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.

Objective : To explore the effect of esketamine on anxiety-depressive-like behavior in mice and its rela- tionship with inflammation． Methods : SPF grade healthy adult male C57BL/6J mice，weighing 20 －24 g，were used in the exprement．The random number table method was used to divide into 5 groups (n = 8) : control group ( Con group) ，esketamine group (ESK group) ，model group ( LPS group) ，model + esketamine prevention group (LPS + ESK1 group) and model + esketamine treatment group ( LPS + ESK2 group) ．An inflammation-induced anxiety-depression model was prepared by intraperitoneal injection of LPS 0. 83 mg / kg．The ESK group was injec- ted with esketamine 10 mg / kg ; LPS group was injected with LPS 0. 83 mg / kg ; LPS + ESK1 group was injected with LPS 0. 83 mg / kg before 24 hours intraperitoneal injection of esketamine 10 mg / kg ; and the LPS + ESK2 group was injected with LPS 0. 83 mg / kg and 30 minutes later with esketamine 10 mg / kg．24 h after intraperitoneal injec- tion of LPS，the anxiety-depression-like behaviors of mice were measured using behavioral experiments．At the end of behavioral experiments，the spleen was taken immediately ; hippocampal tissues were taken and enzyme-linked immunosorbent assay (ELISA) was used to detect the contents of interleukin-1 β (IL-1 β) ，tumor necrosis factor al- pha (TNF-α) and interleukin 6 (IL-6) and neuronal pathological changes in hippocampal tissues were observed by HE staining. Results : Compared with the Con group，mice in the LPS group showed increased anxiety and depres- sion-like behavior (P＜0. 05) ，increased spleen weight / body weight (P ＜0. 05 ) ，increased hippocampal tissue concentrations of IL-1 β , TNF-α and IL-6 (P＜0. 05) ，and increased neuronal degeneration necrosis，there was no statistically significant difference in these indicators in the ESK group compared with the Con group．Compared with the LPS group，mice in the LPS + ESK1 and LPS + ESK2 groups showed reduced anxiety-depression-like behavior (P＜0. 05) ，decreased splenic weight / body weight (P ＜0. 05) ，hippocampal tissue IL-1 β , TNF-α , IL- 6 con- centrations were reduced (P＜0. 05) ，and neuronal degeneration necrosis was reduced．Compared with the LPS + ESK1 group，the LPS + ESK2 group showed an increase in the distance travelled in the central area of the open field experiment and the distance into the open arm of the elevated cross maze experiment (P＜0. 05) ，a decrease in IL-6 and TNF-α concentrations (P＜0. 05) ，and a reduction in the degree of neuronal damage． Conclusion Esketamine ameliorates LPS-induced anxiety-depression-like behavior and neuronal damage in mice by a mechanism that may be related to reduced inflammation.

Objective : To study the protective effect and mechanism of remimazolam on cognitive function in septic mice． Results : In the LPS group，the number of platform crossing times，the percentage of staying time in the first quadrant，GSH level and SOD activity significantly decreased，and TNF-α, IL-1 β and MDA levels significantly increased．In addition，the arrangement of neurons in CA1 area of hippocampus was disturbed ; cytoplasmic staining was deepened ; and the nucleus was solidly stained．Comparing RM10 ，RM15 and RM20 groups with the LPS group，the number of platform crossing times，the sta- ying time in the first quadrant，GSH level and SOD activity increased，and the levels of TNF-α, IL-1 β and MDA decreased．And the results of hippocampal staining showed a decrease in degenerated neuronal cells．When it came to the comparision in the groups with different doses of remimazolam injection，septic mice in the RM20 group showed less improvement in cognitive dysfunction and inflammatory oxidative stress than the RM10 and RM15 groups． Conclusion Remimazolam has a protective effect on cognitive dysfunction in septic mice，and its mechanism may be related to its binding of translocator protein ( TSPO) to inhibit macrophage polarization and thus reduce neuroinflammation and oxidative stress damage．It also reflects that dose of 10 mg / kg and 15 mg / kg has more significant protective effect than that of 20 mg / kg.

