Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome.

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.

Long-Term Outcomes of Cementless Bipolar Hemiarthroplasty in Young Patients With Osteonecrosis of the Femoral Head: The Impact of Implant Improvements and Preoperative Stage.

Introduction Advancements in bipolar hemiarthroplasty (BHA) implants in the mid-1990s contributed to favorable short-term outcomes for osteonecrosis of the femoral head (ONFH), particularly in cases without acetabular cartilage lesions. Nevertheless, long-term results remain unclear. In this study, we investigated (i) the impact of new-generation BHA implants and (ii) the effect of the preoperative stage on long-term outcomes in young patients with ONFH. Methods The records of consecutive patients with ONFH who underwent cementless BHA were retrospectively reviewed. Patients aged ≥60 years, with <10 years of follow-up, or who underwent acetabular reaming during surgery were excluded. Radiographical and clinical outcomes of patients who received first-generation BHAs and new-generation BHAs (developed after 1998) were compared by stratifying based on preoperative stage 2/3A and 3B/4, according to the Japanese Investigation Committee classification. Results Overall, 50 hips from 39 patients (mean age: 44.6 years; 64% male) with an average follow-up of 18.6 years were included. The frequency of advanced-stage patients was significantly higher in the first-generation BHA group than in the new-generation group. Regarding postoperative outcomes, the first-generation BHA group had higher acetabular erosion grades (p<0.001) and more femoral component loosening than those in the new-generation group (p<0.001). Revisions were performed in eight hips (seven in the first-generation and one in the new-generation BHA groups, p<0.001). In the new-generation BHA group, there were no significant differences in patient background between stage 2/3A and 3B/4 groups, and only one case in the stage 3B/4 group required revision. In the new-generation group, the grade of acetabular erosion was significantly higher for stage 3B/4 than stage 2/3A (p<0.001); other radiographical and clinical outcomes did not differ significantly between stages. Conclusion New-generation BHAs have significantly better implant survival rates for early-stage ONFH than those of first-generation BHAs. These findings indicate that BHA is an acceptable treatment option for early-stage ONFH in young patients.

Residual deformity after femoral neck fracture affects the location of osteonecrosis of the femoral head.

Aims: The localization of necrotic areas has been reported to impact the prognosis and treatment strategy for osteonecrosis of the femoral head (ONFH). Anteroposterior localization of the necrotic area after a femoral neck fracture (FNF) has not been properly investigated. We hypothesize that the change of the weight loading direction on the femoral head due to residual posterior tilt caused by malunited FNF may affect the location of ONFH. We investigate the relationship between the posterior tilt angle (PTA) and anteroposterior localization of osteonecrosis using lateral hip radiographs. Methods: Patients aged younger than 55 years diagnosed with ONFH after FNF were retrospectively reviewed. Overall, 65 hips (38 males and 27 females; mean age 32.6 years (SD 12.2)) met the inclusion criteria. Patients with stage 1 or 4 ONFH, as per the Association Research Circulation Osseous classification, were excluded. The ratios of anterior and posterior viable areas and necrotic areas of the femoral head to the articular surface were calculated by setting the femoral head centre as the reference point. The PTA was measured using Palm's method. The association between the PTA and viable or necrotic areas of the femoral head was assessed using Spearman's rank correlation analysis (median PTA 6.0° (interquartile range 3 to 11.5)). Results: We identified a negative correlation between PTA and anterior viable areas (rho -0.477; p = 0.001), and no correlation between PTA and necrotic (rho 0.229; p = 0.067) or posterior viable areas (rho 0.204; p = 0.132). Conclusion: Our results suggest that residual posterior tilt after FNF could affect the anteroposterior localization of necrosis.

Long-term outcomes of the mayo conservative hip system in patients aged 30 years or less with osteonecrosis of the femoral head: mean follow-up of more than 10 years.

