valid questionnaires in this study. A total of 90.8% of rural residents used clean water such as tap water. In the past one year, the people who ate fruits and vegetables, soybean products, onions and garlic in high frequency accounted for 69.5%, 32.8% and 74.5%, respectively; the people who ate kimchi, pickled vegetables, sauerkraut, barbecue, hot food and mildew food in low frequency accounted for 59.2%, 79.6%, 68.2%, 90.3%, 80.9% and 90.3%, respectively. The clustering of risk factors for EC was found in 73.3% of residents, and the aggregation of two risk factors was the most common mode (28.2%), among which tumor history and preserved food was the main clustering pattern (4.6%). The logistic regression model revealed that the gender, age, marital status and occupation were independent influencing factors for the risk factors clustering of EC (P<0.05). Conclusion A majority of rural residents in high-incidence areas of EC in Yanting county have good eating habits, but the clustering of some risk factors is still at a high level. Gender, age, marital status, and occupation are influencing factors of the risk factors clustering of EC.

ObjectiveTo investigate the clinical efficacy of Huangqi injection combined with Buzhong Yiqi acupuncture in the treatment of chronic fatigue syndrome （CFS） with Qi deficiency and its effects on TCM syndromes， fatigue symptoms， serum superoxide dismutase （SOD）， malondialdehyde （MDA）， and oxidized low-density lipoprotein （ox-LDL） levels. MethodA total of 200 patients with CFS of Qi deficiency were randomly divided into a control group （100 cases） and an observation group （100 cases）. The control group was treated with vitamin B compounds， and the observation group was treated with Huangqi injection combined with Buzhong Yiqi acupuncture for two weeks. The scores of TCM syndromes， fatigue symptoms， levels of serum SOD， MDA， and ox-LDL and the incidence of adverse reactions were observed and compared before and after treatment in two groups. ResultAfter treatment， the total effective rate of the control group was 54.34% （50/92）， while that of the observation group was 88.54% （85/96）. The total effective rate of the observation group was higher than that of the control group （χ²=27.13，P<0.05）. Compared with those in the two groups before treatment， scores of fatigue self-assessment scale （FSAS）， physical fatigue and mental fatigue， and sleep/rest response scores of fatigue in the two groups after treatment were significantly decreased （P<0.05）. After treatment， scores of FSAS， physical fatigue and mental fatigue， and sleep/rest response scores of fatigue in the observation group were significantly decreased compared with those in the control group （P<0.05）. Compared with those in the two groups before treatment， TCM syndrome scores in the two groups after treatment were significantly decreased （P<0.05）. After treatment， TCM syndrome scores in the observation group were significantly decreased compared with those in the control group （P<0.05）. Compared with those in the two groups before treatment， MDA levels in the two groups were significantly decreased （P<0.05）， ox-LDL levels in the observation group were significantly decreased （P<0.05）， and SOD levels were significantly increased （P<0.05）. After treatment， compared with those in the control group， the serum MDA and ox-LDL levels in the observation group were significantly decreased （P<0.05）， and the serum SOD was significantly increased （P<0.05）. No serious adverse events or adverse reactions occurred during this clinical trial. ConclusionHuangqi injection combined with Buzhong Yiqi acupuncture has a good clinical curative effect in the treatment of CFS with Qi deficiency， which can effectively improve the fatigue symptoms of patients， increase the level of SOD， and reduce the level of serum MDA and ox-LDL. It is related to the production of antioxidants， inhibiting the production of lipid peroxides， and improving the body's ability to resist oxidative stress.