With the booming development of medical information technology and computer science, the medical services industry is gradually transiting from information technology to intelligence. The medical knowledge graph plays an important role in intelligent medical applications such as knowledge questions and answers and intelligent diagnosis, and is a key technology for promoting wise medical care and the basis for intelligent management of medical information. In order to fully exploit the great potential of knowledge graphs in the medical field, this paper focuses on five aspects: inter-drug relationship discovery, assisted diagnosis, personalized recommendation, decision support and intelligent prediction. The latest research progress on medical knowledge graphs is introduced, and relevant suggestions are made in light of the current challenges and problems faced by medical knowledge graphs to provide reference for promoting the wide application of medical knowledge graphs.
Pattern Recognition, Automated ; Medical Informatics

To establish a disease risk prediction model based on genetic susceptibility genes and environmental risk factors， which can target high-risk population as early as possible， and intervene in the environmental risk factors in this population. Moreover， accurate screening of genetically susceptible populations can enhance the efficiency of health system. In recent years， with the maturation and cost reduction of high-throughput gene testing， gene testing has been widely used in individual clinical decision-making and will play a more important role in medical and health decision-making. The correlation between genetic testing and disease risk prediction is increasing， making it a prominent research topic in this field. This review summarizes the approaches for establishing and evaluating risk prediction models and discusses potential future challenges and opportunities.

Objective To analyze the prognostic value of vascular endothelial growth factor in acute leukemia .Methods 73 pa-tients with acute leukemia as the leukemia group and 80 patients as the control group were selected .The serum and bone marrow tissue taken by puncture biopsy of posterior superior iliac spine of the leukemia group were collected The serum of the control group was collected and compared .The expression of vascular endothelial growth factor was detected by immunohistochemistry .Results The acute leukemia patients with positive and negative serum VEGF or with positive and negative bone marrow VEGF were fol-lowed .The positive expression of serum VEGF was found in 19 recurrent cases of acute myeloid leukemia (57 .58% ) and the nega-tive expression of serum VEGF was found in 1 recurrent cases (20 .00% ) .The recurrence rate in patients with positive serum VEGF was higher than that in patients with negative serum VEGF ,and the difference was statistically significant (P<0 .05);the positive expression of serum VEGF was found in 16 recurrent cases of acute lymphoblastic leukemia (51 .62% );the positive expres-sion of bone marrow VEGF was found in 17 recurrent cases of acute myeloid leukemia and 17 recurrent cases of acute lymphoblastic leukemia respectively (48 .57% ) .The serum VEGF level and the bone marrow VEGF were measured on follow-up one year after treatment ,which showed the levels of recurrent cases of acute myeloid leukemia and acute lymphoblastic leukemia were all higher than those of Remission patients ,and the difference was statistically significant (P< 0 .01) .Conclusion The levels of VEGF in blood and bone marrow cells can be highly expressed in the initial treatment and recurrence of acute leukemia ,especially in the re-lapsed condition ,the expression level is higher ,but the expression level is significantly decreased in the remission state .Increased expression of VEGF in blood and bone marrow cells may help to predict an increased risk of recurrence .

OBJECTIVETo determine the prevalence of mutations in the non-structural protein 5B (NS5B) of the hepatitis C virus (HCV),which are associated with natural resistance to non-nucleoside and nucleoside polymerase inhibitors (PIs),in treatment-naive hepatitis C patients in south China.

METHODSA nested PCR protocol that amplified three different regions of NS5B was used to detect the naturally occurring drag-resistant substitutions.Direct PCR sequencing was performed to analyze the sequences.

RESULTSNS5B mutations known to confer resistance to nucleoside PIs,such as A15G,S96T and S282T,were mainly detected in HCV genotype 6a (20/88,22.73%).Of the NS5B mutations known to confer resistance to non-nucleoside PIs,C316N and S365A were detected in HCV genotype lb (60/60,100% and 2/60,3.33%, respectively) and I482L and V499A were mainly detected in HCV genotype 2a (9/9,100% and 4/4,100%, respectively) and HCV genotype 6a (9/9,100% and 4/4,100%, respectively).Other NS5B mutations found in the study population included A1 5S,S365F,S365P,S368A and S368L;although none of these has been previously shown to confer resistance to PIs.

