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Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
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@#Objective To investigate the effectiveness and safety of totally endoscopic transmitral myectomy (TETM) for hypertrophic obstructive cardiomyopathy (HOCM), comparing with traditional sternotomy modified Morrow procedure (SMMP). Methods Thirty-eight patients with HOCM who needed surgical intervention were selected from our hospital in 2019, including 14 males and 24 females, with an average age of 56 (44-68) years. According to the operation method, they were divided into a TETM group (n=18) and a SMMP group (n=20). Appropriate patients were screened by propensity matching scores. Finally, the clinical data of two matched groups were compared and
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Monitoring neuronal activity in vivo is critical to understanding the physiological or pathological functions of the brain. Two-photon Ca imaging in vivo using a cranial window and specific neuronal labeling enables real-time, in situ, and long-term imaging of the living brain. Here, we constructed a recombinant rabies virus containing the Ca indicator GCaMP6s along with the fluorescent protein DsRed2 as a baseline reference to ensure GCaMP6s signal reliability. This functional tracer was applied to retrogradely label specific V1-thalamus circuits and detect spontaneous Ca activity in the dendrites of V1 corticothalamic neurons by in vivo two-photon Ca imaging. Notably, we were able to record single-spine spontaneous Ca activity in specific circuits. Distinct spontaneous Ca dynamics in dendrites of V1 corticothalamic neurons were found for different V1-thalamus circuits. Our method can be applied to monitor Ca dynamics in specific input circuits in vivo, and contribute to functional studies of defined neural circuits and the dissection of functional circuit connections.
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Objective:To explore the early surgical outcomes of Thoracoscopic Transmitral Myectomy(TTM) on patients with hypertrophic obstructive cardiomyopathy(HOCM).Methods:Preoperative echocardiography and cardiac magnetic resonance were used to evaluate the patient's hypertrophy extent, mitral valve morphology and function. Myocardial resection was performed via the trans-mitral approach under total thoracoscopy, and the surgical methods and early results were analyzed.Results:From April 2019 to October 2019, a total of 15 cases of TTM were performed by a single surgeon in our ward. Preoperative imaging evaluation revealed that 6 patients(40.0%) had predominantly hypertrophic basal septum while another 9 patients(60.0%) had concomitant midventricular septal hypertrophy. Two(13.3%) patients were interrogated ruptured posterior mitral chord by preoperative echocardiogram. After myocardial resection, the mitral valve was treated as follows: 11 patients(73.3%) underwent anterior leaflet enlargement, and 3(20.0%) were directly reattached to mitral valve annulus, and 1(6.7%) underwent bioprosthetic mitral replacement. There was no case of perioperative death, ventricular septal perforation, residual left ventricular outflow tract obstruction and complete atrioventricular block. Median aortic crossclamp time, cardiopulmonary bypass time, postoperative ventilator use time, ICU stay time, and postoperative hospital stay were 129.0min(116.0, 147.0), 184.0 min(158.0, 227.0), 22.0 h(9.0, 26.0), 3 days(2, 7) and 9 days(7, 14) respectively. No patient lost to follow up, the median follow-up time was 4 months(2, 5). One patient(6.7%) underwent mitral angioplasty three months after surgery due to a tear in the A3 area; the ventricular septal thickness and left ventricular outflow tract pressure decreased significantly(preoperative vs follow-up), and were(19.3±3.3)mm vs. (8.9±4.4) mm( P=0.001), (90.8±23.2)mmHg vs. (8.9±4.4) mmHg(1 mmHg = 0.133kPa)( P<0.001) respectively; no residual SAM was observed during follow-up. Patients with moderate-to severe mitral regurgitation were decreased from 12(80.0%) before surgery to 1(6.7%) during follow up( P<0.001). Conclusion:TTM is a safe and effective procedure for HOCM patients with appropriate surgical indications, providing better exposure to septum from basal to apical area, eliminating left ventricular outflow tract obstruction and SAM-related mitral regurgitation. The anterior mitral valve leaflet should be carefully treated during surgery to reduce the occurrence of residual mitral regurgitation resulted in inappropriate selection of patch size and suturing technique.
