Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of thera-peutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of bio-logical and chemical factors,leaving room for improvement.In this study,we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug effi-cacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS in-hibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets.

OBJECTIVE To conduct the epidemiological survey for 4 patients with carbapenem-resistant Klebsiella pneumoniae(CRAB)that gathered to emerge in intensive care unit(ICU)within a short period so as to find out the sources of suspected CRAB.METHODS The clinical data and epidemiological history of the 4 patients with hospital-associated infection with CRAB who were treated in Shandong Provincial Hospital Affiliated to Shandong First Medical University from Mar.31,2023 to Apr.7,2023 were retrospectively analyzed.The whole genome second-generation sequencing was carried out for the CRAB strains isolated from the patients and their surround-ings,and the sources of the CRAB strains were traced by means of the whole genome sequencing.RESULTS The result of the epidemiological survey showed that the case 1,2,3 and 4 were close in spatial position and had the similar drug resistance spectrum,and there might be cross infection.With the combination of the result of genome analysis,it was found that the strain from the case 1 was brought from the community and was the evolutionary branch different from other CRAB strains causing nosocomial infection;the strains from the case 2,3 and 4 had the close original sources with the CRAB strains from surroundings.CONCLUSIONS The CRAB strain from the case 1 is brought from community,which differs in the evolution branch with the strains from the cases of hospi-tal-associated CRAB infection.The transmission of CRAB leading to the incident of suspected hospital-associated infection outbreak is multiple sources.It is an effective measure to early identify the outbreak of hospital-associated infection and take targeted prevention measures so as to control the outbreak of hospital-associated infection.

OBJECTIVE To conduct the epidemiological survey for 4 patients with carbapenem-resistant Klebsiella pneumoniae(CRAB)that gathered to emerge in intensive care unit(ICU)within a short period so as to find out the sources of suspected CRAB.METHODS The clinical data and epidemiological history of the 4 patients with hospital-associated infection with CRAB who were treated in Shandong Provincial Hospital Affiliated to Shandong First Medical University from Mar.31,2023 to Apr.7,2023 were retrospectively analyzed.The whole genome second-generation sequencing was carried out for the CRAB strains isolated from the patients and their surround-ings,and the sources of the CRAB strains were traced by means of the whole genome sequencing.RESULTS The result of the epidemiological survey showed that the case 1,2,3 and 4 were close in spatial position and had the similar drug resistance spectrum,and there might be cross infection.With the combination of the result of genome analysis,it was found that the strain from the case 1 was brought from the community and was the evolutionary branch different from other CRAB strains causing nosocomial infection;the strains from the case 2,3 and 4 had the close original sources with the CRAB strains from surroundings.CONCLUSIONS The CRAB strain from the case 1 is brought from community,which differs in the evolution branch with the strains from the cases of hospi-tal-associated CRAB infection.The transmission of CRAB leading to the incident of suspected hospital-associated infection outbreak is multiple sources.It is an effective measure to early identify the outbreak of hospital-associated infection and take targeted prevention measures so as to control the outbreak of hospital-associated infection.

Objective : To study the effect of crisaborole on imiquimod (IMQ) Ⅳinduced psoriasis in mice. Methods: Forty eight Balb/c mice were randomly divided into crisaborole group (7. 5 , 15 , 30 mg/cm2），halometasone group ( 15 mg/cm2 ) , model group and normal group. IMQ was applied to the back of mice to establish the psoriasis model. Psoriasis area and severity index ( PASI) score was calculated , pathological changes , skin epidermal thickness and inflammatory cell infiltration in the dermis were observed by HE staining. The expressions of keratin (K) 1 , K10 , K6 , K16 and K17 in skin lesions were detected by Western blot and immunohistochemistry. The levels of cyclic adenosine monophosphate ( cAMP) , protein kinase A ( PKA) and phospho⁃cAMP response element binding protein (p⁃CREB) were detected. Results : Compared with the model group , the PASI score of the crisaborole group decreased , the expression levels of proliferative keratin ( K6 , K16 and K17 ) decreased( F = 12. 62、19. 41、28. 39 ,P < 0. 01) , and the expression levels of differentiation keratin (K1 and K10) increased(F = 27. 95、9. 64 , P < 0. 01) . Conclusion Crisaborole plays a therapeutic role in IMQ⁃induced psoriasis in mice by regulating the abnormal proliferation and differentiation of keratinocytes.

