Bacterial therapy has attracted increasing attention due to its special mechanism and abundant applications. With the flourishing development of synthetic biology, therapeutic genes have been introduced into engineering bacteria to improve their antitumor efficacy. However, it is difficult to spatiotemporally control the expression of these therapeutic genes at the tumor site in vivo, thereby considerably limiting the application of engineered bacteria in tumor treatment. To resolve this problem, we constructed a temperature-responsive bacterial strain capable of triggering the expression of exogenous genes in a laser-controllable way. Noxa, a pro-apoptotic protein, is chosen to test the expression of exogenous protein and its anti-tumor effect in engineered bacteria upon laser irradiation. Firstly, Noxa was fused to the C-terminus of the bacterial outer membrane protein cytolysin A (ClyA), and then the recombinant gene fragment ClyA-Noxa was inserted into the temperature-sensitive plasmid pBV220 and the recombinant plasmid was transformed into non-pathogenic Escherichia coli MG1655. Thus, we constructed the engineering strain (TRB@Noxa) that could express Noxa on the bacterial surface. TRB@Noxa could target and colonize the tumor tissue without causing notable host toxicity. The bacterial infection triggered thrombosis in the tumor tissue, resulting in the darkness of tumor sites. In a xenograft mouse tumor model, our strategy demonstrated precise tumor targeting and strong tumor inhibition. In conclusion, we successfully constructed a new engineering bacterial strain TRB@Noxa. TRB@Noxa combined with photothermal therapy could arrest tumor growth in the absence of photosensitizers, which represents an appealing method for antitumor therapy in the future.
Escherichia coli/radiation effects* ; Animals ; Humans ; Lasers ; Mice ; Proto-Oncogene Proteins c-bcl-2/biosynthesis* ; Neoplasms/therapy* ; Genetic Engineering ; Cell Line, Tumor ; Escherichia coli Proteins/genetics*

Objective·To systematically review the effectiveness of actigraphy on the evaluation of circadian rhythm characteristics in patients with depression.Methods·A systematic literature search was conducted in PubMed,Embase,Web of Science,Cochrane Library,PsycINFO,CNKI,WanFang Data,and Chinese biomedical literature database(CBM),from the inception of each database to May 5th,2023.Case control studies that used actigraphy to evaluate circadian rhythms in patients with depression and compared them with healthy controls were collected.Literature was screened according to the inclusion and exclusion criteria,and the quality of the included literature was evaluated by using the Newcastle-Ottawa Scale.The meta-analysis was performed by using RevMan 5.4 software.Results·A total of 9 articles were included,including 390 patients with depression and 288 healthy controls.The meta-analysis showed that the MESOR(midline statistic of rhythm)(SMD=-0.29,95%CI-0.51 ?-0.07,P=0.009)of the circadian cosine function in patients with depression was lower than that in healthy controls;sleep onset(MD=33.06,95%CI 14.90 ? 51.23,P=0.000)and sleep offset(MD=53.80,95%CI 22.38 ? 85.23,P=0.000)were later in patients with depression than those in healthy controls;no statistical difference was found in the activity level of the most active 10 hours(SMD=-0.26,95%CI-0.52 ? 0.01,P=0.060)between patients with depression and healthy controls,although there was a trend for lower activity in patients with depression;no statistical difference was found in the acrophase(MD=25.33,95%CI-12.41 ? 63.06,P=0.190)of the circadian cosine function between patients with depression and healthy controls;no clear statistical significance of the difference was found in the amplitude(SMD=-0.14,95%CI-0.42 ? 0.14,P=0.340)and the activity level of the least active 5 hours(SMD=0.31,95%CI-0.10 ? 0.71,P=0.140)between patients with depression and healthy controls.Conclusion·Actigraphy can reflect circadian rhythm disruption in patients with depression to some extent,but the limited number of included studies and inconsistencies in the study populations and methodologies have affected the quality and results of the analyses.More high-quality clinical trials are needed to provide evidence.