CONCLUSIONNaturally occurring dominant PI resistance mutations in NS5B exist in treatment-na(i)ve hepatitis C patients in south China and may be related to the virus genotype.

Antiviral Agents ; pharmacology ; China ; Drug Resistance, Viral ; Genotype ; Hepacivirus ; drug effects ; genetics ; Hepatitis C ; drug therapy ; virology ; Humans ; Mutation ; Viral Nonstructural Proteins ; genetics

Objective To explore the correlation between renal damage of patients with gestational diabetes mellitus (GDM ) and level of serum cystatin C(Cys C) .Methods Eutocia puerperas with single birth in this center from January 2011 to December 2012 were retrospectively analyzed .400 puerperas ,who were confirmed as GDM by oral glucose tolerance test (OGTT) detection ,were collected .Among them ,200 puerperas with 24 h urinary protein content more than 0 .15 g during their 30 to 40 weeks of pregnancy were served as GDM group ,while another 200 puerperas with those not more than 0 .15 g as GDM control group .200 healthy puer-peras without GDM were served as the normal group .Serum uric acid ,creatinine ,urea ,Cys C and 24 h urinary protein content of them during their 30 to 40 weeks of pregnancy were detected .Results Serum uric acid and Cys C of patients in GDM group were obviously higher than those in the GDM control group(P<0 .05) ,while the differences of serum urea ,creatinine between the two groups showed no statistical significance (P>0 .05) .24 h urinary protein content was positively correlated with the serum uric acid and Cys C(r=0 .715 ,0 .863 ,P<0 .05) ,and had no correlation with urea and creatinine (P>0 .05) .Conclusion Serum Cys C may be used as indicators for early diagnosis and monitoring of renal damage in patients with GDM .

Objective To explore the impact of NaF · EDTA-K2 on blood lipids measurement in pregnant women , determine whetherthe empty-stomach plasma for OGTT could be used as substitute for serumin blood lipids analyses.Methods Fastingplasma with NaF · EDTA-K2 and serumfrom 100 pregnant women werecollected,andconcentration of CHO,TG, HDL,LDL,apoA1 and apoB were tested with Hitachi 7 600 automatic biochemical analyzer.Data were analyzed by SPSS 19.0 software.Results The concentrations oflipids and lipoproteins with NaF · EDTA-K2 were slightly lower than those of serum.There were statistical significances between the means of CHO , HDL, LDL, apoA1 and apoBof two groups ( P<0.05) except TG.Correlation coefficients of the six analyteswere CHO 0.968, TG 0.995, HDL 0.979, LDL 0.991, apoA1 0.692, apoB 0.846respectively.Standard Error of Estimate for plasma were: CHO 0.281, TG 0.094, HDL 0.077, LDL 0.112, apoA1 0.230, apoB 0.111 respectively.The modified coefficients were 1.08 for CHO, HDL and LDL, 1.14 for apoA1 and 1.07 for apoB.Conclusion NaF· EDTA-K2 negatively biased the blood lipidsmeasurement of CHO , HDL, LDL, apoA1 and apoB in pregnant women,yet lipids concentrations in plasma with NaF · EDTA-K2 were closely related to those in serum , which may be used to predict the bloodlipidslevel of pregnant women afterajusted.

Objective To detect the expression of integrin ?5?1 in restenosed human vein grafts.Methods The expression of integrin ?5?1 and ?-smooth muscle actin(?-SMA) in 30 resected restenosed human vein grafts(from Kerfuff clinical hospital of Germany) was detected by confocal immunofluorescence with specific antibodies against ?5?1 and ?-SMA.Images were processed with Silicon Graphics Octane.Results In normal veins,integrin ?5?1 expression was very weak in media smooth muscle cells and in endothelium,and ?-SMA expression was present in media smooth muscle cells.In the restenosed vein grafts,integrin ?5?1 was strongly stained in the media smooth muscle cells and intimal endothelial cells,and moderately in the intimal smooth muscle cells,?-SMA was present in media smooth muscle cells and in the intimal smooth muscle cells.Conclusion Our research reveals that integrin ?5?1 is significantly upregulated in the media smooth muscle cells and intimal endothelial cells in the restenosed human vein grafts,suggesting the participation of integrin ?5?1 in the restenosis formation of human vein grafts.