Deciphering Early-Stage Molecular Mechanisms of Negative Pressure Wound Therapy in a Murine Model.

Negative Pressure Wound Therapy (NPWT) is a commonly employed clinical strategy for wound healing, yet its early-stage mechanisms remain poorly understood. To address this knowledge gap and overcome the limitations of human trials, we establish an NPWT C57BL/6JNarl mouse model to investigate the molecular mechanisms involved in NPWT. In this study, we investigate the intricate molecular mechanisms through which NPWT expedites wound healing. Our focus is on NPWT's modulation of inflammatory immune responses and the concurrent orchestration of multiple signal transduction pathways, resulting in shortened coagulation time and reduced inflammation. Notably, we observe a significant rise in dickkopf-related protein 1 (DKK-1) concentration during NPWT, promoting the differentiation of Hair Follicle Stem Cells (HFSCs) into epidermal cells, expediting wound closure. Under negative pressure, macrophages express and release DKK-1 cytokines, crucial for stimulating HFSC differentiation, as validated in animal experiments and in vitro studies. Our findings illuminate the inflammatory dynamics under NPWT, revealing potential signal transduction pathways. The proposed framework, involving early hemostasis, balanced inflammation, and macrophage-mediated DKK-1 induction, provides a novel perspective on enhancing wound healing during NPWT. Furthermore, these insights lay the groundwork for future pharmacological advancements in managing extensive wounds, opening avenues for targeted therapeutic interventions in wound care.

High-Intensity Interval Training Is Associated With Improved 10-Year Survival by Mediating Left Ventricular Remodeling in Patients With Heart Failure With Reduced and Mid-Range Ejection Fraction.

BACKGROUND: This study aimed to assess the left ventricular (LV) remodeling response and long-term survival after high-intensity interval training (HIIT) in patients with various heart failure (HF) phenotypes during a 10-year longitudinal follow-up. METHODS AND RESULTS: Among 214 patients with HF receiving guideline-directed medical therapy, those who underwent an additional 36 sessions of aerobic exercise at alternating intensities of 80% and 40% peak oxygen consumption (V̇$$ \dot{\mathrm{V}} $$O2peak) were considered HIIT participants (n=96). Patients who did not undergo HIIT were considered participants receiving guideline-directed medical therapy (n=118). Participants with LV ejection fraction (EF) <40%, ≥40% and <50%, and ≥50% were considered to have HF with reduced EF, HF with mid-range EF, and HF with preserved EF, respectively. V̇$$ \dot{\mathrm{V}} $$O2peak, serial LV geometry, and time to death were recorded. In all included participants, 10-year survival was better (P=0.015) for participants who underwent HIIT (80.3%) than for participants receiving guideline-directed medical therapy (68.6%). An increased V̇$$ \dot{\mathrm{V}} $$O2peak, decreased minute ventilation carbon dioxide production slope, and reduced LV end-diastolic diameter were protective factors against all-cause mortality. Regarding 138 patients with HF with reduced EF (P=0.044) and 36 patients with HF with mid-range EF (P=0.036), 10-year survival was better for participants who underwent HIIT than for participants on guideline-directed medical therapy. Causal mediation analysis showed a significant mediation path for LV end-diastolic diameter on the association between HIIT and 10-year mortality in all included patients with HF (P<0.001) and those with LV ejection fraction <50% (P=0.006). HIIT also had a significant direct association with 10-year mortality in patients with HF with LV ejection fraction <50% (P=0.027) but not in those with LV ejection fraction ≥50% (n=40). CONCLUSIONS: Reversal of LV remodeling after HIIT could be a significant mediating factor for 10-year survival in patients with HF with reduced EF and those with HF with mid-range EF.

Trainability for cardiopulmonary fitness is low in patients with peripheral artery disease.

