Five novel nor-eremophilane-type sesquiterpenoids, peniroqueforins E-H and J (1-4 and 7), two new eremophilane-type sesquiterpenoids, peniroqueforins I and K (5 and 8), and a new eudesmane-type sesquiterpenoid, peniroqueforin L (9), along with four known compounds (6 and 10-12), were isolated and characterized from fungus Penicillium roqueforti (P. roqueforti). The structures and absolute configurations of these compounds were determined through comprehensive spectroscopic analyses, electronic circular dichroism (ECD) data analyses, and single-crystal X-ray diffraction methods. The anti-multi-drug resistance (MDR) cancer activity of these compounds was evaluated using SW620/Ad300 cells. Notably, the half maximal inhibitory concentration (IC₅₀) value of paclitaxel (PTX) combined with 1 in SW620/Ad300 cells was 50.36 nmol·L^-1, which was 65-fold more potent than PTX alone (IC₅₀ 3.26 μmol·L^-1). Subsequent molecular docking studies revealed an affinity between compound 1 and P-glycoprotein (P-gp), suggesting that this nor-eremophilane-type sesquiterpenoid (1) could serve as a potential lead for MDR reversal in cancer cells through P-gp inhibition.
Penicillium/chemistry* ; Humans ; Sesquiterpenes/isolation & purification* ; Cell Line, Tumor ; Molecular Structure ; Drug Resistance, Neoplasm/drug effects* ; Antineoplastic Agents/pharmacology* ; Drug Resistance, Multiple/drug effects* ; Molecular Docking Simulation

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

AIM: To evaluate the performance of three distinct large language models(LLM), including GPT-3.5, GPT-4, and PaLM2, in responding to queries within the field of ophthalmology, and to compare their performance with three different levels of medical professionals: medical undergraduates, master of medicine, and attending physicians.METHODS: A total of 100 ophthalmic multiple-choice tests, which covered ophthalmic basic knowledge, clinical knowledge, ophthalmic examination and diagnostic methods, and treatment for ocular disease, were conducted on three different kinds of LLM and three different levels of medical professionals(9 undergraduates, 6 postgraduates and 3 attending physicians), respectively. The performance of LLM was comprehensively evaluated from the aspects of mean scores, consistency and confidence of response, and it was compared with human.RESULTS: Notably, each LLM surpassed the average performance of undergraduate medical students(GPT-4:56, GPT-3.5:42, PaLM2:47, undergraduate students:40). Specifically, performance of GPT-3.5 and PaLM2 was slightly lower than those of master's students(51), while GPT-4 exhibited a performance comparable to attending physicians(62). Furthermore, GPT-4 showed significantly higher response consistency and self-confidence compared with GPT-3.5 and PaLM2.CONCLUSION: LLM represented by GPT-4 performs well in the field of ophthalmology, and the LLM model can provide clinical decision-making and teaching aids for clinicians and medical education.

Objective To explore the value of CT-derived fractional flow reserve(CT-FFR)and pericoronary fat attenuation index(FAI)combined with clinical and coronary CT angiography(CCTA)characteristics for predicting major adverse cardiovascular events(MACE)after aortic valve replacement(AVR).Methods Data of 139 patients with aortic stenosis who underwent AVR were retrospectively analyzed.According to occurrence of MACE or not during follow-up,the patients were divided into MACE group and non-MACE group.Cox proportional hazard regression was used to analyze clinical and CCTA data,as well as CT-FFR and FAI to screen independent predictors of MACE after AVR,and nested models based on clinical data,CCTA characteristics,CT-FFR and right coronary artery(RCA)FAI were constructed.Receiver operating characteristic(ROC)curves were drawn,the area under the curve(AUC)and Harrell C index(C-index)were calculated to assess the diagnostic efficacy of each model,and their goodness of fit were evaluated.Results There were 22 cases in MACE group and 117 in non-MACE group.CT-FFR(HR=3.683)and RCA-FAI(HR=3.261)were both independent predictors of MACE in patients after AVR.The AUC of clinical model,modelclinical+CCTA,modelclinical+CCTA+CT-FFR and modelclinical+CCTA+CT-FFR+RCA-FAI was 0.636,0.730,0.758 and 0.817,and the C-index was 0.614,0.707,0.733 and 0.782,respectively.The predicted results of modelclinical+CCTA+CT-FFR+RCA-FAI were most consistent with actual results,with the best goodness of fit.Conclusion CT-FFR and RCA-FAI combined with clinical and CCTA characteristics could effectively predict MACE in patients after AVR.