INTRODUCTION: Historically, total hip arthroplasty (THA) in very young patients has been associated with lower survivorship. However, the long-term outcomes of THA using short stems for osteonecrosis of the femoral head (ONFH) in very young patients remain unclear. Therefore, this study aimed to investigate the long-term outcomes of the Mayo conservative hip system, a short metaphyseal stabilised stem, in patients with ONFH aged ≦30 years. MATERIALS AND METHODS: We retrospectively reviewed 104 joints in 76 patients with ONFH who underwent THA using the Mayo conservative hip system with a minimum follow-up of 8 years. The mean follow-up period was 12.5 (range, 8-19) years. Patients were categorised into two age groups (≦30 years, n = 21 and > 30 years, n = 83). Radiographic evaluation was used to assess stem sinking, stress shielding, and spot welds. The clinical evaluations were performed using the Japanese Orthopedic Association (JOA) hip score. Postoperative major complication and revision surgery rates were also assessed. RESULTS: The patient characteristics were similar between the two groups, except for the age. Revision surgeries were performed in five cases, with similar implant survival rates between the groups. Dislocations occurred in the older age group alone (four joints). One case of intra-operative periprosthetic femoral fracture was found in the younger age group. Stem sinking of > 3 mm occurred in one and seven joints in the younger and older age groups, respectively. Spot welds were observed in most joints (93.2%) in modified Gruen zones 2 and 6 without significant differences between the groups. Stress shielding showed no significant differences in the frequency of occurrence or location between the two groups. Furthermore,the JOA score showed no significant difference between the two groups. CONCLUSION: The use of short stems in patients aged ≤ 30 years with ONFH showed favourable long-term outcomes.

Mid-term outcomes of surgical aortic valve replacement using a mosaic porcine bioprosthesis with concomitant mitral valve repair.

This study retrospectively evaluated the mid-term outcomes of surgical aortic valve replacement (SAVR) using a stented porcine aortic valve bioprosthesis (Mosaic; Medtronic Inc., Minneapolis, MN, USA) with concomitant mitral valve (MV) repair. From 1999 to 2014, 157 patients (median [interquartile range] age, 75 [70-79] years; 47% women) underwent SAVR with concomitant MV repair (SAVR + MV repair), and 1045 patients (median [interquartile range] age, 76 [70-80] years; 54% women) underwent SAVR only at 10 centers in Japan as part of the long-term multicenter Japan Mosaic valve (J-MOVE) study. The 5-year overall survival rate was 81.5% ± 4.1% in the SAVR + MV repair group and 85.1% ± 1.4% in the SAVR only group, and the 8-year overall survival rates were 75.2% ± 5.7% and 78.1% ± 2.1%, respectively. Cox proportional hazards analysis showed no significant difference in the survival rates between the two groups (hazard ratio, 0.87; 95% confidence interval, 0.54-1.40; P = 0.576). Among women with mild or moderate mitral regurgitation who were not receiving dialysis, those who underwent SAVR + MV repair, were aged > 75 years, and had a preoperative left ventricular ejection fraction of 30-75% tended to have a lower mortality risk. In conclusion, this subgroup analysis of the J-MOVE cohort showed relevant mid-term outcomes after SAVR + MV repair.

Impact of complete revascularization in coronary artery bypass grafting for ischemic cardiomyopathy.

