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 intrinsic connection between traditional Chinese medicine culture and Chinese civilization,excavate and inherit the core values of traditional Chinese medicine culture,and lay a solid foundation for the high-quality development of the traditional Chinese medicine career.[Methods]Through systematic literature review,based on the five prominent characteristics of Chinese civilization,this study deeply analyzes how traditional Chinese medicine culture carries and demonstrates the continuity,innovation,unity,inclusiveness and peaceful nature of Chinese civilization.[Results]The continuity of traditional Chinese medicine culture highlights the continuity of Chinese civilization;traditional Chinese medicine culture upholds integrity and innovation,demonstrating the innovation of Chinese civilization;the unity of heaven and man in traditional Chinese medicine culture highlights the unity of Chinese civilization;the cultural diversity of traditional Chinese medicine highlights the inclusiveness of Chinese civilization;traditional Chinese medicine culture emphasizes the peaceful nature of Chinese civilization by putting people first.Among them,continuity is the most prominent feature of traditional Chinese medicine culture,innovation is the driving force for the inheritance and development of traditional Chinese medicine culture,unity is the foundation for the millennium existence of traditional Chinese medicine culture,inclusiveness is the bridge for the integration of traditional Chinese medicine culture inside and outside,and peaceful nature is the necessary condition for the long-term preservation of traditional Chinese medicine culture.The five prominent characteristics have inherent logical relationships and form a unified whole.[Conclusion]Traditional Chinese medicine culture deeply embodies the prominent characteristics of Chinese civilization.Digging into the essence of traditional Chinese medicine culture can help strengthen the confidence of traditional Chinese medicine culture,activate the modern vitality of Chinese civilization and accelerate the promotion of traditional Chinese medicine culture towards the world.

Objective:To elucidate the causal association between gut microbiota and osteoporosis, we conducted a two-sample Mendelian randomization(MR)analysis to evaluate the causality between gut microbiota and osteoporosis.Methods:We assessed genome-wide association study (GWAS)summary statistics for gut microbiota and osteoporosis in older patients to perform the MR analysis.Independent single nucleotide polymorphisms closely associated with 211 gut bacterial taxa were identified as instrumental variables.The summary statistic data for osteoporosis were obtained from the latest release from the FinnGen consortium as the outcome of interest.Two-sample MR was performed to evaluate the causal effect of gut microbiota on osteoporosis, including the inverse-variance-weighted(IVW)method, weighted median method, MR-Egger, mode-based estimation, and MR-PRESSO.A series of sensitivity analyses were conducted to validate the robustness of the results.The robustness of the estimation was assessed through a series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plot to evaluate the causal association. Results:The population primarily consisted of individuals from Europe, with a total sample size of 7 300, including 1 762 males and 5 538 females, and average ages of 65.6 years for males and 67.8 years for females, respectively.The mean ages of the 5 538 patients were 65.6 years for males and 67.8 years for females, respectively.Through MR analysis in this study, 10 intestinal flora(comprising 1 class, 7 genera, and 2 orders)were identified as being associated with senile osteoporosis.Notably, the phylum Firmicutes( OR=1.324, P=0.019), Clostridium difficile( OR=1.274, P=0.038), fecal coliforms( OR=1.565, P=0.009), Verrucomicrobium( OR=1.231, P=0.033), and Selenomonas( OR=1.324, P=0.019)may serve as risk factors for senile osteoporosis.Conversely, Coprococcus( OR=0.620, P=0.024), Haemophilus( OR=0.815, P=0.016), Prevotella( OR=0.813, P=0.027), Sellimonas( OR=0.858, P=0.034), and RF9( OR=0.821, P=0.021)may function as protective factors against senile osteoporosis. Conclusions:This study suggests a causal relationship between the Firmicutes phylum and its nine subgroups and senile osteoporosis, thereby providing new insights into the mechanisms by which gut microbiota mediate senile osteoporosis and confirming the significant role of gut microbiota in this condition.

