Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Tyrosine-decahydrofluorene derivatives are a class of hybrid compounds that integrate the properties of polyketides and nonribosomal peptides. These compounds feature a [6.5.6] tricarbocyclic core and a para-cyclophane ether moiety in their structures and exhibit anti-tumor and anti-microbial activities. In this study, we constructed the biosynthetic pathway of xenoacremones from Xenoacremonium sinensis ML-31 in the Aspergillus nidulans host, resulting in the identification of four novel tyrosine-decahydrofluorene analogs, xenoacremones I-L (1-4), along with two known analogs, xenoacremones A and B. Remarkably, compounds 3 and 4 contained a 12-membered para-cyclophane ring system, which is unprecedented among tyrosine-decahydrofluorene analogs in X. sinensis. The successful reconstruction of the biosynthetic pathway and the discovery of novel analogs demonstrate the utility of heterologous expression strategy for the generation of structurally diverse natural products with potential biological activities.
Aspergillus nidulans/metabolism* ; Biological Products/metabolism* ; Polyketides/metabolism* ; Peptides/metabolism* ; Biosynthetic Pathways ; Multigene Family

Objective To evaluate biomechanical strength of locking compression plate (LCP) for fixation of periprosthetic proximal femur fractures (PPFF). Methods Eight matched pairs of Vancouver type B1 adult cadaveric PPFF specimens were fixed with the LCP and the inverted distal femoral less invasive stabilization system (LISS), respectively. Four bicortical locking screws (LCP group) and four unicortical locking screws were used to the length of prosthesis stem, and four double cortical locking screws were used to fix the distal end of the fracture in two groups, the distance from the locking screws to the fracture were also equal. The maximum bending load, maximum bending displacement, bending stiffness, maximum torque, maximum torsional angle and torsional stiffness of two groups in four-point bending test and torsion test were compared and analyzed. Results The maximum bending load, maximum bending displacement and bending stiffness of LCP group were all larger than those of LISS group, but the difference was not statistically significant (P>0.05). The maximum torque, maximum torsional angle and torsional stiffness of LCP group were obviously larger than those of LISS group，and there was a statistical difference between two groups (P<0.05). Conclusions The stiffness of anti-torsion with LCP is significantly better than that with LISS. Consequently, LCP has better biomechanical stability for PPFF.

Objective:To observe the influence of Xuebijing injection on the inflammatory markers and prognosis of coronavirus disease 2019 (COVID-19) patients.Methods:Sixty severe COVID-19 patients admitted to Changsha Public Health Treatment Center (North Hospital of the First Hospital of Changsha City) from January to March in 2020 were randomly divided into routine treatment group, Xuebijing 50 mL group and Xuebijing 100 mL group, with 20 cases in each group. The routine treatment group was treated according to the National Health Commission's guide for COVID-19. On the basis of conventional treatment, Xuebijing injection was injected by 50 mL twice a day for 7 days in Xuebijing 50 mL group, while by 100 mL twice a day for 7 days in Xuebijing 100 mL group. The blood routine test, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), acute physiology and chronic health evaluationⅡ(APACHEⅡ) score, 2019 novel coronavirus (2019-nCoV) nucleic acid test and disease classification of three groups before and 8 days after treatment were observed.Results:① After treatment, the white blood cell count (WBC) and lymphocyte count (LYM) of three groups increased, meanwhile CRP and ESR decreased. Compared with routine treatment group, the WBC count of Xuebijing 100 mL group after treatment significantly increased (×10 9/L: 7.12±0.55 vs. 5.67±0.51, P < 0.05), and the levels of CRP and ESR in Xuebijing 50 mL and 100 mL groups significantly decreased [CRP (mg/L): 32.3±4.6, 28.0±6.2 vs. 37.3±5.9; ESR (mm/1 h): 45.9±5.7, 40.5±7.4 vs. 55.3±6.6, all P < 0.05]. Compared with Xuebijing 50 mL group, the increase of WBC, and the decrease of CRP and ESR were more significant in Xuebijing 100 mL group [WBC (×10 9/L): 7.12±0.55 vs. 5.82±0.49, CRP (mg/L): 28.0±6.2 vs. 32.3±4.6, ESR (mm/1 h): 40.5±7.4 vs. 45.9±5.7, all P < 0.05]. ② After treatment, the APACHEⅡscore of three groups decreased. In Xuebijing 100 mL group, the APACHEⅡscore after treatment was significantly lower than those in routine treatment and Xuebijing 50 mL groups (12.3±1.5 vs. 16.5±1.6, 15.9±1.4, both P < 0.05). After treatment, the 2019-nCoV nucleic acid test in three groups partly turned negative, with 9 cases in routine treatment group, 8 cases in Xuebijing 50 mL group and 9 cases in Xuebijing 100 mL group, without significant difference ( P > 0.05). The conditions of patients in the three groups were improved after treatment, among them, 8 cases in the routine treatment group were transformed into common type, 1 case into critical type; 9 cases and 12 cases of Xuebijing 50 mL group and 100 mL group were transformed into common type respectively. Xuebijing 100 mL group was improved more obviously than Xuebijing 50 mL group and routine treatment group (both P < 0.05). Conclusion:The Xuebijing injection can effectively improve the inflammatory markers and prognosis of severe COVID-19 patients.