Objective: In patients with ischemic cardiomyopathy, coronary artery bypass grafting ensures better survival than medical therapy. However, the long-term clinical impact of complete revascularization remains unclear. This observational study aimed to evaluate the effects of complete revascularization on long-term survival and left ventricular functional recovery in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting. Methods: We retrospectively reviewed outcomes of 498 patients with ischemic cardiomyopathy who underwent complete (n = 386) or incomplete (n = 112) myocardial revascularization between 1993 and 2015. The baseline characteristics were adjusted using inverse probability of treatment weighting to reduce the impact of treatment bias and potential confounding. The mean follow-up duration was 77.2 ± 42.8 months in survivors. Results: The overall 5-year survival rate (complete revascularization, 72.5% vs incomplete revascularization, 57.9%, P = .03) and freedom from all-cause death and/or readmission due to heart failure (54.5% vs 40.1%, P = .007) were significantly greater in patients with complete revascularization than those with incomplete revascularization. After adjustments using inverse probability of treatment weighting, the complete revascularization group demonstrated a lower risk of all-cause death (hazard ratio, 0.61; 95% confidence interval, 0.43-0.86; P = .005) and composite adverse events (hazard ratio, 0.59; 95% confidence interval, 0.44-0.79; P < .001) and a greater improvement in the left ventricular ejection fraction 1-year postoperatively (absolute change: 11.0 ± 11.9% vs 8.3 ± 11.4%, interaction effect P = .05) than the incomplete revascularization group. Conclusions: In patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting, complete revascularization was associated with better long-term outcomes and greater left ventricular functional recovery and should be encouraged whenever possible.

Pump Exchange from a Left Ventricular Assist Device to a Jarvik 2000 with a Postauricular Cable Due to Abdominal Driveline Infection.

Driveline infection in patients with implantable left ventricular assist devices (LVAD) remains common and crucial. Once a driveline exit-site infection reaches the LVAD component, radical treatment such as LVAD exchange may become necessary, although the clinical results are unsatisfactory. The Jarvik 2000 device, which utilizes a postauricular cable, allows the driveline to exit the body behind the ear (postauricular) instead of through an abdominal site. Here, we report the case of a patient who had awaited heart transplantation for more than 6 years and had a critical driveline infection that almost reached the LVAD pump. The patient underwent a pump exchange using the Jarvik 2000 with a postauricular cable, with excellent results. It is a useful replacement option for patients with abdominal driveline infections, owing to its small pump pocket and the availability of an alternative pathway for the driveline.

Midterm outcomes after surgical aortic valve replacement with the INSPIRIS RESILIA from a multicenter AVR registry.

BACKGROUND: There have been few reports on the mid- to long-term safety and efficacy validation of the INSPIRIS RESILIA aortic bioprosthesis (Edwards Lifesciences LLC, Irvine, CA, USA) in Japan. Herein, we report the mid-term results of surgical aortic valve replacement (AVR) for aortic stenosis using INSPIRIS and evaluate the hemodynamics compared to the CEP Magna series from the multicenter AVR registry (the ACTIVIST registry). METHODS: Of the 1967 patients who underwent surgical or transcatheter AVR from the ACTIVIST registry, 66 patients who underwent isolated surgical AVR with INSPIRIS by December 2020 were included in this study, and the early and mid-term results were evaluated. Hemodynamics were evaluated by comparing 272 patients undergoing isolated surgical AVR with the Magna group using propensity score matching. RESULTS: The mean age was 74.0 ±â€¯7.8 years, and 48.5 % were women. In-hospital mortality was 1.5 %, and the survival rates at 1- and 2-years were 95.2 % and 95.2 %, respectively. After propensity score matching, echocardiographic findings at discharge demonstrated that peak velocity and mean pressure gradient in the INSPIRIS group were comparable, while the effective orifice area in the INSPIRIS group was significantly larger than those in the Magna group (p = 0.048). A patient-prosthesis mismatch at discharge was significantly lower in the INSPIRIS group (11.8 %) than in the Magna group (36.4 %) (p = 0.004). CONCLUSIONS: Surgical AVR with INSPIRIS was performed safely and the mid-term results were satisfactory. The hemodynamics of INSPIRIS were comparable to those of Magna.

Role of Aggressive Aneurysm Sac Embolization Before Endovascular Abdominal Aneurysm Repair in Preventing Type II Endoleak and Sac Expansion.