Objective:To investigate the efficacy of tibiofibular-based reconstruction technique with single femoral tunnel for Fanelli type C posterolateral complex (PLC) injury.Methods:A retrospective case series study was conducted to analyze the clinical data of 16 patients with Fanelli type C PLC injury admitted to Tianjin Hospital from July 2016 to July 2019, including 10 males and 6 females, aged 20-61 years [(36.5±13.9)years]. PLC reconstruction was performed by tibiofibular-based technique with single femoral tunnel using gracilis tendon and semi-tendinosus autografts. If the posterior and anterior cruciate ligaments (PCL/ACL) rupture were combined, arthroscopic single bundle reconstruction was performed simultaneously. If the posteromedial corner (PMC) injury was combined, PMC repair or reconstruction surgery was performed simultaneously. Operation time and intraoperative blood loss were recorded. When the bone needle and tunnel for PLC were drilled during the operation, the interference of the femoral tunnel through the cruciate ligament was observed under the arthroscope. Before and at 6 and 12 months after operation, the varus stability of the knee joint was evaluated with the difference of lateral joint space width of both knees and the International Knee Documentation Committee (IKDC) objective classification of varus stability of the knee joint; the external rotation stability was evaluated with the difference of external rotation angle of both knees and the IKDC objective classification of external rotation stability of the knee joint. Before, at 6 and 12 months after operation and at the last follow-up, IKDC 2000 subjective score and Lysholm score were compared. The occurrence of complications was observed.Results:All the patients were followed up for 12-36 months [24(15, 33)months]. The operation time was 100-220 minutes [175.0(111.3, 200.0)minutes], with intraoperative blood loss of 30-150 ml [(84.3±36.5)ml]. Intraoperative arthroscopy showed no interference of perforation between PLC and cruciate ligament femoral tunnel. The differences of lateral joint space width of both knees at 6 and 12 months after operation were 0.5(0.2, 1.4)mm and 0.6(0.2, 1.5)mm respectively, which were both significantly improved compared with 12.1(10.8, 12.6)mm before operation ( P<0.05), while there was no significant difference at 6 and 12 months after operation ( P>0.05). The IKDC objective classification of varus stability of the knee joint was grade A in 13 patients, grade B in two and grade C in one at 6 or 12 months after operation, and showed statistical difference from grade D in all the patients before operation ( P<0.01). At 6 and 12 months after operation, the difference of external rotation angle of both knees was -2.0(-3.2, 1.3)° and -1.4(-3.0, 1.7)° respectively, which were significantly improved compared with 16.8(13.9, 18.4)° before operation ( P<0.05), while there was no significant difference at 6 and 12 months after operation ( P>0.05). IKDC objective classification of external rotation stability of the knee joint was grade A in 14 patients, grade B in one and grade C in one at 6 or 12 months after operation, and showed statistical difference from grade C in 14 patients and grade D in 2 before operation ( P<0.01). At 6 and 12 months after operation and at the last follow-up, the IKDC 2000 subjective scores [(76.3±4.7)points, (80.3±4.4)points, (79.9±3.8)points respectively] and the Lysholm scores [(76.1±3.9)points, (81.1±4.3)points, (82.8±3.2)points respectively] were significantly improved compared with those before operation [(48.6±3.7)points and (52.6±2.4)points] ( P<0.05). The IKDC 2000 subjective scores and Lysholm scores were significantly improved at 12 months after operation and at the last follow-up than those at 6 months after operation ( P<0.05). There were no significant differences in the IKDC 2000 subjective scores and Lysholm scores at 12 months after operation and at the last follow-up ( P>0.05). There were no complications such as wound infection, vascular and nerve injury, joint stiffness or ectopic ossification. Conclusion:For Fanelli type C PLC injury, tibiofibular-based reconstruction technique with single femoral tunnel reduces the interference between the lateral femoral tunnels, significantly improves the varus and external rotation stability and the function of the knee joint, and has few complications and satisfactory short-term clinical efficacy.

Objective To evaluate the efficacy of Huachansu tablets combined with transarterial chemoembolization(TACE)for treatment of primary hepatocellular carcinoma(HCC)and prognostic influence factors.Methods One hundred and eight patients with HCC were recruited according to the inclusion and exclusion criteria.Patients were randomly divided into treatment group and control group.The treatment group was treated with Huachansu tablets combined with TACE,and the control group was treated with TACE alone,with overall survival time(OS)and progression-free survival time(PFS)as the evaluation indexes.The COX regression analysis was used to evaluate the survival and prognostic effects and their influence factors in both groups.Results A total of 108 HCC patients were enrolled.The OS was 13.5 months in treatment group and 9.2 months in control group;the PFS was 6.8 months in treatment group and 5.3 months in control group,and the differences were significant statistically(all P<0.05).Multivariate COX regression analysis showed that Child-Pugh grade and cirrhosis were the independent risk factors for PFS in HCC patients.Child-Pugh grade were the independent risk factors for OS in HCC patients.ALBI is a protective factor for OS in HCC patients.Conclusions The treatment of HCC by Huachansu tablets combined with TACE can delay the progression of HCC and prolong PFS and OS of the patients with HCC.Child-Pugh grade,cirrhosis status,and ALBI were important factors affecting the prognosis of the patients with HCC.