Objective To analyze the incidence and mortality of gastric cancer in countries and territories with different human development index(HDI)levels in 2022,and to understand the burden of gastric cancer globally and in China.Methods Data on gastric cancer incidence and mortality were collected from GLOBOCAN 2022 and HDI data for all countries were obtained from the Human development report 2022.Spearman correlation was applied to examine the associations between the age-standardized incidence rate(ASIR),age-standardized mortality rate(ASMR),mortality-to-incidence ratio(M/I),and HDI for gastric cancer.The Wilcoxon rank-sum test was used to assess the differences in ASIR and ASMR between males and females.Results In 2022,gastric cancer ranked the 5th in both incidence and mortality among all cancer types globally.In China,gastric cancer ranked the 5th in incidence and the 3rd in mortality among all cancer types.The ASIR and ASMR of gastric cancer showed a descending trend from high,very high,medium to low HDI countries and territories.The ASIR of gastric cancer was positively correlated with HDI(rs=0.256,P=0.001),while ASMR showed no significant correlation with HDI(rs=-0.008,P=0.918).The M/I was negatively correlated with HDI(rs=-0.831,P＜0.001).The ASIR and ASMR of gastric cancer in males were significantly higher than those in females globally,in China,and across all HDI groups(all P＜0.05).Globally,both ASIR and ASMR of gastric cancer remained relatively stable before the age of 45,but showed a consistently rising trend after the age of 45.In China,the ASIR and ASMR of gastric cancer exceeded global average level across all age groups.Conclusion The burden of gastric cancer incidence and mortality is higher in very high and high HDI countries and territories compared to medium and low HDI countries and territories.In China,the burden of gastric cancer incidence and mortality is above the global average,highlighting the need for targeted prevention and control measures.

Objective To compare the incidence and mortality of brain and central nervous system(CNS)tumors in countries and territories with different human development index(HDI)in 2022,to make a comparison with the current epidemiological situation in China,and to assess the association between HDI and the incidence and mortality of brain and CNS tumors.Methods The data on brain and CNS tumors from GLOBOCAN 2022 were collected,and HDI data were organized based on the Human development report 2022.Generalized additive model(GAM)was used to analyze the relationships between standardized incidence ratio(SIR),standardized mortality ratio(SMR),mortality-to-incidence ratio(M/I),and HDI.Results The incidence and mortality of brain and CNS tumors increased with age in 2022,with a significant increasing trend in countries and territories with very high HDI.Countries and territories with high and very high HDI had more cases and more deaths,and countries and territories with very high HDI had the highest SIR and SMR.SIR for brain and CNS tumors in China was higher than the global average,while China's SMR was lower.M/I varied among countries and territories with different HDI,with lower M/I in countries and territories with high and very high HDI.HDI had a significant nonlinear effect on SIR(edf=1.740,P＜0.000 1)and M/I(edf=1.809,P＜0.000 1),and a significant linear effect on SMR(edf=1,P＜0.000 1).As HDI increased,SIR and SMR generally showed an increasing trend,while M/I showed a decreasing trend.Conclusion There are significant global differences in incidence and mortality of brain and CNS tumors in patients with different HDI in 2022;increasing HDI can reduce the risk of brain and CNS tumors and improve treatment outcomes,and prevention and control strategies should be made for different age groups and HDI.

