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.

OBJECTIVE To analyze the quantity transfer rule in the processing of Astragalus membranaceus before and after moistening-soaking and steaming-soaking followed by cutting. METHODS Three batches of A. membranaceus decoction pieces processed through moistening-soaking and steaming-soaking followed by cutting were prepared. The HPLC overlapping fingerprints of A. membranaceus and its decoction pieces were established through the Similarity Evaluation System of Chromatographic Fingerprints of TCM （2012 edition）. Combined with the previous qualitative analysis results， the common peaks were identified， the changes of common peak area were analyzed， and the principal component analysis was carried out. The contents of calycosin-7-glucoside， astragaloside Ⅰ and astragaloside Ⅳ in A. membranaceus and its decoction pieces were determined by HPLC， and the content differences of each component in different samples were compared. RESULTS The results of fingerprint analysis showed that 17 common peaks were identified. After steaming-soaking and moistening-soaking of A. membranaceus， the proportion of common peak area in the decoction pieces changed compared with the original medicine （for example， in A. membranaceus steaming-soaking decoction pieces， the proportion of peak area of malonyl calycosin-7-glucoside and malonyl astragaloside Ⅰ decreased， while the proportion of peak area of calycosin-7-glucoside increased）. The results of principal component analysis showed that A. membranaceus， and its decoction pieces after moistening-soaking and steaming-soaking followed by cutting were all clustered into one category respectively. The results of content determination showed that， compared with A. membranaceus， the average content of calycosin-7-glucoside in A. membranaceus moistening-soaking decoction pieces was significantly reduced （P＜0.05）； the average contents of calycosin-7-glucoside and astragaloside Ⅳ in A. membranaceus steaming- soaking decoction pieces were significantly increased （P＜0.05）； there was no significant difference in the average content of astragaloside Ⅳ in A. membranaceus moistening-soaking decoction pieces and astragaloside Ⅰ in the two decoction pieces （P＞ 0.05）. CONCLUSIONS There are differences in the quantity transfer rules of A. membranaceus before and after moistening-soaking and steaming-soaking followed by cutting. Steaming-soaking followed by cutting may make the transformation of unstable components （such as malonyl calycosin-7-glucoside and malonyl astragaloside Ⅰ） more complete.

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.

AIM: To evaluate the effect of remimazolam on early postoperative cognitive function in elderly patients with hip fracture based on a randomized controlled trial. METHODS: A total of 106 elderly patients, aged 65-90 years, ASA grade Ⅱ or III, who underwent hip fracture surgery under combined spinal-epidural anesthesia in the Sixth Affiliated Hospital of Wenzhou Medical University from December 2022 to June 2023 and met the inclusion criteria, were selected and randomized into remimazolam group (group R) and propofol group (group P) according to the random number table, with 53 cases in each group. Patients in group P received a slow intravenous injection of propofol at a dose of 0.3-0.5 mg / kg (injection time of 1min), followed by a pump infusion at 0.5-3 mg · kg

Objective To summarize the clinical features,characteristics of cerebrospinal fluid,electrophysiological manifestations,imaging changes,treatment strategies,and prognosis of patients with varicella zoster virus(VZV)complicated by neurological involvement.Methods A retrospective analysis was conducted on 33 patients diagnosed with VZV-associated neurological infections and treated at Beijing Jishuitan Hospital,Capital Medical University,between 2013 and 2024.The clinical characteristics of these patients were thoroughly examined.Results Among the 33 patients,22 were males(66.7%)and 11 were females(33.3%),with a mean age of(60.7±14.3)years.All patients presented with cutaneous herpes zoster,with 22 cases(66.7%)starting with herpes zoster and 11 cases(33.3%)starting with symptoms of neurological damage.Neurological involvement predominantly affected the cranial nerves in 27 cases(81.8%),with facial nerve being the most commonly involved(51.5%).The most common manifestation was facial paralysis(51.5%),followed by head and facial pain(33.3%).It could also be manifested as dizziness(12.1%),ophthalmoplegia(9.1%),hearing loss(9.1%),fever(3.0%),hoarseness(3.0%),and bucking(3.0%).Spinal nerve was involved in 3 cases(9.1%):2 with spinal radiculitis and 1 with Guillain-Barré syndrome,which was characterized by limb numbness,weakness,and dysuria.Additionally,spinal cord was involved in 3 cases(9.1%)including 2 involving the thoracic spinal cord and 1 involving the cervical spinal cord,which was presented as limb numbness,pain,and weakness.No cases of VZV-induced encephalitis,meningitis,or vasculitis were reported.14 patients underwent cerebrospinal fluid examination,and 5 patients(35.7%)had elevated pressure,11 patients(78.6%)had elevated white blood cells,and 5 patients(35.7%)had elevated protein.Neuroimaging did not revealed any responsible lesion in 21 patients with cranial nerve involvement who underwent cranial magnetic resonance image.Among the three patients with spinal cord involvement,the lesion segment was all one vertebral segment.Two cases(2/3)showed circular or mild enhancement after enhancement,while one case(1/3)had no enhancement.Except for one patient who was transferred to another hospital due to HIV infection,all other patients showed clinical improvement upon discharge following antiviral therapy,with or without adjunctive glucocorticoid treatment.Conclusions The primary neurological complications of VZV include cranial nerve paralysis,spinal radiculitis,Guillain-Barré syndrome and myelitis.Early initiation of antiviral therapy,particularly when combined with glucocorticoids,is associated with improved clinical outcomes.