Objective:To explore the effect of the interval of radical prostatectomy after prostate puncture on the perioperative period and prognosis of patients.Methods:Patient’s data from September 2016 to September 2018 whom performed laparoscopic radical prostatectomy at the Affiliated Hospital of Xuzhou Medical University were collected and retrospectively analyzed. All prostate biopsy confirmed prostate cancer and 66 patients underwent laparoscopic radical prostatectomy. The average age was (70.11 ± 5.01) years, ranged from 60 to 79 years. The patients were divided into two groups according to the interval time from prostate biopsy to laparoscopic radical prostatectomy: <7 d group ( n=32) and 6-8 weeks group ( n= 34). The operation time, intraoperative blood loss, postoperative hospital stays, positive rate of incisional margin, postoperative urinary incontinence rate and the rate of urinary incontinence 6 months after operation, rate of postoperative erectile dysfunction and bone metastasis were compared and analyzed between the two groups. When the data conformed to the normal distribution, the data were expressed in Mean±standard deviation ( Mean± SD), and the independent sample t-test was used to evaluate the statistical significance between groups. When the data did not conform to the normal distribution, the measurement data was expressed as Median (interquartile range) [ M( P25, P75)], and the Mann-Whitney U test was used for the comparison between groups. Count data comparison between groups using Chi-square test or Fisher exact probability method. Unconditional multivariate Logistic regression was used to analyze the relationship between outcome and exposure. Results:All the 66 patients successfully underwent surgery, the surgery success rate was 100%. The average operation time of <7 d group and group 6-8 weeks group was [185.00(174.50, 193.50)] min and [183.00(175.00, 187.50) min], respectively, the difference was not statistically significant ( P=0.685 8, U=512.0). The average intraoperative blood loss of group <7 d group and 6-8 weeks group was [185.50(177.75, 205.25)]ml, [189.00(180.75, 206.00)] ml, respectively, the difference was not statistically significant ( P=0.685 9, U=512.0). The average postoperative hospital stays of <7 d group and 6-8 weeks group was [14.00(11.75, 16.00)] d, [13.50(12.00, 15.00)] d, respectively, the difference was not statistically significant ( P=0.785 7, U=522.5). The positive rate of incisal margin of<7 d group and 6-8 weeks group was 18.75%, 14.71%, respectively, the difference was not statistically significant ( P=0.659 5, χ2=0.194). The postoperative urinary incontinence rate of <7 d group and 6-8 weeks group was 6.25% and 8.82%, respectively, the difference was not statistically significant ( P=1.000 0). The urinary control after follow-up for six months of <7 d group and 6-8 weeks group was 6.25% and 2.94%, respectively, the difference was not statistically significant ( P=0.607 7). The postoperative erectile dysfunction rate of<7 d group and group 6-8 weeks group was 9.38% and 8.82%, respectively, the difference was not statistically significant ( P=1.000 0). The postoperative bone metastasis rate of group<7 d and 6-8 weeks group was 6.25% and 5.88%, respectively, the difference was not statistically significant ( P=1.000 0). Conclusions:Performing laparoscopic radical prostatectomy within 7 days following prostate biopsy did not adversely affect the postoperative outcomes and prognosis, also not increased postoperative complications, can shorten the patient′s treatment cycle.

Objective To explore the correlation between exon region polymorphism of PPP1R3A gene and schizophrenia in Uygur Chinese population. Methods PPP1R3A gene exon region DNA amplification was performed using multiple PCR targeted capture next-generation sequencing method in 528 patients with schizophrenia and 576 healthy controls of Uyghur descent, Illumina HiSeq X Ten was used for sequencing, the symptoms of schizophrenia were assessed by positive and negative symptoms scale (PANSS). Results The allelic and genotypic distributions in rs1800000 of PPP1R3A gene between patients with schizophrenia and healthy controls had significant difference (P＜0.05), rs1799999 in genotype frequency between the female case and control groups showed significant difference (P＜0.05). Furthermore, the allelic distributions of rs8192686 between male cases and controls had significant difference (P＜0.05). Conclusion PPP1R3A gene rs1800000 may be associated with the development of schizophrenia in Uygur Chinese population; rs1799999 may be a risk factor for susceptibility of female Uygur Chinese schizophrenia; The C allele at rs8192686 may be associated with male Uygur Chinese schizophrenia.