The structures and activities of enzymes are influenced by pH of the environment. Understanding and distinguishing the adaptation mechanisms of enzymes to extreme pH values is of great significance for elucidating the molecular mechanisms and promoting the industrial applications of enzymes. In this study, the ESM-2 protein language model was used to encode the secreted microbial proteins with the optimal performance above pH 9 and below pH 5, which yielded 47 725 high-pH protein sequences and 66 079 low-pH protein sequences, respectively. A deep learning model was constructed to identify protein acid-base tolerance based on amino acid sequences. The model showcased significantly higher accuracy than other methods, with the overall accuracy of 94.8%, precision of 91.8%, and a recall rate of 93.4% on the test set. Furthermore, we built a website (https://enzymepred.biodesign.ac.cn), which enabled users to predict the acid-base tolerance by submitting the protein sequences of enzymes. This study has accelerated the application of enzymes in various fields, including biotechnology, pharmaceuticals, and chemicals. It provides a powerful tool for the rapid screening and optimization of industrial enzymes.
Deep Learning ; Hydrogen-Ion Concentration ; Amino Acid Sequence ; Enzymes/metabolism* ; Sequence Analysis, Protein ; Proteins/metabolism* ; Bacterial Proteins/metabolism*

OBJECTIVE: To summarize the clinical features, surgical methods, and prognosis of bucket-handle meniscal tears (BHMTs), and provide guidance for clinical treatment. METHODS: The clinical data of 91 BHMTs patients (91 knees), who met the selection criteria and were admitted between January 2015 and January 2021, was retrospectively analyzed. There were 68 males and 23 females. Age ranged from 16 to 58 years with an average of 34.4 years. The injury was caused by sports in 68 cases, traffic accident in 15 cases, and falls or sprains in 8 cases. There were 49 cases of left knee injury and 42 cases of right knee injury. The time from the onset of symptoms to the admission ranged from 1 day to 13 months (median, 18 days), including >1 month in 35 cases and ≤1 month in 56 cases. Medial BHMTs occurred in 52 cases and lateral BHMTs in 39 cases. There were 36 cases with ACL rupture and 12 cases with discoid meniscus. The knee extension was limited more than 10° in 55 cases. According to the condition of meniscus injury, the meniscus suture with Inside-out combined with All-inside techniques (54 cases) or meniscoplasty (37 cases) under arthroscopy were selected. ACL reconstruction was performed in all patients with ACL rupture with autogenous hamstring tendon. Postoperative complications were observed. International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner score were used to evaluate knee function, and clinical failure was recorded. RESULTS: Two patients developed intermuscular venous thrombosis, which improved after oral anticoagulant therapy. No vascular injury, postoperative infection, joint stiffness, or other complications occurred in all patients. All patients were followed up 24-95 months, with a median of 64 months. A total of 12 cases (13.19%) failed the operation and were re-operated or given oral anti-inflammatory analgesics and rehabilitation therapy. At last follow-up, IKDC score and Lysholm score of 91 patients significantly increased when compared with those before operation ( P<0.05), while Tegner score significantly decreased ( P<0.05). The above indexes of patients treated with meniscus suture and meniscoplasty were also significantly different from those before operation ( P<0.05). CONCLUSION BHMTs occurs mostly in young men and is one of the important reasons for the limitation of knee extension after trauma. Arthroscopic meniscus suture and meniscoplasty can obtain good effectiveness according to individual conditions of patients. But the latter can better preserve the shape and function of meniscus, and theoretically can obtain better long-term outcomes, which needs to be confirmed by further research with larger sample size.
Male ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Treatment Outcome ; Retrospective Studies ; Meniscus ; Knee Joint/surgery* ; Menisci, Tibial/surgery* ; Knee Injuries/diagnosis* ; Rupture ; Tibial Meniscus Injuries/surgery* ; Arthroscopy/methods* ; Anterior Cruciate Ligament Injuries/surgery*

