Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H₂O₂-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H⁺ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H₂O₂-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

Objective To observe the application effect of transcutaneous acupoint electrical stimulation in the psychological craving and protracted abstinence symptoms of alcohol-dependent patients. Methods A total of 120 male alcohol-dependent patients who completed the acute alcohol withdrawal phase and were hospitalized in the Department of Alcoholism in Hunan Brain Hospital were selected as the study subjects. They were divided into conventional drug group, transcutaneous acupoint electrical stimulation group and placebo group according to different treatment methods, with 40 patients in each group. The conventional drug group was treated with benzodiazepine drugs for replacement and reduction and supportive symptomatic treatment. The transcutaneous acupoint electrical stimulation group was treated with conventional treatment combined with transcutaneous acupoint electrical stimulation. The placebo group was treated with conventional treatment combined with simulated transcutaneous acupoint electrical stimulation. The Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), Alcohol Urge Questionnaire (AUQ), Visual Analogue Scale (VAS), Pittsburgh Sleep Quality Index (PSQI) score and recurrence conditions were compared before and after treatment among the three groups. Results After treatment, the SAS, SDS, AUQ and VAS scores of the three groups were lower than those before treatment, and the above scores of the transcutaneous acupoint electrical stimulation group were lower than those of the conventional drug group and placebo group (P < 0.05). After treatment, the scores of sleep quality, the time to fall asleep, sleep duration, sleep efficiency, sleep disturbance, hypnotic drugs, daytime dysfunction and total PSQI score of the three groups were lower than those before treatment, and the above scores of the transcutaneous acupoint electrical stimulation group were lower than those of the conventional drug group and placebo group (P < 0.05). The recurrence rate of the transcutaneous acupoint electrical stimulation group was lower than that of the conventional drug group and placebo group (P < 0.05). Conclusion Compared with conventional treatment and simulated transcutaneous electrical stimulation, transcutaneous acupoint electrical stimulation is more effective in reducing the severity of protracted abstinence symptoms such as anxiety, depression and insomnia, and is also beneficial in reducing patients' psychological craving, thereby reducing the recurrence rate.

This article elaborates how to facilitate the cultivation reform of medical graduate innovation ability from four perspectives: graduates, colleges or universities, supervisors and the society. Graduates should focus on studying high-quality academic papers, participate in various academic competitions, and actively apply for research projects; universities should innovate education philosophy, optimize curriculum system, create innovation-stimulating cultural atmosphere, establish quality supervision mechanism; supervisors should set a good example for their students, maintain a harmonious relationship with students, take the responsibility of fostering virtue though education and organize excellent supervisor team; and the society should support universities to realize "industry-education collaboration".

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd

ObjectiveTo analyze the mental health status and the influencing factors among the residents taking standardized residency training during the outbreak and stable period of COVID-19， so as to provide theoretical basis for their mental health education. MethodsOn February 8 to February 10 and April 11 to April 13， 2020， Symptom Checklist 90 （SCL-90）， Beck Srivastava Stress Inventory （BSSI） and Simplified Coping Style Questionnaire （SCSQ） were distributed in online chat groups involving all grades of residents taking standardized residency training in the Second Affiliated Hospital of Kunming Medical University. Through two rounds of questionnaire survey， non-probability sampling method was used to obtain survey samples， and their mental status were analyzed. ResultsA total of 159 valid questionnaires were collected in the first round， and 99 valid questionnaires in the second round. The first survey showed that the total score of SCL-90 was （117.69±37.74） and the detection rate of positive symptoms in SCL-90 was 25.8%， and mainly dominated by obsession， fear and interpersonal sensitivity. In the second survey， the results showed that the total score of SCL-90 was （127.19±51.44）， and the main positive symptoms included obsession， depression and interpersonal sensitivity， with a positive detection rate of 30.3 %. The first survey found that the mental health status had significant differences among residents of different grades （χ²=7.46， P<0.05）， furthermore， the results indicated that lower grade was a risk factor while non-singleton was the protective factor of mental health status （P<0.05）， and SCL-90 total score was positively correlated with score of negative coping styles （r=0.45， P<0.01）. The second survey also classified lower grade as risk factor and non-singleton as protective factor （P<0.05）， and SCL-90 total score was positively correlated with study stress， economic pressure， interpersonal relationship， clinical practice and negative coping styles （r=0.52， 0.46， 0.55， 0.54， P<0.05 or 0.01）. ConclusionResidents under standardized residency training have obvious mental health problems during the outbreak of COVID-19， and the problems become more serious during the stable period of COVID-19.