Background: This study aimed to evaluate the effect of aggressive embolization of side branches arising from the aneurysmal sac before endovascular aneurysm repair. Methods: This retrospective study included 95 patients who underwent endovascular infrarenal abdominal aortic aneurysm repair at Tottori University Hospital between October 2016 and January 2021. Of these, 54 underwent standard endovascular aneurysm repair (conventional group), and 41 underwent coiling of the inferior mesenteric and lumbar arteries before undergoing endovascular aneurysm repair (embolization group). The occurrence of type II endoleak, change in aneurysmal sac diameter, and reintervention rate due to type II endoleak during follow-up were evaluated. Results: Compared to the conventional group, the embolization group had a significantly lower incidence of type II endoleak, more frequent aneurysmal sac shrinkage, and lower aneurysmal sac growth related to type II endoleak. Conclusion: Our results demonstrated the effectiveness of aggressive aneurysmal sac embolization before endovascular aneurysm repair to prevent type II endoleak and the consequent long-term aneurysmal sac enlargement.

High-Degree Valgus Osteotomy for Severe Femoral Head Osteonecrosis After Femoral Neck Fracture with Nonunion: A Case Report.

CASE: A 15-year-old adolescent boy had severe groin pain because of extensive osteonecrosis of the femoral head with collapse, joint space narrowing, and nonunion after a failed internal fixation for femoral neck fracture. We performed a 60° valgus osteotomy that moved the posteromedial small viable portion of the femoral head to the weight-bearing acetabular area. The femoral neck nonunion and the necrosis healed completely, and the spherical contour of the femoral head was regained after postoperative hip joint remodeling. CONCLUSIONS: Good remodeling and congruency were achieved by performing high-degree valgus osteotomy to obtain sufficient viable area below the acetabular roof.

High-degree posterior rotational osteotomy for extensive collapsed femoral head osteonecrosis in teenagers: remodeling and results with a mean of 10-year follow-up.

INTRODUCTION: This study evaluated the effectiveness of high-degree posterior rotational osteotomy for teenagers with extensively collapsed femoral head osteonecrosis. MATERIALS AND METHODS: We reviewed 40 hips in 35 patients with severely collapsed femoral head osteonecrosis treated by this procedure with a mean follow-up period of 9.7 years (range 5-25 years). Thirteen hips had a history of steroid administration. Nine had slipped capital femoral epiphysis. Nine had femoral neck fracture. Two had traumatic dislocation and fracture. Seven had no apparent risk factors. The mean age of the patients (18 women and 17 men) was 14.8 years. All femoral heads were extensively collapsed below the acetabular roof, and 20 hips showed preoperative joint space narrowing (ARCO stage 4). Lateral radiographs of the femoral head revealed extensive lesions from the posterior to anterior portion. The mean degree of posterior rotation was 118° with intentional varus positioning [mean: 19° (range 10-30)]. The pre- and postoperative extent of the viable area of the femoral head was assessed using conventional anteroposterior radiographs and 45-degree flexion radiography. Further collapse, joint space narrowing, femoral head morphology, and congruency with the acetabulum based on the Stulberg classification were assessed using conventional anteroposterior radiographs. The clinical assessment was conducted using the Merle d'Aubigné hip scores at the last follow-up. RESULTS: The viable area of the femoral head on the loaded portion was seen during a short period after operations. The necrotic lesions were gradually improved postoperatively. The mean extent of viable bone below the acetabular roof was 48% at less than 6 months after surgery and 92% at the final follow-up. The mean extent on 45° flexion radiography was 54% at less than 6 months after surgery and 89% at the final follow-up. Further collapse was prevented in 38 hips (95%). In 19 of 20 hips with preoperative narrowing of the joint space, the joint space was first improved, but narrowing progressively observed in 9 of 40 hips at the final follow-up. Thirty-four hips had excellent or good clinical outcomes, whereas 6 had fair or poor outcomes. CONCLUSIONS: We concluded that this procedure is effective at delaying the progression of degeneration if adequate area of viable bone can be moved under the loaded portion of the acetabulum in teenagers with severe femoral head osteonecrosis.