[Objective]To explore the intrinsic connection between traditional Chinese medicine culture and Chinese civilization,excavate and inherit the core values of traditional Chinese medicine culture,and lay a solid foundation for the high-quality development of the traditional Chinese medicine career.[Methods]Through systematic literature review,based on the five prominent characteristics of Chinese civilization,this study deeply analyzes how traditional Chinese medicine culture carries and demonstrates the continuity,innovation,unity,inclusiveness and peaceful nature of Chinese civilization.[Results]The continuity of traditional Chinese medicine culture highlights the continuity of Chinese civilization;traditional Chinese medicine culture upholds integrity and innovation,demonstrating the innovation of Chinese civilization;the unity of heaven and man in traditional Chinese medicine culture highlights the unity of Chinese civilization;the cultural diversity of traditional Chinese medicine highlights the inclusiveness of Chinese civilization;traditional Chinese medicine culture emphasizes the peaceful nature of Chinese civilization by putting people first.Among them,continuity is the most prominent feature of traditional Chinese medicine culture,innovation is the driving force for the inheritance and development of traditional Chinese medicine culture,unity is the foundation for the millennium existence of traditional Chinese medicine culture,inclusiveness is the bridge for the integration of traditional Chinese medicine culture inside and outside,and peaceful nature is the necessary condition for the long-term preservation of traditional Chinese medicine culture.The five prominent characteristics have inherent logical relationships and form a unified whole.[Conclusion]Traditional Chinese medicine culture deeply embodies the prominent characteristics of Chinese civilization.Digging into the essence of traditional Chinese medicine culture can help strengthen the confidence of traditional Chinese medicine culture,activate the modern vitality of Chinese civilization and accelerate the promotion of traditional Chinese medicine culture towards the world.

Objective:To elucidate the causal association between gut microbiota and osteoporosis, we conducted a two-sample Mendelian randomization(MR)analysis to evaluate the causality between gut microbiota and osteoporosis.Methods:We assessed genome-wide association study (GWAS)summary statistics for gut microbiota and osteoporosis in older patients to perform the MR analysis.Independent single nucleotide polymorphisms closely associated with 211 gut bacterial taxa were identified as instrumental variables.The summary statistic data for osteoporosis were obtained from the latest release from the FinnGen consortium as the outcome of interest.Two-sample MR was performed to evaluate the causal effect of gut microbiota on osteoporosis, including the inverse-variance-weighted(IVW)method, weighted median method, MR-Egger, mode-based estimation, and MR-PRESSO.A series of sensitivity analyses were conducted to validate the robustness of the results.The robustness of the estimation was assessed through a series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plot to evaluate the causal association. Results:The population primarily consisted of individuals from Europe, with a total sample size of 7 300, including 1 762 males and 5 538 females, and average ages of 65.6 years for males and 67.8 years for females, respectively.The mean ages of the 5 538 patients were 65.6 years for males and 67.8 years for females, respectively.Through MR analysis in this study, 10 intestinal flora(comprising 1 class, 7 genera, and 2 orders)were identified as being associated with senile osteoporosis.Notably, the phylum Firmicutes( OR=1.324, P=0.019), Clostridium difficile( OR=1.274, P=0.038), fecal coliforms( OR=1.565, P=0.009), Verrucomicrobium( OR=1.231, P=0.033), and Selenomonas( OR=1.324, P=0.019)may serve as risk factors for senile osteoporosis.Conversely, Coprococcus( OR=0.620, P=0.024), Haemophilus( OR=0.815, P=0.016), Prevotella( OR=0.813, P=0.027), Sellimonas( OR=0.858, P=0.034), and RF9( OR=0.821, P=0.021)may function as protective factors against senile osteoporosis. Conclusions:This study suggests a causal relationship between the Firmicutes phylum and its nine subgroups and senile osteoporosis, thereby providing new insights into the mechanisms by which gut microbiota mediate senile osteoporosis and confirming the significant role of gut microbiota in this condition.

At the time of the reform and adjustment of discipline transformation,the Institute of Respiratory and Critical Care Medicine,the 8th Medical Center of Chinese PLA General Hospital,relies on Beijing Key Laboratory of Organ Transplantation and Immunology Regulatory,to build a multidisciplinary postgraduate joint training mode based on immunology.From the aspects of indi-vidualized postgraduate training background,teaching mode,ability training,etc.,the practice mode of joint training of postgraduates in multiple clinical disciplines is explored.In order to cultivate medical thinking talents with systematic and holistic theory,and pre-pare for future clinical work.