Objective To evaluate the analgesic effects of ultrasound-guided hip capsule block and fascia iliaca block in elderly patients undergoing hip replacement surgery and their impacts on postoperative rehabilitation.Methods A total of 44 patients who underwent total hip replacement in the Second Affiliated Hospital of Wenzhou Medical University from May to December in 2023 were selected and divided into fascia iliaca block group(group F)and hip capsule block group(group H)according to the random number table,with 22 cases in each group.All patients were anesthetized by lumbar anesthesia combined with nerve block.The primary indicators included the recovery of lower limb muscle strength at 8h,24h,48h after operation and the rest and movement visual analogue scale(VAS)scores at each observation point.The secondary indicators were sufentanil consumption of analgesic pump,the number of compressions,the use rates of additional parecoxib sodium in ward,the length of hospital stay and the occurrence of adverse reactions.Results The recovery of lower limb muscle strength in group H was better than that in group F at 8h and 24h after operation,and the difference was statistically significant(P<0.05).The rest and movement VAS scores at 30min after block and 4h after operation in group H were significantly lower than those in group F(P<0.05),while there were no significant differences in the rest and movement VAS scores between two groups at other time points(P>0.05).The rest and movement VAS scores at each time point after blockade were lower than those before blockade in two groups(P<0.05).The sufentanil consumption in analgesic pump and the number of compressions in group H was lower than that in group F at 4h after operation(P<0.05),and there were no significant differences in analgesic pump data and the use rates of parecoxib sodium between two groups at subsequent time points(P>0.05).There were no statistically significant difference in the incidence of nausea within 48h after operation and hospital stay between two groups(P>0.05).Conclusion Both fascia iliaca block and hip capsule block can be safely and effectively used in elderly patients with hip replacement,but the analgesic effect of hip capsule block is faster,the early postoperative analgesic effect is better,and the impact on lower limb movement is less.

Objective To evaluate the analgesic effects of ultrasound-guided hip capsule block and fascia iliaca block in elderly patients undergoing hip replacement surgery and their impacts on postoperative rehabilitation.Methods A total of 44 patients who underwent total hip replacement in the Second Affiliated Hospital of Wenzhou Medical University from May to December in 2023 were selected and divided into fascia iliaca block group(group F)and hip capsule block group(group H)according to the random number table,with 22 cases in each group.All patients were anesthetized by lumbar anesthesia combined with nerve block.The primary indicators included the recovery of lower limb muscle strength at 8h,24h,48h after operation and the rest and movement visual analogue scale(VAS)scores at each observation point.The secondary indicators were sufentanil consumption of analgesic pump,the number of compressions,the use rates of additional parecoxib sodium in ward,the length of hospital stay and the occurrence of adverse reactions.Results The recovery of lower limb muscle strength in group H was better than that in group F at 8h and 24h after operation,and the difference was statistically significant(P<0.05).The rest and movement VAS scores at 30min after block and 4h after operation in group H were significantly lower than those in group F(P<0.05),while there were no significant differences in the rest and movement VAS scores between two groups at other time points(P>0.05).The rest and movement VAS scores at each time point after blockade were lower than those before blockade in two groups(P<0.05).The sufentanil consumption in analgesic pump and the number of compressions in group H was lower than that in group F at 4h after operation(P<0.05),and there were no significant differences in analgesic pump data and the use rates of parecoxib sodium between two groups at subsequent time points(P>0.05).There were no statistically significant difference in the incidence of nausea within 48h after operation and hospital stay between two groups(P>0.05).Conclusion Both fascia iliaca block and hip capsule block can be safely and effectively used in elderly patients with hip replacement,but the analgesic effect of hip capsule block is faster,the early postoperative analgesic effect is better,and the impact on lower limb movement is less.