AIMS: In patients with peripheral arterial disease (PAD), exercise therapy is recommended to relieve leg symptoms, as noted in the 2016 AHA/ACC and 2017 ESC/ESVS guidelines. We assessed the trainability for cardiopulmonary fitness (CPF) and quality of life (QOL); three distinct patient types, namely, PAD, heart failure (HF), and stroke, were compared. METHODS AND RESULTS: This is a multicentre, retrospective analysis of prospectively collected data from three clinical studies. Data collected from 123 patients who completed 36 sessions of supervised aerobic training of moderate intensity were analysed, with 28 PAD, 55 HF, and 40 stroke patients totalling 123. Before and after training, cardiopulmonary exercise testing with non-invasive cardiac output monitoring and QOL evaluation using a 36-Item Short Form Survey (SF-36) were performed. Non-response was defined as a negative change in the post-training value compared with that in the pre-training value. The result showed an improvement in CPF in all three groups. However, cardiorespiratory fitness (CRF) increased by a lesser extent in the PAD group than in the HF and stroke groups; the physical and mental component scores (MCS) of SF-36 exhibited a similar pattern. Non-response rates of peak V˙O2, oxygen uptake efficiency slope, and MCS were higher in the PAD group. In the PAD group, non-responders regarding peak V˙O2 had a higher pulse wave velocity than responders. CONCLUSION: In patients with PAD following exercise therapy, CRF and QOL improved to a lesser extent on average; their non-response rate was also higher compared with that of HF or stroke patients. Therefore, a higher dose of exercise might be needed to elicit adaptation in PAD patients, especially those with high pulse wave velocity.

Interval aerobic/resistance exercise training depresses adrenergic-induced apoptosis of lymphocytes in sedentary males.

PURPOSE: Adrenergic stimulation affects lymphocyte autophagy and apoptosis by activating ß1-adrenergic receptor (ß1-AR) and G protein-coupled receptor kinase 2 (GRK-2) downstream signaling. This study investigated how combined aerobic and resistance exercise training on the interval or continuous pattern influences aerobic/muscular fitness and ß1-AR/GRK-2 signaling, and corresponding apoptosis/autophagy of lymphocytes in sedentary males. METHODS: Thirty-four sedentary males were randomized into interval training (IT, age = 22.5 ± 0.6 years, fitness level = 47.5 ± 0.9 mL/min/kg, body mass index (BMI) = 22.4 ± 0.4 kg/m2, n = 17) and continuous training (CT, age = 21.6 ± 0.4 years, fitness level = 45.2 ± 1.0 mL/min/kg, BMI = 22.2 ± 0.3 kg/m2, n = 17) groups. These subjects performed IT (bicycle exercise at alternating 40% and 80%VO2 reserve (VO2R) and isokinetic exercise at alternating 60°/s and 180°/s) or CT (bicycle exercise at continuously 60%VO2R and isokinetic exercise at continuously 120°/s) for 30 min/day, 5 days/week for 6 weeks. Aerobic capacity and muscular strength/endurance were determined by the graded exercise test (GXT) and isokinetic strength test, respectively. Blood lymphocyte autophagy/apoptosis and ß1-AR/GRK-2 signaling were analyzed using flow cytometry. RESULTS: Both IT and CT groups increased isokinetic strengths at various angular velocities, whereas only IT significantly enhanced muscle endurance, indicated by lowered fatigue index from 47.0 ± 1.3% to 41.8 ± 1.6% (P < 0.05). Moreover, the IT group (143 ± 7%) revealed a higher improvement in VO2peak than CT group (132 ± 6%) (P < 0.05). Acute GXT augmented (i) GRK-2 and protein kinase A expressions, (ii) LAMP-2 upregulation and acridine orange staining, (iii) mitochondrial transmembrane potential diminishing, caspase-3 activation, and phosphatidylserine (PS) exposure caused by epinephrine in blood lymphocytes. However, the degree of epinephrine-induced lymphocyte PS exposure potentiated by GXT was suppressed from 65.2 ± 5.2% to 47.4 ± 6.5% following 6 weeks of the IT (P < 0.05). CONCLUSION: The IT may be considered more beneficial than CT in terms of improving aerobic/muscular fitness and simultaneously ameliorating apoptosis of blood lymphocyte evoked by intense exercise or adrenergic stimulation in sedentary males.

Lidocaine inhibits migration of tenocytes by downregulating focal adhesion kinase and paxillin phosphorylation.