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Filamentous fungi are one of the platforms for producing fermented products. The specific characteristic of their submerged fermentation is the aggregation of mycelia that is affected by environmental conditions, leading to significantly different rheology for fermentation broth. Such a rheological change not only affects the transfer of mass, heat and momentum, but also the biosynthesis of target products and the efficiency of their production. In this article, strategies for morphological regulation of filamentous fungi are reviewed, and the impact of calcium signal transduction and chitin biosynthesis on apical growth of hyphae and branching of mycelia for their aggregation are further commented.
Subject(s)
Fermentation , Fungi , Physiology , Hot Temperature , Mycelium , Metabolism , RheologyABSTRACT
Objective: To summarize the mid-term effect of modified extended Morrow procedure in patients with hypertrophic obstructive cardiomyopathy (HOCM) combining sub aortic valve obstruction and mid left ventricular obstruction. Methods: We studied 34 consecutive HOCM patients with sub aortic and midventricular obstruction who received modiifed extended Morrow procedure with extracorporeal circulation in our hospital from 1996-11 to 2015-01. Transthoracic echocardiography was conducted at pre-, post-operation and follow-up period to evaluate the changes of mid-ventricular gradient, subarctic gradient and each heart valve function. Results: The average follow-up time was (25.7 ± 14.9) months, 2 patients lost contact and no death occurred. In rest 32 patients, the mid ventricular gradient decreased from (60.3 ± 29.4) mmHg to (21.0 ± 19.8) mmHg, subaortic valve gradient decreased from (77.9 ± 26.2) mmHg to (11.6 ± 6.5) mmHg, the maximum ventricular septal thickness dropped from (25.2 ± 4.9) mm to (17.9 ± 7.2) mm, left atrial diameter reduced from (41.1 ± 7.8) mm to (37.6 ± 6.4) mm, left ventricular end-diastolic diameter increased from (39.8 ± 5.1) mm to (42.2 ± 4.3) mm, allP<0.05; there were 5 patients without obviously improved mid ventricular gradient because of insufifcient resection of septal myocardium in mid-ventricle. The post-operative NYHA classiifcation was improved,P<0.01, mitral valve regurgitation degree was decreased,P<0.01 and SAM phenomenon was disappeared. Complications included 3 (8.8%) patients of III atrio-ventricular block, 1 (2.9%) patient of re-admission due to poorly healed sternum combining pneumonia Conclusion: Modified extended Morrow procedure may relieve sub aortic valve and mid ventricular obstruction, therefore improve left ventricular diastolic function and prognosis in relevant patients.
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Objective: To report the medium-long term survival rates of ventricular septal myectomy for treating the patients with hypertrophic obstructive cardiomyopathy and to analyze the predictive factors affecting the outcomes. Methods: A total of 655 consecutive patients who received ventricular septal myectomy in our hospital from 1984-10 to 2014-12 were retrospectively summarized. The cohort study was conducted with questionnaires by cardiovascular nurses. Result: The operative mortality was 1.4% (9/655). The mean follow-up time was (30.8 ± 30.9, from 3 to 213) months, there were 52/646 (7.9%) patients lost contact and 583 patients having NYHA classification at I or II during that period. The overall survival rates for 1 year, 5-year and 8-year were 98.3%, 90.5% and 88.3% respectively. There were 80 patients suffered from end point events including HCM-related death, heart transplantation, repeated myectomy, permanent pacemaker implantation and re-admission for ischemic stroke, tachyarrhythmia, myocardial ischemia or infarction, congestive heart failure. The end point events free survival rates for 1 year, 5-year and 8-year were 94.2%, 76.7% and 65.9% respectively. Multivariable Cox regression analysis presented that age>50 years (HR=2.16, 95% CI 1.36-3.46,P=0.001) and pre-operative atrial ifbrillation (FA) (HR=2.31, 95% CI 1.35-3.94,P=0.002) were the independent predictors for end point events occurrence. Conclusion: Ventricular septal myectomy may achieve good medium-long term survival rate with less adverse event in patients with hypertrophic obstructive cardiomyopathy. Elder than 50 years of age and with pre-operative FA were the independent predictors for adverse events occurrence.