Objective To study the effect of pirfenidone (PFD) on the transformation of rat corneal stromal cells into fibroblasts in vitro and further explore the anti-fibrotic effect of PFD. Methods The corneal stromal cells from SD rat was isolated and cultured ,and was determined by vimentin stain. The experiment was divided into control group(DMEM+10%FBS),TGF-β1 group(2 ng/mL TGF-β1+DMEM+10%FBS)and PFD group(1 mg/mL PFD+ 2 ng/mL TGF-β1+DMEM+ 10%FBS). Cell proliferation was detected by CCK-8 assay. Collagen Ⅰ,Collagen Ⅲ,Keratocan and CD99 expression were detected by Western blot. Results Compared with control group and TGF-β1 group,the cell proliferation were significantly decreased in PFD group(P<0.05). Western blot showed that PFD can up-regulated Collagen Ⅰand Keratocan but down-regulated Collagen ⅢCD90 expression(P < 0.05). The ratio of Collagen Ⅲ/Collagen Ⅰ in PFD group was lowest in all groups(P < 0.05). Conclusion PFD can resistant fibration in corneal stromal cells may through the inhibition of TGF-β ,which affect the collagen synthesis and Keratocan,CD90 expression.

Objective To explore the prevalence of depressive disorder in the Mosuo ethnic minority in Ninglang district,Yunnan Province.Methods By stratified random sampling,1 121 Mosuo subjects aged 15 or above were selected and assessed by the MINI-international neuropsychiatric interview according to the Structured Clinical Interview for DSM-V-TR Axis I Disorders-Patient Edition for mental disorders.Results The standardized time-point prevalence of major depressive disorder in Mosuo nationality was 1.74％,and 1.69％ (95 ％ CI =1.32％-2.15 ％) in males and 1.77％ (95 ％ CI =1.39％-2.15 ％) in females.There was no statistically significant difference in the prevalence of major depressive disorder between males and females (x2 =0.051,P＞0.05).The standardized time-point prevalence of dysthymic disorder in Mosuo nationality was 0.78％,and 0.66％ (95％ CI=0.54％-0.78％) in males and 0.88％ (95％ CI=0.74％-1.02％) in females (x2=1.232,P＞0.05).Those aged 40-54 years old had the highest adjusted prevalence of depressive episodes(1.48％ (95％CI=0.77％-2.18％)).Conclusion The prevalence of depressive disorder in Mosuo nationality is in a low level,and the middle-age Mosuo people has the highest time-point prevalence.