Lidocaine is the most frequently applied local infiltration anesthetic agent for treating tendinopathies. However, studies have discovered lidocaine to negatively affect tendon healing. In the current study, the molecular mechanisms and effects of lidocaine on tenocyte migration were evaluated. We treated tenocytes intrinsic to the Achilles tendons of Sprague-Dawley rats with lidocaine. The migration ability of cells was analyzed using electric cell-substrate impedance sensing (ECIS) and scratch wound assay. We then used a microscope to evaluate the cell spread. We assessed filamentous actin (F-actin) cytoskeleton formation through immunofluorescence staining. In addition, we used Western blot analysis to analyze the expression of phospho-focal adhesion kinase (FAK), FAK, phospho-paxillin, paxillin, and F-actin. We discovered that lidocaine had an inhibitory effect on the migration of tenocytes in the scratch wound assay and on the ECIS chip. Lidocaine treatment suppressed cell spreading and changed the cell morphology and F-actin distribution. Lidocaine reduced F-actin formation in the tenocyte during cell spreading; furthermore, it inhibited phospho-FAK, F-actin, and phospho-paxillin expression in the tenocytes. Our study revealed that lidocaine inhibits the spread and migration of tenocytes. The molecular mechanism potentially underlying this effect is downregulation of F-actin, phospho-FAK, and phospho-paxillin expression when cells are treated with lidocaine.

Prediction for blood lactate during exercise using an artificial intelligence-Enabled electrocardiogram: a feasibility study.

Introduction: The acquisition of blood lactate concentration (BLC) during exercise is beneficial for endurance training, yet a convenient method to measure it remains unavailable. BLC and electrocardiogram (ECG) both exhibit variations with changes in exercise intensity and duration. In this study, we hypothesized that BLC during exercise can be predicted using ECG data. Methods: Thirty-one healthy participants underwent four cardiopulmonary exercise tests, including one incremental test and three constant work rate (CWR) tests at low, moderate, and high intensity. Venous blood samples were obtained immediately after each CWR test to measure BLC. A mathematical model was constructed using 31 trios of CWR tests, which utilized a residual network combined with long short-term memory to analyze every beat of lead II ECG waveform as 2D images. An artificial neural network was used to analyze variables such as the RR interval, age, sex, and body mass index. Results: The standard deviation of the fitting error was 0.12 mmol/L for low and moderate intensities, and 0.19 mmol/L for high intensity. Weighting analysis demonstrated that ECG data, including every beat of ECG waveform and RR interval, contribute predominantly. Conclusion: By employing 2D convolution and artificial neural network-based methods, BLC during exercise can be accurately estimated non-invasively using ECG data, which has potential applications in exercise training.

Vascular risk factors and astrocytic marker for the glymphatic system activity.

OBJECTIVES: Glymphatic system maintains brain fluid circulation via active transportation of astrocytic aquaporin-4 in perivascular space. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an established method measuring perivascular glymphatic activity, but comprehensive investigations into its influential factors are lacking. METHODS: Community-dwelling older adults underwent brain MRI scans, neuropsychiatric, and multi-domain assessments. Blood biomarker tests included glial fibrillary acidic protein (GFAP) for astrocyte injury. RESULTS: In 71 enrolled participants, the DTI-ALPS index was associated with modifiable factors, including lipid profile (high-density lipoprotein, r = 0.396; very-low-density lipoprotein, r = - 0.342), glucose intolerance (diabetes mellitus, standardized mean difference (SMD) = 0.7662; glycated hemoglobin, r = - 0.324), obesity (body mass index, r = - 0.295; waist, r = - 0.455), metabolic syndrome (SMD = - 0.6068), cigarette-smoking (SMD = - 0.6292), and renal clearance (creatinine, r = - 0.387; blood urea nitrogen, r = - 0.303). Unmodifiable associative factors of DTI-ALPS were age (r = - 0.434) and sex (SMD = 1.0769) (all p < 0.05). A correlation of DTI-ALPS and blood GFAP was noticed (r = - 0.201, one-tailed t-test for the assumption that astrocytic injury impaired glymphatic activity, p = 0.046). Their cognitive correlations diverged, domain-specific for DTI-ALPS (Facial Memory Test, r = 0.272, p = 0.022) but global cognition-related for blood GFAP (MoCA, r = - 0.264, p = 0.026; ADAS-cog, r = 0.304, p = 0.010). CONCLUSION: This correlation analysis revealed multiple modifiable and unmodifiable association factors to the glymphatic image marker. The DTI-ALPS index correlated with various metabolic factors that are known to increase the risk of vascular diseases such as atherosclerosis. Furthermore, the DTI-ALPS index was associated with renal indices, and this connection might be a link of water regulation between the two systems. In addition, the astrocytic biomarker, plasma GFAP, might be a potential marker of the glymphatic system; however, more research is needed to confirm its effectiveness.

Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

Integrated diffusion image operator (iDIO): A pipeline for automated configuration and processing of diffusion MRI data.

The preprocessing of diffusion magnetic resonance imaging (dMRI) data involve numerous steps, including the corrections for head motion, susceptibility distortion, low signal-to-noise ratio, and signal drifting. Researchers or clinical practitioners often need to configure different preprocessing steps depending on disparate image acquisition schemes, which increases the technical threshold for dMRI analysis for nonexpert users. This could cause disparities in data processing approaches and thus hinder the comparability between studies. To make the dMRI data processing steps transparent and adapt to various dMRI acquisition schemes for researchers, we propose a semi-automated pipeline tool for dMRI named integrated diffusion image operator or iDIO. This pipeline integrates features from a wide range of advanced dMRI software tools and targets at providing a one-click solution for dMRI data analysis, via adaptive configuration for a set of suggested processing steps based on the image header of the input data. Additionally, the pipeline provides options for post-processing, such as estimation of diffusion tensor metrics and whole-brain tractography-based connectomes reconstruction using common brain atlases. The iDIO pipeline also outputs an easy-to-interpret quality control report to facilitate users to assess the data quality. To keep the transparency of data processing, the execution log and all the intermediate images produced in the iDIO's workflow are accessible. The goal of iDIO is to reduce the barriers for clinical or nonspecialist users to adopt the state-of-art dMRI processing steps.

Factors Associated With Participation Rate and Predictive of Improvement After Cardiac Rehabilitation in Patients With Heart Failure.

PURPOSE: Patients with heart failure (HF) are often limited in their ability to perform exercise. Cardiac rehabilitation (CR) improves aerobic capacity and quality of life (QOL) and is recommended for patients with clinically stable HF; however, it is underutilized. The aim of this study was to investigate the factors associated with participation and completion rates and predictive of improvement after phase II CR in patients with HF. METHODS: Participation and completion rates were calculated for all patients with HF enrolled in a multidisciplinary management program from October 2008 to December 2018. Functional capacity and QOL were estimated. In patients undergoing CR, changes in peak oxygen uptake (V˙ o2peak ) were measured. RESULTS: Of 662 patients enrolled, 448 (68%) completed the cardiopulmonary exercise test (CPX). Phase II CR was recommended in 411 patients, of whom 291 (71%) participated in CR. Participation was significantly related to sex and the time interval in days between hospital discharge and the CPX. Overall, 171 patients completed 36 sessions of CR (with a completion rate of 59%). During CR, there were 18 (6%) adverse events. Cardiac rehabilitation was associated with improvement in V˙ o2peak from 1153 ± 393 to 1342 ± 470 mL/min (a 16% improvement; P < .001) and in QOL. The independent predictors of increase in V˙ o2peak included sex, age, diabetes mellitus, and entry V˙ o2peak . CONCLUSIONS: In patients with HF, factors associated with CR participation rate included sex and days between hospital discharge and the CPX. Participation in CR improved V˙ o2peak and QOL. The improvement was related to male sex, younger age, no diabetes mellitus, and higher entry V˙ o2peak .

Intra-Articular Laser Therapy May Be a Feasible Option in Treating Knee Osteoarthritis in Elderly Patients.

Knee osteoarthritis (OA) is a common problem in elderly patients. They are often troubled with altered knee function, such as pain and weakness. However, not all these patients are able to receive autologous platelet-rich plasma (PRP) injections as they may be taking antiplatelet or anticoagulant medications. Their physical condition may not allow them to receive total knee replacement surgery as well. Long-term oral intake of nonsteroidal anti-inflammatory drugs may be detrimental to the gastrointestinal tract. As a result, it is crucial to discover new treatment options that can alleviate painful knee symptoms in elderly knee OA patients. In this study, 19 elderly patients diagnosed with moderate degree of knee OA as well as suprapatellar bursitis were recruited. They received low-level laser therapy (LLLT) to their affected knees. Under ultrasound guidance, flexible fiber optic wire was inserted intra-articularly into the knee joint. Red laser followed by infrared irradiation was performed once every 2 weeks for a total of 3 times. The Lequesne index for knee OA and the volume of suprapatellar synovial fluid (SF) were measured. SF proteomic analyses were also performed up to a period of 6 months. The results revealed that after 3 LLLT, the Lequesne index significantly decreased, signifying improvement in the knee joint functional status. The volume of suprapatellar SF and SF proteins associated with inflammation also decreased significantly in the SF. These findings lasted up to a period of at least 3 months. Therefore, LLLT may be considered as a feasible option in treating elderly patients with knee OA who are not suitable for surgical interventions or intra-articular PRP injections.