To determine the physicians′compliance of hour-1 bundle for sepsis. A management system of hour-1 bundle for sepsis was established. The clinical data of 286 sepsis patients were collected, who were classified into 3 months before the bundle (control group), 9 months during process (observation group) and 3 months after bundle (study group). The compliance of hour-1 bundle implementation was compared in three groups. The results showed that with the application and implementation of the management system, the compliance of hour-1 bundle for sepsis in the control group, observation group and study group was 58.3%(28/48), 69.1%(105/152) and 88.4%(76/86) respectively (χ 2=7.053, P=0.029). The 28 day mortality in sepsis patients was 41.7%(20/48), 34.9%(53/152) and 23.3%(20/86) respectively (χ 2=5.576, P=0.062).The management system of hour-1 bundle for sepsis can effectively improve the physicians′ compliance.

Objective To study the clinical value of combined detection of serum interleukin(IL)-8 ,tumor necrosis factor(TNF)-α,alvedar cell surface antigen Ⅱ(KL-6) and surface protein D(SP-D) in the diagnosis of idiopathic pulmonary fibrosis(IPF) .Meth-ods Seventy three patients with IPF were selected as the research subjects ,other 73 patients with bacterial pneumonia were taken as the bacterial pneumonia group .The levels of serum IL-8 ,TNF-α,KL-6 and SP-D were detected by enzyme-linked immunosorbent assay (ELISA) .The serum levels of IL-8 ,TNF-α,KL-6 and SP-D were compared between the IPF group and bacterial pneumonia group .The sensitivity and specificity of IPF detection were compared between the 4-index combined detection and single item de-tection .Results The levels of IL-8 ,TNF-α,KL-6 and SP-D in the IPF group were significantly higher than those in the bacterial pneumonia group (P<0 .05) .The positive rate of single detection of four indexes in the IPF group was significantly higher than that in the bacterial pneumonia group (P<0 .05) .The sensitivity and specificity of the 4-index combined detection for diagnosing IPF were 90 .4% and 93 .2% respectively ,which were significantly higher than the those of single index detection (P<0 .05) .Con-clusion The combined detection of IL-8 ,TNF-α,KL-6 and SP-D has better sensitivity and specificity in IPF diagnosis compared with single detection of IL-8 ,TNF-α,KL-6 and SP-D .

OBJECTIVETo assess the impact of natural selection and genetic background on the polymorphisms of HLA-G 3-untranslated regions (UTR) among five ethnic Chinese populations.

METHODSPCR and DNA sequencing were used to determine the polymorphisms among 432 individuals from the five ethnic populations. Their genetic background was determined by genotyping of 10 short tandem repeats (STRs).

RESULTSEight variations were identified among Gelao, Mongolian and Kirgiz populations, while only 7 were found in Shui and Dai people. For all 3 southern populations (Gelao, Shui, and Dai), the observed heterozygosites (Ho) was higher than expected heterozygosities (He). But this was reversed for the 2 northern populations (Mongolian and Kirgiz). The Ho and He of the 10 neutral STRs were in random distribution. Ewens-Watterson testing based on haplotypes of the HLA-G 3'UTR has suggested that a natural selection had occurred in the region where Dai and Shui had inhabited, but not in the northern region where Mongolian and Kirgiz population inhabited. Polygenetic trees based on the HLA and STRs were also different.