Robot-Assisted Aortic Valve Replacement　- First Clinical Report in Japan.

BACKGROUND: Robot-assisted valve surgery represents the latest development in the field of minimally invasive approaches. Robotic assistance may provide greater visualization, enhanced dexterity, and greater precision than traditional mini-thoracotomy aortic valve replacement.Methods and Results: Aortic valve replacement operations using the da Vinci Xi Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA) were performed on 2 patients, 1 with severe aortic insufficiency and the other with aortic stenosis. Both patients had an uneventful postoperative course and were discharged without any adverse events. CONCLUSIONS: Robot-assisted assisted aortic valve replacement appears feasible and safe in limited cases.

Safe launch of a robotically assisted mitral valve repair program in a single center: experience of initial 20 cases under the Center for Minimally Invasive Surgery.

Robotically assisted mitral valve repair was approved by the Japanese government in April 2018. However, understanding robotic surgery involves steep learning curves of surgeons and dedicated cardiac teams. The Center for Minimally Invasive Surgery (CMIS) of Tottori University Hospital is a multidisciplinary organization established in 2011 with seven surgical departments. In this study, we report strategies for improving the safety of robotic surgery in the CMIS and early results of robotic mitral valve repair at our hospital. We reviewed the first 20 patients who underwent robotic primary mitral valve repair, including concomitant procedures, from October 2019 to September 2021 under the supervision of the CMIS. Before starting the program, the CMIS requires setting console time limit to 180 min and implementing risk management strategies through simulation training for various mechanical failures. Mitral valve repair was completed in all patients. There was no in-hospital or 30-day mortality. No conversion to median sternotomy was necessary. The analysis of mitral pathology revealed 1 case of functional mitral regurgitation, 12 cases of posterior lesions, 3 cases of anterior lesions, 3 cases of bileaflet lesions, and 1 case of commissural lesion. The average cross-clamp time was 133 ± 27 min. Sixteen cases had trace mitral regurgitation postoperatively, and 4 cases had mild mitral regurgitation. The median (interquartile range) postoperative hospital stay was 10 (8.5-12.5) days. Robotically assisted mitral valve repair was performed safely with assistance from the multidisciplinary CMIS, and the early results were satisfactory without compromising clinical outcomes.

Effective Protein-Ligand Docking Strategy via Fragment Reuse and a Proof-of-Concept Implementation.

Virtual screening is a commonly used process to search for feasible drug candidates from a huge number of compounds during the early stages of drug design. As the compound database continues to expand to billions of entries or more, there remains an urgent need to accelerate the process of docking calculations. Reuse of calculation results is a possible way to accelerate the process. In this study, we first propose yet another virtual screening-oriented docking strategy by combining three factors, namely, compound decomposition, simplified fragment grid storing k-best scores, and flexibility consideration with pregenerated conformers. Candidate compounds contain many common fragments (chemical substructures). Thus, the calculation results of these common fragments can be reused among them. As a proof-of-concept of the aforementioned strategies, we also conducted the development of REstretto, a tool that implements the three factors to enable the reuse of calculation results. We demonstrated that the speed and accuracy of REstretto were comparable to those of AutoDock Vina, a well-known free docking tool. The implementation of REstretto has much room for further performance improvement, and therefore, the results show the feasibility of the strategy. The code is available under an MIT license at https://github.com/akiyamalab/restretto.

[Current Status and Prospective of Robot-assisted Cardiac Surgery in Japan].

Recently, in the field of minimally invasive approach, robotic technology has represented the latest development. Robot-assisted cardiac surgery has advantages against standard minimally invasive cardiac surgery( MICS) in terms of greater visualization, enhanced dexterity, and greater precision. However, Robot-assisted cardiac surgery requires long learning curves and a dedicated heart team. In order to avoid various risks peculiar to Robot-assisted cardiac surgery, surgical indications and safety measurement are important. In this article, surgical indications, risk management by a multidisciplinary team, and tips and tricks are described.