The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included "mitochondria", "exercise", "aerobic capacity", and "cardiovascular disease" in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I2 = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.

Forensic Death Investigations of Dog Bite Injuries in 31 Cats.

Animal bite injuries are common in free-ranging cats in Taiwan, and most fatal animal bite events are presumed to be caused by dogs. However, speculation regarding animal abuse may occur when carcasses with prominent injuries are found by members of the general public. Local animal protection offices and veterinary clinicians sometimes face difficulties in convincing these individuals by identifying specific features of dog bite injuries in cat carcasses. Therefore, the present study analyzed injury patterns and distribution in 31 necropsied cats with animal bite injuries, and applied deoxyribonucleic acid (DNA) analysis for canine DNA identification in 13 cats. The main necropsy findings included puncture wounds (26 (83.9%)), linear or small, round contusions/abrasions (20 (64.5%)), lacerations/avulsions (17 (54.8%)), abdominal wall rupture/laceration (19 (61.3%)), herniation (16 (51.6%)), fractures (21 (67.7%)), broken claws (16 (51.6%)), and hair tufts on the body surface (28 (90.3%)). The most-commonly injured regions were the ventral thorax and axilla (23 (74.2%)), hind limbs (22 (71.0%)), shoulder-to-dorsal thorax (21 (67.7%)), back and flank (20 (64.5%)), abdomen (19 (61.3%)), neck (19 (61.3%)), and hip/tail/perineum (17 (54.8%)). Canine mitochondrial DNA was identified in 3 out of 11 cases (27.3%) that were sampled using wound swabs and in 4 out of 5 cases that had hair entrapped in broken claws. In conclusion, this study determined the distribution and features of dog bite injuries in cats and developed an elemental method using trace evidence for DNA identification in animal bites.

Intra-Articular Leukocyte-Rich Platelet-Rich Plasma versus Intra-Articular Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-Analysis of 14 Randomized Controlled Trials.

(1) Background: To evaluate the clinical effects of leukocyte-rich platelet-rich plasma (LR-PRP) and hyaluronic acid (HA) injections in treating patients suffering from knee osteoarthritis (OA); (2) Methods: Randomized controlled trials (RCTs) were searched from PubMed, Web of Science, and Cochrane Library. Keywords were: platelet-rich plasma, LR-PRP, leukocyte-rich, hyaluronic acid, and knee osteoarthritis. The included RCTs were published between the 1st of November 2011 and the 3rd of February 2021. Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, visual analog scale (VAS) scores, International Knee Documentation Committee (IKDC) scores, and adverse events were used as outcomes for evaluation; (3) Results: A total of 14 RCTs were enrolled. At 6 months, revealed that the LR-PRP group was better than the HA group in WOMAC total, pain, and physical function scores. At 12 months, the LR-PRP group was better than the HA group in WOMAC stiffness and physical function scores. There was no significant difference in adverse events; (4) Conclusion: LR-PRP injection showed no significant pain relief effect as compared with HA injection. However, LR-PRP demonstrated better overall outcomes as compared to HA in knee OA patients at the follow-up periods of 3, 6, and 12 months. LR-PRP injection may be recommended as a feasible option in treating patients with knee OA.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Semantic segmentation guided detector for segmentation, classification, and lesion mapping of acute ischemic stroke in MRI images.