Objective To investigate the relationship between the catechol-O-methyl transferase (COMT) gene polymorphism and the clinical efficacy and cognitive function of risperidone in the treatment of schizophrenia.Methods 105 cases of Han Chinese patients with schizophrenia who were treated with risperidone for 12 weeks and healthy controls of 168 cases were collected.The effect of the drug therapy with the PANSS,digit vigilance test,Raven Standard Progressive Matrices,forward and backward subtests of the digit span test were evaluated,and then the rs 165599,rs4680,rs6267,rs737865 loci in COMT gene were detected.Results (1)rs737865 was not the polymorphic locus in this sample.(2) There was statistically significant between schizophrenia patients and controls in the distribution of allele frequency and genotype frequency in rs4680 (x2=8.16,P=0.02).Haplotype GA in rs165599-rs4680 was statistically significant in schizophrenia patients and controls (x2 =4.35,P =0.04).(3) After treatment,the total score ((47.64±5.75) points),subscale scores (positive symptoms (11.66±2.90) points,negative symptoms (13.79±3.18)points,general psychotic symptoms (22.09±3.59) points) and scores of five factors model in PANSS decreased and the difference was significant (P＜0.05);the scores of digital cancellation test increased significantly compared with those before treatment(t value respectively were 12.34,10.17,4.34,all P＜0.05);the scores of forward and backward subtests of the digit span test were significantly increased compared with those before treatment (t=-5.57,P=0.00) and Raven standard reasoning test scores had increased significant (t=-19.05,P=0.00).(4) The difference of instantaneous memory score changes among rs 165599 genotypes was statistically significant after treatment (F=4.06,P=0.02).(5) The difference of negative syndromes of PANSS among rs 165599 genotypes was statistically significant after treatment (F=3.11,P=0.049).(6) The difference of negative symptoms (F=4.64,P=0.01),cognitive impairment (F=3.21,P =0.045) and instantaneous memory (F=4.86,P=0.03) among rs 6267 genotype were statistically significant after treatment.Condusion Risperidone can effectively improve the psychotic symptoms of schizophrenia patients,and promote the recovery of cognitive function.Rs165599-rs4680 haplotype GA might be risk factor for the onset of schizophrenia.