Relationship Between Acetabular Hounsfield Unit Values and Periprosthetic Fractures in Cementless Total Hip Arthroplasty: A Matched Case-Control Study.

Background: The association between regional bone status around the acetabulum and the incidence of intraoperative acetabulum fractures has not been extensively studied. We investigated the association of Hounsfield unit (HU) values on computed tomography in the regions of the acetabulum with periprosthetic fractures. Methods: We retrospectively reviewed records of 301 consecutive patients who underwent cementless total hip arthroplasty between October 2016 and December 2020. Using preoperative computed tomography taken in the 4 weeks preceding total hip arthroplasty, we measured HU values in 4 different acetabulum regions (anterior, medial, posterior, and superior). After identifying fracture cases, we identified a control group-matched in terms of sex, age, and preoperative diagnosis-selected in a 1:3 ratio among nonfracture patients treated in the same inclusive period. As the average HU values differed by region, we used the standardized value to compare fracture-site HUs. We ranked the standardized HU values for each acetabular site and compared the fracture site rank between the groups. Results: Intraoperative acetabular fractures were observed in 10 hips (3.2%), occurring most frequently in the superior region (40%). The standardized HU values of the fracture site were statistically lower in the fracture group (P = .039). We compared the ranks of the standardized HUs of the fractured parts with those of the corresponding parts in the control group; the fracture site had a significantly lower standardized HU rank, indicating that fractures tended to occur in the relatively "weaker-than-expected" parts. Conclusions: Periprosthetic fractures tended to occur at relatively weak parts of the acetabulum.

Impact of frailty on early and mid-term outcomes of hybrid aortic arch repair.

PURPOSE: The purpose of this study was to investigate the impact of frailty on the clinical outcomes of hybrid aortic arch repair with debranching of the supra-aortic arteries. METHODS: Consecutive patients ≥ 75 years old who underwent hybrid aortic arch repair from January 2010 to December 2019 were retrospectively analyzed. Using the Canadian Study of Health and Aging (CSHA) scale, all patients with a CSHA scale score > 4 were defined as frail. The frail patients (FP) group and the non-frail patients (NFP) group were compared regarding the early and mid-term outcomes of hybrid aortic arch repair. RESULTS: A total of 84 patients were included. The early postoperative results were not markedly different between the groups, except that the rate of transfer to a rehabilitation hospital was higher in the FP group than in the NFP group. The survival at 5 years was significantly lower in the FP group at 43.0% than in the NFP group at 67.7% (P = 0.015). However, the freedom from aorta-related death was not significantly different between the two groups. CONCLUSION: Frailty did not affect the short-term outcomes of hybrid aortic arch repair; however, the mid-term outcomes, including the survival, of the frail patients were significantly worse than those of the non-frail patients, mostly because of non-aorta-related causes.

Long-Term Outcomes of the Mosaic Mitral Porcine Bioprosthesis in Japan　- Results From the Japan Mosaic Valve Long-Term Multicenter Study.

BACKGROUND: This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic mitral porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods and Results:The medical records of 390 patients who underwent mitral valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999-2014) were reviewed. Patient data were collected using the Research Electronic Data Capture software. Patient survival was determined using the Kaplan-Meier method. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined using actuarial methods. The median (interquartile range [IQR]) age of the cohort was 73 (69-77) years. The median (IQR) follow-up period was 4.83 (1.84-8.26) years. The longest follow-up period was 15.8 years. The 30-day mortality rate was 5.4%. The 12-year actuarial survival rate was 54.1±4.5%, and the freedom from valve-related death was 85.3±3.4%. The freedom from reoperation at 12 years was 74.3±5.7%. The freedom from SVD at 12 years was 81.4±6.6% for patients aged ≥65 years and 71.6±11.1% for those aged <65 years. The median (IQR) mean pressure gradient was 4.1 (3.0-6.0) and 5.6 (4.0-6.7) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.7 (1.4-2.0) and 1.4 (1.2-1.6) cm2at 1 and 10 years, respectively. CONCLUSIONS: The Mosaic porcine bioprosthesis offered satisfactory long-term outcomes for up to 12 years.