Objective To summarize the clinical features,characteristics of cerebrospinal fluid,electrophysiological manifestations,imaging changes,treatment strategies,and prognosis of patients with varicella zoster virus(VZV)complicated by neurological involvement.Methods A retrospective analysis was conducted on 33 patients diagnosed with VZV-associated neurological infections and treated at Beijing Jishuitan Hospital,Capital Medical University,between 2013 and 2024.The clinical characteristics of these patients were thoroughly examined.Results Among the 33 patients,22 were males(66.7%)and 11 were females(33.3%),with a mean age of(60.7±14.3)years.All patients presented with cutaneous herpes zoster,with 22 cases(66.7%)starting with herpes zoster and 11 cases(33.3%)starting with symptoms of neurological damage.Neurological involvement predominantly affected the cranial nerves in 27 cases(81.8%),with facial nerve being the most commonly involved(51.5%).The most common manifestation was facial paralysis(51.5%),followed by head and facial pain(33.3%).It could also be manifested as dizziness(12.1%),ophthalmoplegia(9.1%),hearing loss(9.1%),fever(3.0%),hoarseness(3.0%),and bucking(3.0%).Spinal nerve was involved in 3 cases(9.1%):2 with spinal radiculitis and 1 with Guillain-Barré syndrome,which was characterized by limb numbness,weakness,and dysuria.Additionally,spinal cord was involved in 3 cases(9.1%)including 2 involving the thoracic spinal cord and 1 involving the cervical spinal cord,which was presented as limb numbness,pain,and weakness.No cases of VZV-induced encephalitis,meningitis,or vasculitis were reported.14 patients underwent cerebrospinal fluid examination,and 5 patients(35.7%)had elevated pressure,11 patients(78.6%)had elevated white blood cells,and 5 patients(35.7%)had elevated protein.Neuroimaging did not revealed any responsible lesion in 21 patients with cranial nerve involvement who underwent cranial magnetic resonance image.Among the three patients with spinal cord involvement,the lesion segment was all one vertebral segment.Two cases(2/3)showed circular or mild enhancement after enhancement,while one case(1/3)had no enhancement.Except for one patient who was transferred to another hospital due to HIV infection,all other patients showed clinical improvement upon discharge following antiviral therapy,with or without adjunctive glucocorticoid treatment.Conclusions The primary neurological complications of VZV include cranial nerve paralysis,spinal radiculitis,Guillain-Barré syndrome and myelitis.Early initiation of antiviral therapy,particularly when combined with glucocorticoids,is associated with improved clinical outcomes.

Objective To investigate the association of copy number variations (CNVs) in the FCGR3A and FCGR3B genes with different outcomes and disease progression after hepatitis B virus (HBV) infection. Methods Peripheral blood samples were collected from 841 patients with chronic HBV infection and 296 patients with self-limited HBV infection, an according to the degree of disease progression, the patients with chronic HBV infection were further divided into chronic hepatitis B (CHB) group, liver cirrhosis (LC) group, and hepatocellular carcinoma (HCC) group. The AccuCopy technique was used for the quantitative analysis of CNVs in the FCGR3A and FCGR3B genes in peripheral blood. The independent samples t -test was used for comparison of continuous data between two groups, and a one-way analysis of variance and the Kruskal-Wallis H test were used for comparison between multiple groups; the chi-square test was used for comparison of categorical data between groups. The chi-square test was also used to investigate the difference in the distribution of CNVs in the FCGR3 gene between different groups. The age-and sex-adjusted logistic regression model was used to investigate the influence of CNVs on the chronicity of HBV infection. Results There was a significant difference in the frequency distribution of CNVs in the FCGR3A and FCGR3B genes between the chronic HBV infection group and the self-limited HBV infection group ( χ 2 =11.406 and 19.143, both P < 0.05). As for disease progression after chronic HBV infection, there were no significant differences in CNVs of the FCGR3A and FCGR3B genes between the CHB group, the LC group, and the HCC group (FCGR3A: χ 2 =3.125, P =0.537; FCGR3B: χ 2 =5.274, P =0.260). There were also no significant differences in CNVs of the FCGR3A and FCGR3B genes between the HBeAg-positive group and the HBeAg-negative group (FCGR3A: χ 2 =1.025, P =0.599; FCGR3B: χ 2 =0.712, P =0.701). Reduction or deletion of the copy number of the FCGR3A and FCGR3B genes was a risk factor for the chronicity of HBV infection (FCGR3A: odds ratio [ OR ]=0.621, 95% confidence interval [ CI ]: 0.513-0.752; FCGR3B: OR =0.594, 95% CI : 0.491-0.719). Conclusion Reduction or deletion of the copy number of the FCGR3A and FCGR3B genes may be a genetic susceptibility factor for the chronicity of HBV infection, but it is not associated with disease progression.

A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or off-target effects. Recently, the fast accumulation of gene transcriptional profiling data provides us an unprecedented opportunity to explore the protein targets of chemical compounds from the perspective of cell transcriptomics and RNA biology. Here, we propose a novel Siamese spectral-based graph convolutional network (SSGCN) model for inferring the protein targets of chemical compounds from gene transcriptional profiles. Although the gene signature of a compound perturbation only provides indirect clues of the interacting targets, and the biological networks under different experiment conditions further complicate the situation, the SSGCN model was successfully trained to learn from known compound-target pairs by uncovering the hidden correlations between compound perturbation profiles and gene knockdown profiles. On a benchmark set and a large time-split validation dataset, the model achieved higher target inference accuracy as compared to previous methods such as Connectivity Map. Further experimental validations of prediction results highlight the practical usefulness of SSGCN in either inferring the interacting targets of compound, or reversely, in finding novel inhibitors of a given target of interest.
Drug Delivery Systems ; Proteins ; Transcriptome