Migraine is one of the most prevalent and disabling neurological disease, but the current pharmacotherapies show limited efficacy and often accompanied by adverse effects. Acupuncture is a promising complementary therapy, but further clinical evidence is needed. The influence of acupuncture on migraine is not an immediate effect, and its mechanism remains unclear. This study aims to provide further clinical evidence for the anti-migraine effects of acupuncture and explore the mechanism involved. A randomized controlled trial was performed among 10 normal controls and 38 migraineurs. The migraineurs were divided into blank control, sham acupuncture, and acupuncture groups. Patients were subjected to two courses of treatment, and each treatment lasted for 5 days, with an interval of 1 day between the two courses. The effectiveness of treatment was evaluated using pain questionnaire. The functional magnetic resonance imaging (fMRI) data were analyzed for investigating brain changes induced by treatments. Blood plasma was collected for metabolomics and proteomics studies. Correlation and mediation analyses were performed to investigate the interaction between clinical, fMRI and omics changes. Results showed that acupuncture effectively relieved migraine symptoms in a way different from sham acupuncture in terms of curative effect, affected brain regions, and signaling pathways. The anti-migraine mechanism involves a complex network related to the regulation of the response to hypoxic stress, reversal of brain energy imbalance, and regulation of inflammation. The brain regions of migraineurs affected by acupuncture include the lingual gyrus, default mode network, and cerebellum. The effect of acupuncture on patients' metabolites/proteins may precede that of the brain.
Humans ; Migraine Disorders/etiology* ; Brain/diagnostic imaging* ; Acupuncture Therapy/methods* ; Magnetic Resonance Imaging

Objective:To investigate the effect of medial open wedge high tibial osteotomy (HTO) on moderate and severe medial compartmental knee osteoarthritis.Methods:This study retrospectively reviewed patients treated with medial open wedge HTO between January 2017 and January 2019. All cases were followed up for more than 2 years. There were 28 patients with severe osteoarthritis, including 11 males and 17 females, aged 56.36±5.06 years. There were 32 patients with moderate osteoarthritis, including 12 males and 20 females, aged 54.16±6.3 years. Kellgren-Lawrence (K-L) grading, hip-knee-ankle angle (HKA), weight bearing line (WBL) ratio, joint line convergence angle (JLCA), medial joint space (MJS), posterior tibial slope (PTS), medial meniscus extrusion (MME) and medial meniscus extrusion ratio (MMER) were evaluated on radiographs before and 2 years after surgery. The International Cartilage Repair Society (ICRS) of the cartilage of medial femoral condyle (MFC) and medial tibial condyle (MTC) were evaluated under arthroscopy. The clinical outcomes were assessed by the Western Ontario and McMaster University (WOMAC) score, visual analogue scale (VAS) and the degree of medial collateral ligament (MCL) pseudo-relaxation. Predictors of MCL pseudo-relaxation were screened by binary logistic regression analysis.Results:K-L grading, HKA, WBL ratio and MJS improved in both groups after surgery, with no statistical significance between groups ( P>0.05). The postoperative JLCA was improved, whereas MME and MMER were not. And the severe group was higher than the moderate group before and after surgery ( P<0.05). Cartilage of MFC: in the severe group, 2 cases of ICRS 3 grade, 26 of 4 grade improved to 11 of 2 grade, 12 of 3 grade, 5 of 4 grade; in the moderate group, 12 cases of ICRS 2 grade, 18 of 3 grade, 2 of 4 grade improved to 30 of 2 grade, 2 of 3 grade. Cartilage of MTC: in the severe group, 2 cases of ICRS 3 grade, 26 of 4 grade improved to 17 of 2 grade, 8 of 3 grade, 3 of 4 grade; in the moderate group, 11 of 2 grade, 8 of 3 grade, 3 of 4 grade improved to 27 of 2 grade, 5 of 3 grade. The postoperative WOMAC score of the severe group improved from 50.71±8.07 to 3.86±1.84, while in the moderate group it improved from 44.09±6.63 to 3.34±2.24. The postoperative VAS score of the severe group decreased from 7.14±1.21 to 3.34±2.24, whereas it decreased from 6.38±1.24 to 0.44±0.62 in the moderate group ( P<0.05). There was no significant difference between the postoperative groups ( P>0.05). In the severe group, the degree of pseudo-relaxation of the MCL improved from preoperative 25 of I degree, 3 of II degree to postoperative 28 of 0 degree at the 0° position, and from 25 of I degree, 3 of II degree to 24 of 0 degree, 4 of I degree at 30° position ( P<0.05). In the moderate group, the degree of pseudo-relaxation of the MCL improved from preoperative 31 of 0 degree, 1 of I degree to postoperative 32 of 0 degree at the 0° position, and from 28 of 0 degree, 4 of I degree to 32 of 0 degree at the 30° position ( P<0.05). JLCA ( OR=0.08, 95% CI: 0.007, 0.948, P=0.045), MME ( OR=0.11, 95% CI: 0.100, 1.32, P=0.082) and MMER ( OR=0.66, 95% CI: 0.422, 1.030, P=0.067) were independent predictors of MCL pseudo-relaxation (the difference was statistically significant at P<0.10). Conclusion:Medial open wedge HTO has significant short-term clinical effect on the treatment of moderate and severe medial compartmental knee osteoarthritis, which can effectively relieve pain symptoms, improve joint function, and restore medial knee stability. Preoperative large JLCA, MME and MMER indicate pseudo-relaxation of the MCL.