Plasma protein binding prediction focusing on residue-level features and circularity of cyclic peptides by deep learning.

MOTIVATION: In recent years, cyclic peptide drugs have been receiving increasing attention because they can target proteins that are difficult to be tackled by conventional small-molecule drugs or antibody drugs. Plasma protein binding rate (%PPB) is a significant pharmacokinetic property of a compound in drug discovery and design. However, due to structural differences, previous computational prediction methods developed for small-molecule compounds cannot be successfully applied to cyclic peptides, and methods for predicting the PPB rate of cyclic peptides with high accuracy are not yet available. RESULTS: Cyclic peptides are larger than small molecules, and their local structures have a considerable impact on PPB; thus, molecular descriptors expressing residue-level local features of cyclic peptides, instead of those expressing the entire molecule, as well as the circularity of the cyclic peptides should be considered. Therefore, we developed a prediction method named CycPeptPPB using deep learning that considers both factors. First, the macrocycle ring of cyclic peptides was decomposed residue by residue. The residue-based descriptors were arranged according to the sequence information of the cyclic peptide. Furthermore, the circular data augmentation method was used, and the circular convolution method CyclicConv was devised to express the cyclic structure. CycPeptPPB exhibited excellent performance, with mean absolute error (MAE) of 4.79% and correlation coefficient (R) of 0.92 for the public drug dataset, compared to the prediction performance of the existing PPB rate prediction software (MAE=15.08%, R=0.63). AVAILABILITY AND IMPLEMENTATION: The data underlying this article are available in the online supplementary material. The source code of CycPeptPPB is available at https://github.com/akiyamalab/cycpeptppb. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

α1-Adrenergic receptor mediates adipose-derived stem cell sheet-induced protection against chronic heart failure after myocardial infarction in rats.

Cell-based therapy using adipose-derived stem cells (ADSCs) has emerged as a novel therapeutic approach to treat heart failure after myocardial infarction (MI). The purpose of this study was to determine whether inhibition of α1-adrenergic receptors (α1-ARs) in ADSCs attenuates ADSC sheet-induced improvements in cardiac functions and inhibition of remodeling after MI. ADSCs were isolated from fat tissues of Lewis rats. In in vitro studies using cultured ADSCs, we determined the mRNA levels of vascular endothelial growth factor (VEGF)-A and α1-AR under normoxia or hypoxia and the effects of norepinephrine and an α1-blocker, doxazosin, on the mRNA levels of angiogenic factors. Hypoxia increased α1-AR and VEGF mRNA levels in ADSCs. Norepinephrine further increased VEGF mRNA expression under hypoxia; this effect was abolished by doxazosin. Tube formation of human umbilical vein endothelial cells was promoted by conditioned media of ADSCs treated with the α1 stimulant phenylephrine under hypoxia but not by those of ADSCs pretreated with phenylephrine plus doxazosin. In in vivo studies using rats with MI, transplanted ADSC sheets improved cardiac functions, facilitated neovascularization, and suppressed fibrosis after MI. These effects were abolished by doxazosin treatment. Pathway analysis from RNA sequencing data predicted significant upregulation of α1-AR mRNA expression in transplanted ADSC sheets and the involvement of α1-ARs in angiogenesis through VEGF. In conclusion, doxazosin abolished the beneficial effects of ADSC sheets on rat MI hearts as well as the enhancing effect of norepinephrine on VEGF expression in ADSCs, indicating that ADSC sheets promote angiogenesis and prevent cardiac dysfunction and remodeling after MI via their α1-ARs.