BACKGROUND AND PURPOSE: MRI images timely and accurately reflect ischemic injuries to the brain tissues and, therefore, can support clinical decision-making of acute ischemic stroke (AIS). To maximize the information provided by the MRI images, we leverage deep learning models to segment, classify, and map lesion distributions of AIS. METHODS: We evaluated brain MRI images of AIS patients from 2017 to 2020 at a tertiary teaching hospital and developed the Semantic Segmentation Guided Detector Network (SGD-Net), composed of the first U-shaped model for segmentation in diffusion-weighted imaging (DWI) and the second model for binary classification of lesion size (lacune vs. non-lacune) and circulatory territory of lesion location (anterior vs. posterior circulation). Next, we modified the two-stage deep learning model into SGD-Net Plus by automatically segmenting AIS lesions in DWI images and registering the lesion in T1-weighted images and the brain atlases. RESULTS: The final enrollment (216 patients with 4606 slices) was divided into 80% for model development and 20% for testing. S1 model segmented AIS lesions in DWI images accurately with a pixel accuracy > 99% (Dice 0.806-0.828 and IoU 0.675-707). In comprehensive evaluation of classification performance, the two-stage SGD-Net outperformed the traditional one-stage models in classifying AIS lesion size (accuracy 0.867-0.956 vs. 0.511-0.867, AUROC 0.962-0.992 vs. 0.528-0.937, AUPRC 0.964-0.994 vs. 0.549-0.938) and location (accuracy 0.860-0.930 vs. 0.326-0.721, AUROC 0.936-0.988 vs. 0.493-0.833, AUPRC 0.883-0.978 vs. 0.365-0.695). The precise lesion segmentation at the first stage of the deep learning model was the basis for further application. After that, the modified two-stage model SGD-Net Plus accurately reported the volume, region percentage, and lesion percentage of each region on the selected brain atlas. Its reports provided clear descriptions and quantifications of the AIS-related brain injuries on white matter tracts, Brodmann areas, and cytoarchitectonic areas. CONCLUSION: Domain knowledge-oriented design of artificial intelligence applications can deepen our understanding of patients' conditions and strengthen the use of MRI for patient care. SGD-Net precisely segments AIS lesions on DWI and accurately classifies the lesions. In addition, SGD-Net Plus maps the AIS lesions and quantifies their occupancy in each brain region. They are practical tools to meet the clinical needs and enrich educational resources of neuroimage.

Stretch-Induced Healing of Injured Muscles Is Associated With Myogenesis and Decreased Fibrosis.

BACKGROUND: Alghouth therapeutic stretching exercise has been applied to accelerate the healing of injured skeletal muscles, mechanisms behind the mechanical stretch-induced muscle recovery remain unclear. PURPOSE: To examine stretch-associated antifibrotic and myogenic responses in injured muscles and to evaluate the feasibility of the ultrasonic Nakagami parametric index (NPI) in assessing muscle morphology during recovery. STUDY DESIGN: Controlled laboratory study. METHODS: Skeletal muscle fibrosis was induced in the right hind legs of 48 rats by making a posterior transverse incision in the gastrocnemius muscle; the left hind legs remained intact as a comparative normal reference. After surgery, the 48 rats were randomly divided into the stretch (S) and control (C) groups. The S group received stretching interventions on the injured hind leg from week 3 to week 7 after surgery, while the C group did not receive stretching throughout the study period. The muscle fibrosis percentage and the ultrasonic NPI were examined sequentially after surgery. Relative expressions of myogenesis-related proteins, including myoblast determination protein 1 (MyoD), myogenin, and embryonic myosin heavy chain (MHCemb), were also evaluated during the follow-up. RESULTS: Mean fibrosis percentages in the injured hind leg were approximately 25% at week 3 in both groups, but they were significantly decreased by approximately 20% from week 4 to the end of the follow-up in the S group only (all, P < .05). Upon injury, the NPI values of injured hind legs in both groups dramatically dropped. Within the S group, stretching increased the NPI values of injured hind legs, which approached those of control hind legs at weeks 6 and 7. The highest MyoD, myogenin, and MHCemb levels were observed at week 6 in both groups. The NPI values corresponded to the MyoD expression in the S group during the follow-up. CONCLUSION: Stretching induced a decrease in muscle fibrosis and an increase in myogenesis in injured muscles. The NPI values correspond to the myogenesis process. CLINICAL RELEVANCE: The NPI may be capable of continuously monitoring the injured skeletal muscle morphology during the healing process in clinical settings.