Objective To systematically evaluate the relation between prognostic nutrition index (PNI) and prognosis of bladder cancer (BC) patients treated with radical cystectomy (RC). Methods We searched the literatures about the relation between PNI and the prognosis of patients treated with radical cystectomy published from the inception to January 30, 2021 in PubMed, Embase, Web of Science, CNKI, Wanfang, VIP and Chinese Medical Journal Database, and used RevMan5.3 software for Meta analysis. Results We included six literatures which comprise a total of 1273 patients. The results showed that there was a significant correlation between low PNI and OS of BC patients treated with RC (HR=2.0, 95%CI: 1.56-2.56), and there was a significant difference in RFS, PFS and DSS between low PNI and BC patients treated with RC (HR=1.93, 95%CI: 1.51-2.48). In the subgroup analysis, there were statistical differences in PNI and the prognosis of BC patients treated with RC between the Chinese group (HR=2.13, 95%CI: 1.62-2.81) and the Japanese group (HR=1.78, 95%CI: 1.08-2.94), and the PNI cutoff value had a good predictive effect on the prognosis of patients in the range of 46.08-51.30. Conclusion There is a significant relation between the level of PNI and OS of bladder cancer patients treated with radical cystectomy. Low PNI can be used as an effective marker to predict the prognosis of patients.

Objective:To investigate the relationship between blood glucose fluctuation and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes mellitus (T2DM) and the predictive value of betatrophin.Methods:A total of 180 newly diagnosed T2DM patients in Taiyuan Central Hospital from June 2018 to December 2019 were included for the study. And they were divided into normal intima-media group (81 cases), intima-media thickening group (60 cases) and plaque formation group (39 cases) according to the results of carotid ultrasound. The body test indexes, glucose and lipid metabolism indexes, blood glucose fluctuation and betatrophin level were compared among the three groups, and the correlation of these indexes with CIMT and risk factors of CIMT were analyzed.Results:The mean and maximal amplitude of glycemic excursions (AGE) in the plaque formation group and intima-media thickening group were significantly higher than those in the normal intima-media group [(5.08±0.62), (4.06±0.54) vs (3.17±0.41) mmol/L and (5.20±0.72), (4.26±0.54) vs (3.34±0.59) mmol/L] (all P<0.05), and these indexes in the plaque formation group were significantly higher than the intima-media thickening group (all P<0.05). Betatrophin levels in intima-media thickening group and plaque formation group were significantly higher than those in normal intima-media group [(423.35±76.24) and (490.68±97.84) vs (358.29±92.27) ng/L] (both P<0.05). Hip circumference and triglyceride (TG) in plaque formation group were obviously higher than those of the normal intima-media group and intima-media thickening group [(103.5±6.3) vs (97.6±7.0), (99.5±7.4) cm and 2.99 (1.32, 3.92) vs 1.70 (1.21, 2.39), 1.84(1.43, 2.93) mmol/L] (all P<0.05), and waist circumference, systolic blood pressure, fasting blood glucose (FBG), total cholesterol (TC), insulin resistance of homeostasis model assessment (HOMA-IR) levels in plaque formation group were significantly higher than those in normal intima-media group [(94.0 (86.0, 102.0) vs 88.0 (82.5, 94.0) cm, (136.2±18.0) vs (125.9±15.3) mmHg, 10.16 (8.43, 13.23) vs 8.49 (6.98, 9.97) mmol/L, (6.31±0.90) vs (4.99±0.99) mmol/L, 4.90 (3.50, 7.13) vs 2.77 (1.32, 5.07)] (all P<0.05). CIMT was positively correlated with waist circumference, hip circumference, systolic blood pressure (SBP), FBG, TC, TG, HOMA-IR, betatrophin, the mean and maximal AGE, blood glucose fluctuation coefficient (BGFC) (all P<0.05), and it was negatively correlated with time in range (TIR) ( P<0.05). The mean and maximal AGE, TC, TG and betatrophin were independent risk factors of CIMT (all P<0.05). Conclusion:Blood glucose fluctuation is closely related to CIMT in patients with T2DM, and betatrophin is expected to be an early predictor of diabetic macroangiopathy.