Objective To study the relationship of three-dimensional power Doppler ultrasonographic parameters and endocrine profile in different symptoms of patients with polycystic ovary syndrome(PCOS).Methods One hundred and forty nine women with PCOS were divided into two groups,which included obese PCOS(OB-PCOS) group and non-obese PCOS (NOB-PCOS) group.The ultrasonic parameters such as follicle number,ovarian average diameter,ovarian volume,stromal volume,follicle volume,vascularization index(Ⅵ),flow index(FI),vascularization flow index(VFI) were measured and compared.Serum levels of luteinizing hormone (LH),follicle stimulating hormone (FSH),progesterone (P),estradiol (E2),testosterone(T),prolactin (PRL),sex hormone binding globulin (SHBG),free androgen index (FAI),fasting plasma glucose (FPG),fasting insulin (FINS),homeostasis model assessment-IR(HOMA-IR) were also measured and compared.The correlation of the ultrasonic parameters and hormonal factors were analyzed.Results The follicle number,ovarian average diameter,ovarian volume,stromal volume,follicle volume,FI and VFI,FINS,HOMA-IR,FAI of OB-PCOS were significantly higher than those of NOB-PCOS (P ＜0.01 or 0.05),the FSH,SHBG were significantly lower than those of NOB-PCOS (P ＜0.05 or 0.01).In OB-PCOS group,the follicle number was significantly associated with FSH(r =0.771,P ＜0.01).The ovarian volume,stromal volume,FI and VFI were significantly associated with HOMA-IR(r =0.412,0.842,0.389,0.415,P ＜0.05 or 0.01),FI was significantly associated with FAI (r =0.812,P ＜0.01).In NOB-PCOS group,the follicle number,ovarian volume were significantly associated with FAI(r =0.472,0.552,P ＜0.05)..Conclusions There are some different characters in ultrasonography and endocrine parameters between obese and non-obese PCOS patients.

Objective To establish the reference ranges for fetal cardiac axis in the mid-second trimester and to evaluate the use of fetal cardiac axis in prenatal diagnosis.Methods 6744 unselected singleton pregnancies were enrolled from September 2008 to October 2010.Routine screening scan of second trimester and fetal echocardiography were performed at 18- 23+6 weeks gestation.Fetal cardiac axis was measured on the four-chamber view of the heart.Results The 6744 fetuses had a mean cardiac axis of (37.03 ± 6.10)°,ranging from 9.80° to 102.41°. Using above or below 95％ range of population (26.63° -49.40°) as a cut-off,there were significant difference of cardiac axis between normal group [(36.96 ± 5.91)°,P ＜0.01] and the group with heart defects [(43.12 ± 15.67)°,P ＜0.01],the group with intrathoricic anomalies or abdominal wall defect [(51.74 ± 15.97)°].ConclusionsThe reference ranges of fetal cardiac axis for local population in mid-second trimester may helpful for detecting congenital defects.Presence of an abnormal cardiac axis in the fetuses is associated with a substantial risk of congenital heart disease and/or other extra cardiac defects.

Objective To assess prenatal heart disease screening program by ultrasound. Methods A total of 11 544 second-trimester screening scans were performed before 24 weeks′ gestation on 11 410 women between February 2004 and May 2007 in Obstetrics and Gynecology Hospital of Fudan University. Fetal heart screening was based on four-chamber and outflow tract views( left ventricular outflow + three vessel view). The sensitivity and specificity of different views were evaluated. Follow-up data of newborns was obstained. Results (1) Among 11 544 cases, 48 cases of congenital heart disease (CHD) were diagnosed in utero. Six cases were false negative, and 2 cases were false positive. The incidence of CHD was 0.47% (54/11 544). (2) Thirty-three CHDs were detected based on the four-chamber view, including 18 ventricular septal defect (9 with conotroncal anomalies),6 anomalous atrioventricle valve, 9 disproportion of left/right ventricle. The sensitivity of the four-chamber view alone was 61.11% (33/54), and the specificity was 99. 98% ( 11 488/11 490). Fifteen CHDs were detected based on the left ventricular outflow and three vessel views, including 1 pulmonary atresia, 3 pulmonary valve stenosis, 2 transposition of the great arteries ( TGA ), 1 pulmonary stanosis with TGA, 6 tetralogy of Fallot, and 2 pulmonary stenosis. The sensitivity of the combination of the four-chamber and outflow tract views was 88. 89% (48/54), and the specificity was 99. 98% (11 488/11 490). (3)Of 48 CHDs,11 cases were eceompanied by other malformations. Eleven cases were performed amniocentesis, amony whom 5 cases were trisemy 21. Conclusion The screening program based on four-chamber and outflow tract views shows good sensitivity and excellent specificity. Our prenatal heart screening program is clinically feasible.

Adult ; Diagnostic Errors ; Female ; Humans ; Laryngitis ; diagnosis ; microbiology ; Male ; Middle Aged ; Mycoses ; diagnosis ; Pharyngitis ; diagnosis ; microbiology