CONCLUSIONThe HLA-G 3'UTR of Dai and Shui people who lived in southern China may have subjected to a selection pressure. Based on current knowledge, this pressure may have been driven by a pathogenic selection.

3' Untranslated Regions ; genetics ; China ; ethnology ; Female ; HLA-G Antigens ; genetics ; Humans ; Male ; Microsatellite Repeats ; Polymorphism, Genetic ; Selection, Genetic

Objective To explore the action mechanism of shenxiong glucose injection in treatment of acute spinal cord injury(SCI) through observing its effects on the recovery of motor function and the expression of aquaporin-4(AQP-4) in SCI rats.Methods Totally 90 healthy,aduh,Sprague-Dawley rats were randomly divided into a sham operation group (n=30),aSCI group (n=30) and a drug group (n=30).The SCI rat models in both the SCI group and the drup group were established aecording to the modified Allen's method,while the sham operation group was only given laminectomy.After the operation,the drug group was given intraperitoneal shenxiong glucose injection of 30 rnl/kg a day,while the other two groups were injected in the same way with normal saline.The neural function recovery,the pathological changes after SCI and the expressions of AQP-4 were observed 1,3,7,14 and 21 d after the operation using the Tarlov score,the hematoxylin and eosin staining,as well as immunofluorescence techniques and Western blotting.And the correlation of Tarlov scores with AQP-4 expressions was analyzed.Results No significant changes in Tarlov scores were observed in the sham operation group (P ＞ 0.05),while in the SCI group and the drug group,postoperative Tarlov scores decreased significantly.The hindlimb nerve function recovered to some degree with time in the SCI group and drug group.At 3,7,14 and 21 days after the operation,the Tarlov scores in the drug group were significantly higher than the SCI group (P ＜ 0.05).The drug group showed less severe pathological changes,with more residual neurons still visible of nucleoli than the SCI group 21 days after the operation.Compared with the sham operation group,the expression levels of AQP-4 were significantly higher in the SCI group and drug group at all the time points (P ＜ 0.05).However,the expression levels of AQP-4 in the drug group were significantly lower than the SCI group accordingly (P ＜ 0.05).The Tarlov scores were found to be significantly and negatively related to the AQP-4 protein expression levels 3 days(r =-0.523,P =0.003),7 days(r =-0.437,P=0.016),14 days(r=-0.417,P=0.022) and 21 days(r=-0.377,P=0.040)after the operation.Conclusion Injecting shenxiong with glucose can effectively promote the recovery of motor function after SCI,at least in rats.And its mechanism may be that the development of spinal cord edema is prevented and the secondary spinal cord injury alleviated by restraining the expressions of AQ P-4 in the injured areas.

Objective To analyze the clinical infection distribution and drug resistance status of 442 strains of Escherichia coli to provide the basise for the treatment of Escherichia coli infection and the control of nosocomial infection.Methods The clinically submitted various kinds of specimens during 2013 were performed the bacterial culture and identification.The susceptibility of Escherichia coli to commonly used bacterial drugs were detected by adopting the MIC method.The data were analyzed by WHO-NET V5.5 and SPSS V13.0 softwares.Results 442 strains of Escherichia coli were isolated from the middle urine and secretion. The detection rate of ESBLs-producing Escherichia coli was 61.3%.442 strains of Escherichia coli had the high resistance to peni-cillins,cephalosporins and fluoroquinolones,better sensitivity toβ-lactam/β-lactamase inhibitor compounds and highest sensitivity to carbapenems.ESBLs-producing Escherichia coli had the higher resistance to commonly used antibacterial drugs than non-ESBLs-producing Escherichia coli .Conclusion The drug resistance of Escherichia coli is severe.ESBLs-producing Escherichia coli are u-sually resistant to many different types of antimicrobial drugs.Carbapenems are the first choice to treatment of severe infections of Escherichia coli .