Objective To evaluate computed tomography venography (CTV) in diagnosis of iliac vein stenosis or occlusion.Methods From Jun 2015 to Jun 2017,168 CVD patients with CEAP clinically graded at 4 to 6 underwent evaluation with digital subtraction angiography (DSA) CTV and colour Doppler ultrasound.Taking DSA as standard,the diagnostic value of CTV and colour Doppler ultrasound were analyzed and compared.Results DSA established diagnosis of 95 cases,compared with DSA,CTV's and colour Doppler ultrasound's sensitivity,specificity,positive likelihood ratio and negative likelihood ratio was 87.4％ and 64.2％,94.5％ and 98.6％,15.89 and 45.86 and 0.13 and 0.36.Compared with colour Doppler ultrasound,CTV's sensitivity was significantly higher (P ＜ 0.05,the 95 ％ confidence intervals were 0.764-14.257),and there was no significant difference between them in aspect of specificity (P =0.375,the 95％ confidence intervals were 0.943-0.986),Kappa value was 0.809(P ＜0.05,the 95％ confidence intervals were 0.714-0.893),0.597 (P ＜ 0.05,the 95％ confidence intervals were 0.464-0.717).Conclusion In the diagnosis of CVD combined with iliac and femoral venous stenosis,CTV has outstanding sensitivity,specificity,and good conformancy with that of DSA.

Chinese medicine prescription is the main form and means to treat diseases in traditional Chinese medicine (TCM). However, the disjointing situation is generally present between "systemic" and "local", "macro" and "micro", " process" and "activity evaluation" in the study of TCM at present. An urgent task for the modernization of TCM is to establish new strategies and methods which can reflect the overall characteristics of TCM. The introduction of integrative pharmacology provided a feasible approach to solve the problem of the fragmentation of TCM. Internet-based computation platform method was adopted in this study to explore the active molecular mechanism of Yinchenhao decoction in the treatment of cirrhosis. Based on the analysis of the functional integration of Internet-based Computation Platform V1.0 version software, the "core components-key target- main pathway" multidimensional network of Yinchenhao decoction in treatment of cirrhosis disease was constructed to explore the potential molecular mechanism of Yinchenhao decoction in treatment of cirrhosis from multiple perspectives. The molecular mechanism analysis of Yinchenhao decoction showed that Yinchenhao decoction can achieve the therapeutic effect on cirrhosis and the mechanism might be associated with oxidative phosphorylation, energy metabolism, circulatory system, glycerophospholipid metabolis, lipid metabolism and other pathways. Yinchenhao decoction in treatment of cirrhosis may be associated with energy metabolism and lipid metabolism.

At present, the disjointing situation is generally present between "systemic"and "local", "macro" and "micro", " process" and "activity evaluation" in the study of traditional Chinese medicine (TCM). An urgent task for the modernization of TCM is to establish new strategies and methods which can reflect the overall characteristics of TCM. The introduction of integrative pharmacology provided a feasible approach to solve the problem of the fragmentation of TCM. Internet-based computation platform method was adopted in this study to explore the active molecular mechanism of Mylabris in the treatment of colorectal cancer. Based on the analysis of the functional integration of internet-based computation platform V1.0 version software, the "core components-key target- main pathway" multidimensional network of Mylabris in treatment of colorectal cancer disease was constructed to explore the potential molecular mechanism of Mylabris in treatment of colorectal cancer from multiple perspectives. The results showed that Mylabris can treat the colorectal cancer and the mechanism might be associated with amino acid metabolism, NF-κB signaling pathway, immune system, endocrine system, nervous system, and chemokine signal transduction pathway, epithelial cell signaling in helicobacter pylori infection, T cell receptor signaling pathway, B cell receptor signaling pathway and so on.

Objective To evaluate the value of utility of bronchoscopy in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients with Bacteria sputum negative pulmonary tuberculosis.Methods Bronchoscopy was conducted to 65 AIDS patients with bacteria sputum negative pulmonary tuberculosis in the first hospital of Changsha. The patients’ bronchoalveolar lavage fluid through the electronic bronchoscopy, mycobacterium tuberculosis (MTB) culture, brushings and biopsy pathology were analyzed.Results 65 cases, bronchoscope alveolar lavage lfuid smear positive acid-fast stain 14 cases (21.54%), BAL mycobacterium tuberculosis culture positive 20 cases (30.76%), a bronchoscope brush positive 24 cases (36.92%), 35 cases of bronchoscopy biopsy, according to the performance under the bronchoscope positive 21 cases (60.00%), bronchoscopy combined different methods conifrmed 43 cases (66.15%).Conclusions Bronchoscopy in AIDS with bacteria sputum negative pulmonary tuberculosis diagnosis, it has important application value.