The Spt-Ada-Gcn5-acetyltransferase (SAGA) is an ancillary transcription initiation complex which is highly conserved. The ADA1 (alteration/deficiency in activation 1, also called histone H2A functional interactor 1, HFI1) is a subunit in the core module of the SAGA protein complex. ADA1 plays an important role in plant growth and development as well as stress resistance. In this paper, we performed genome-wide identification of banana ADA1 gene family members based on banana genomic data, and analyzed the basic physicochemical properties, evolutionary relationships, selection pressure, promoter cis-acting elements, and its expression profiles under biotic and abiotic stresses. The results showed that there were 10, 6, and 7 family members in Musa acuminata, Musa balbisiana and Musa itinerans. The members were all unstable and hydrophilic proteins, and only contained the conservative SAGA-Tad1 domain. Both MaADA1 and MbADA1 have interactive relationship with Sgf11 (SAGA-associated factor 11) of core module in SAGA. Phylogenetic analysis revealed that banana ADA1 gene family members could be divided into 3 classes. The evolution of ADA1 gene family members was mostly influenced by purifying selection. There were large differences among the gene structure of banana ADA1 gene family members. ADA1 gene family members contained plenty of hormonal elements. MaADA1-1 may play a prominent role in the resistance of banana to cold stress, while MaADA1 may respond to the Panama disease of banana. In conclusion, this study suggested ADA1 gene family members are highly conserved in banana, and may respond to biotic and abiotic stress.
Musa/genetics* ; Phylogeny ; Fungal Proteins ; Cell Nucleus ; Histones ; Stress, Physiological/genetics*

Objective:To develop a recombinant protein vaccine based on KPC-2, a drug resistance target in Klebsiella pneumoniae, and evaluate its immunogenicity, protective efficacy and mechanism in a mouse model of pneumonia. Methods:KPC-2 was expressed in Escherichia coli and purified using GST affinity chromatography. A recombinant protein vaccine was prepared with KPC-2 and used to immunize New Zealand rabbits through subcutaneous injection. Serum samples were isolated from cardiac blood and Protein G chromatography was used to purify polyclonal antibodies against KPC-2. Opsonophagocytic killing assay was used to assess the bactericidal activity of the polyclonal antibodies in vitro. Female BALB/c mice were immunized three times with the recombinant protein vaccine, and the titers of specific IgG antibodies in serum were measured by indirect ELISA. One week after the last vaccination, the mice were infected with Klebsiella pneumoniae strain SRT through tracheal intubation, and received a single intravenous dose of meropenem (0.1 mg) 1 h later. The protective efficacy of the KPC-2 recombinant protein vaccine was evaluated by comparing the survival rates, bacterial colonization and histopathological changes between vaccine group and adjuvant group as well as the survival rates between meropenem group and normal saline group. Moreover, the protective efficacy of polyclonal antibodies against KPC-2 was evaluated through passive immunization. Results:The level of specific IgG antibodies in serum was significantly higher in the vaccine group than in the adjuvant group ( t=4.325, P<0.05). The survival rate in the vaccine group was also higher than that of the adjuvant group [70% (7/10) vs 10% (1/10), P<0.05]. Furthermore, lung inflammation was less severe and bacterial burden was reduced in the vaccine group as compared with those of the control group ( t=3.127, P<0.05). Both active and passive vaccination strategies demonstrated strong protective efficacy against Klebsiella pneumoniae infection, and had a synergistic effect when used in combination with antibiotic therapy. The polyclonal antibodies against KPC-2 had bactericidal activity in vitro ( t=5.427, P<0.05). Conclusions:The prepared KPC-2 vaccine has better immunogenicity and protective efficacy. It can induce strong humoral immune responses. This study suggest that drug resistance target may be used as a candidate antigen for future vaccine development.