Objective To explore the effect of heme oxygenase-1 (HO-1) on expressions of hypoxia inducing factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF)and regeneration of hepatic vascular plexus after orthotopic liver transplantation ischemia-reperfusion injury in rats.Methods Theexperimental study was conducted.According to the random number table,240 SD rats were divided into the 3 groups,80 rats in each group.Empty virus group:rats were transfected with the empty virus.Induced group:rats were transfected with HO-1 overexpression adenovirus.Inhibited group:rats were transfected with HO-1 RNAi adenovirus.Rats were made pairs (1 ∶ 1) and established rat liver transplantation model according to two cuffs method.Rats with less weight and with heavier weight were respectively chosen as donor rats and recipient rats,and then recieved tail intravenous injection of adenovirus at 24 hours before operation.(1) Detection of transfection efficiency of adenovirus before operation:HO-1 expression of liver tissue of rats in each group was detected by Western blot at 12 and 24 hours after injection of adenovirus.(2) Liver function test of recipient rats after liver transplantation:liver functions of recipient rats [alanine transaminase (ALT),aspartate transaminase (AST),alkaline phosphatase (ALP),gamma-glutamyl transferase (GGT)] were detected at l,3,7 and 14 days postoperatively.(3) Pathological histology of liver tissue and injury scores of recipient rats in the 3 groups after liver transplantation:paraffin sections of recipient rats in the 3 groups at postoperative 1 and 14 days were stained by HE staining and observed by light microscope,and were evaluated by Suzuki damage score standard.(4) Relative expressions of HIF-1α,VEGF and HO-1 in liver tissue of recipient rats were detected by Western blot.(5) Von Willebrand factor (vWF) in liver tissue of recipient rats at 14 days postoperatively was detected by immunofluorescence staining and small vessels were counted.Measurement data with normal distribution were represented as x ±s.Comparison between groups was analyzed by the independent-sample t test,comparison among groups was done using one-way ANOVA,and pairwise comparison was analyzed by the LSD test.Results (1) Detection of transfection efficiency of adenovirus before operation:the relative expression of HO-1 of liver tissue of rats at 12 and 24 hours preoperatively after injection of adenovirus was 1.08±0.16 and 1.08±0.26 in the empty virus group,1.18±0.21 and 1.39±0.19 in the induced group,0.87±0.26 and 0.57±0.12 in the inhibited group,respectively,with statistically significant differences in different time points (F =4.232,36.513,P＜ 0.05).(2) Liver function test of recipient rats after liver transplantation:level of ALT at 3 days postoperatively in the empty virus group,induced group and inhibited group was (504±67)U/L,(438±47)U/L and (490±39)U/L,with a statistically significant difference (F=3.517,P＜0.05).Levels of ALT,AST and ALP at 7 days posto-peratively were (443±49) U/L,(430± 34) U/L,(455± 38) U/L in the empty virus group and (382± 49) U/L,(372±50) U/L,(394±25) U/L in the induced group and (493±44) U/L,(455±62) U/L,(470±72) U/L in the inhibited group,respectively,with statistically significant differences (F =10.950,5.667,5.398,P＜0.05).Levels of ALT,AST,ALP and GGT at 14 days postoperatively were (394±46)U/L,(361 ±68)U/L,(417 ±17)U/L,(4.5±1.1)U/L in the empty virus group and (283±47) U/L,(288±60) U/L,(332±46) U/L,(2.5±0.5) U/L in the induced group and (446± 43) U/L,(422± 51) U/L,(423± 63) U/L,(4.3 ± 1.3) U/L in the inhibited group,respectively,with statistically significant differences (F=26.906,9.924,8.013,9.279,P＜ 0.05).(3) Pathological histology of liver tissue and injury scores of recipient rats in the 3 groups after liver transplantation:liver cell swelling,loose cytoplasm and a varying quantity of inflammatory cell infiltration in the portal regions in the liver tissue of 3 groups were observed at 1 day postoperatively.A few inflammatory cell infiltrations in the portal regions,basically normal liver cell arrangement and a slightly swelling of liver cell were found in the empty virus group at 14 days postoperatively.Reduced liver cell swelling and basically normal structure of liver lobule were observed in the induced group.There were small patchy or focal necrosis of liver cell,masses of inflammatory cell infiltration in the portal regions and damage of bile duct in the inhibited group.Suzuki score at 1 day postoperatively in the empty virus group,induced group and inhibited group were respectively 6.7± 1.7,6.1 ± 1.2 and 7.6± 1.3,with no statistically significant difference (F=2.257,P＞0.05).Suzuki score at 14day postoperatively in the empty virus group,induced group and inhibited group were respectively 4.0±0.8,2.9± 0.8 and 5.1± 1.4,with a statistically significant difference (F=9.776,P＜0.05).(4) Western blot results:the relative expressions of HIF-1α and VEGF (43 KD) in liver tissue of recipient rats at 1 day postoperatively were 0.21±0.10,0.30±0.12 in the empty virus group and 0.23±0.09,0.34±0.14 in the induced group and 0.17± 0.06,0.29±0.11 in the inhibited group,respectively,with no statistically significant difference (F =0.902,0.410,P＞0.05).The relative expressions of VEGF (24 KD) and HO-1 in liver tissue of recipient rats at 1 day postoperatively were 1.21 ±0.25,0.55±0.12 in the empty virus group and 2.13±0.40,0.72±0.12 in the induced group and 0.91±0.22,0.26±0.07 in the inhibited group,respectively,with statistically significant differences (F=35.158,39.082,P ＜ 0.05).The relative expressions of HIF-1α,VEGF (43 KD),VEGF (24 KD) and HO-1 in liver tissue of recipient rats at 7 days postoperatively were 0.49±0.22,0.46±0.13,0.98± 0.37,0.98±0.37 in the empty virus group and 0.83±0.26,0.63±0.19,1.60±0.33,1.49±0.46 in the induced group and 0.24±0.09,0.30±0.12,0.64±0.18,0.75±0.26 in the inhibited group,respectively,with statistically significant differences (F=16.853,10.021,20.756,8.156,P＜0.05).(5) Immunofluorescence staining results:number of small vessels at 14 days postoperatively in the empty virus group,induced group and inhibited group was respectively 7.9±2.0,10.6± 1.9 and 7.6 ± 1.9,with a statistically significant difference (F=5.921,P＜0.05).Conclusion HO-1 could promote expressions of HIF-1α and VEGF in liver tissue after liver transplantation ischemia-reperfusion injury and regeneration of intrahepatic vascular plexus,and it also alleviate bile duct ischemia-reperfusion injury after liver transplantation.

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