Stepper-Based Training Improves Monocyte-Platelet Aggregation and Thrombin Generation in Nonambulatory Hemiplegic Patients.

PURPOSE: Nonambulatory stroke patients are extremely sedentary, but most available data concerning exercise training in stroke patients are related to ambulatory patients. This study aimed to investigate the efficacy of stepper-based exercise training on cardiopulmonary fitness, monocyte subtypes, and associated monocyte-platelet aggregates (MPA) and thrombin generation (TrG) in nonambulatory hemiplegic patients with ischemic stroke. METHOD: Thirty-eight patients were randomized into exercise training (ET, n = 20) and usual care (UC, n = 18) groups. The ET underwent supervised exercise training (60% peak work rate) using a recumbent stepper for two to four sessions per week and 36 sessions in total. In addition, 12 healthy participants were enrolled as healthy controls. Monocyte characteristics, MPA, and plasma TrG kinetics were determined before and after intervention by flow cytometry and calibrated automated thrombogram® (CAT). RESULTS: Seventeen and 15 patients completed the protocol in the ET and UC groups. Peak V̇O2 improved in ET (15.7 ± 4.8 vs 18.9 ± 5.3 mL·min-1·kg-1, +20%), so did the phase angle of the hemiplegic limbs. The counts of total MPA and MPA associated with three monocyte subtypes, alongside CD42b expression all declined in ET with subtypes 2 and 1 being the most prominent. Macrophage inflammatory protein 1ß (MIP-1 ß) level also declined. The TrG kinetics was attenuated after ET by delaying initiation and reducing the rising slope and peak of thrombin production. In UC, no difference was revealed in the pre-post comparison. CONCLUSIONS: Stepper-based ET is feasible in nonambulatory hemiplegic patients and is effective in improving aerobic fitness. Moreover, it decreases heteroaggregation of monocytes with platelets, especially in monocyte subtypes 2 and 1. Thrombin generation was also attenuated. Hence, stepper-based ET may be incorporated in the rehabilitation of nonambulatory hemiplegic patients.

Exercise Training Improves Mitochondrial Bioenergetics of Natural Killer Cells.

INTRODUCTION: Mitochondrial bioenergetics is critical for immune function in natural killer (NK) cell. Physical exercise modulates NK cell functionality, depending on the intensity and type of exercise. This study elucidates how interval and continuous exercise regimens affect the phenotypes and mitochondrial bioenergetics of NK cells. METHODS: Sixty healthy sedentary males were randomly assigned to engage in either high-intensity interval training (HIIT, 3-min intervals at 80% and 40% maximal O2, n = 20; age, 22.2 yr; body mass index [BMI], 24.3 kg·m-2) or moderate-intensity continuous training (MICT, sustained 60% maximal O2, n = 20; age, 22.3 yr; BMI, 23.3 kg·m-2) for 30 min·d-1, 5 d·wk-1 for 6 wk or were assigned to a control group that did not receive exercise intervention (n = 20; age, 22.6 yr; BMI, 24.0 kg·m-2). Natural killer cell phenotypes, granule proteins, and mitochondrial oxidative stress/oxidative phosphorylation after graded exercise test (GXT) were measured before and after the various interventions. RESULTS: Before the intervention, the GXT increased the mobilization of CD57+NK cells into the blood and elevated mitochondrial matrix oxidant burden (MOB) in NK cells, Following the 6 wk of interventions, both HIIT and MICT (i) diminished mobilization of CD57+NK cells into the blood and depressed mitochondrial MOB level in NK cells immediately after GXT, (ii) increased mitochondrial membrane potential and cellular perforin and granzyme B levels in NK cells, and (iii) enhanced the maximal and reserve O2 consumption rates and heightened bioenergetic health index in NK cells. In addition, HIIT increased maximal work rate than those of MICT. CONCLUSIONS: Either HIIT or MICT increases the expressions of cytotoxic granule proteins and depresses mitochondrial MOB elevated by GXT, along with improving mitochondrial bioenergetic functionality in NK cells. Moreover, HIIT is superior to MICT in improving aerobic capacity.

Corrigendum: Exploring Peritumoral Neural Tracts by Using Neurite Orientation Dispersion and Density Imaging.

[This corrects the article DOI: 10.3389/fnins.2021.702353.].