Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these ...diseases. The triphenylphosphonium (TPP
) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP
is not inert; TPP
conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP
-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP
phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP
moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP
structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF
-phenyl TPP
moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.
Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in ...accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RsET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mouse heart and liver mitochondria under conditions which mimic the onset of reperfusion (i.e., high ADP), we show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.
Display omitted
•ROS from complex I (Cx-I) reverse electron transport (RET) is enhanced at acidic pH.•Mitochondrial complex II (Cx-II) activity is inhibited at acidic pH.•These effects cancel out, yielding no net pH response of Cx-II to Cx-I RET ROS.
A
BSTRACT
Physical rehabilitation is evolving day by day. In the same way, simulation in rehabilitation is increasing and has now become a cornerstone for rehabilitation programs. Increase in the ...number of new protocols, clinical methods, and treatment standardization, virtual reality is appearing as a new medium to deliver the simulation. Virtual reality gives the benefits of forming standardized treatment protocols on demand for various conditions repetitively with a cost-effective delivery system. This was an observational retrospective study. The PubMed database was used to obtain the available material related to virtual reality and rehabilitation and was searched using the same keywords. The articles were then sorted as the subject to the recent decade. The basic information was then obtained, which included timespan, sources of the document, average years of publication, document types we collected, and average citation per year per document. Analysis of the literature that was available online related to virtual reality and rehabilitation between 2011 and 2021 generated a list of 813 documents from 275 sources, of which 810 were from journal articles and 3 were book chapters with an average year of publication of 2.16. The highest number of publications was 480 in 2020, followed by 150 in 2019, 95 in 2018, and 28 in 2017. The annual growth rate percentage of scientific publications was 26.1%. Therefore, more studies should be performed on virtual reality.
Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in ...adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that I
and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.
Introduction
In laparoscopic surgery, looking in the target areas is an indicator of proficiency. However, gaze behaviors revealing feedforward control (i.e., looking ahead) and their importance have ...been under-investigated in surgery. This study aims to establish the sensitivity and relative importance of different scene-dependent gaze and motion metrics for estimating trainee proficiency levels in surgical skills.
Methods
Medical students performed the Fundamentals of Laparoscopic Surgery peg transfer task while recording their gaze on the monitor and tool activities inside the trainer box. Using computer vision and fixation algorithms, five scene-dependent gaze metrics and one tool speed metric were computed for 499 practice trials. Cluster analysis on the six metrics was used to group the trials into different clusters/proficiency levels, and ANOVAs were conducted to test differences between proficiency levels. A Random Forest model was trained to study metric importance at predicting proficiency levels.
Results
Three clusters were identified, corresponding to three proficiency levels. The correspondence between the clusters and proficiency levels was confirmed by differences between completion times (
F
2,488
= 38.94,
p
< .001). Further, ANOVAs revealed significant differences between the three levels for all six metrics. The Random Forest model predicted proficiency level with 99% out-of-bag accuracy and revealed that scene-dependent gaze metrics reflecting feedforward behaviors were more important for prediction than the ones reflecting feedback behaviors.
Conclusion
Scene-dependent gaze metrics revealed skill levels of trainees more precisely than between experts and novices as suggested in the literature. Further, feedforward gaze metrics appeared to be more important than feedback ones at predicting proficiency.
Graphical abstract
IntroductionTai chi, an ancient Chinese martial art, was originally developed for combat and self-defense. Over time, it has evolved into both a sport and a form of exercise. This gentle, low-impact ...exercise involves performing a series of deliberate, flowing motions while focusing on deep, slow breaths. This study investigates the effects of chen tai chi and aerobic exercises on cognition, balance, cardiopulmonary fitness, and quality of life in older adults.MethodologyThis study employed a single-blinded randomized control trial design, enrolling 60 participants aged between 60 and 75 years. Participants were divided into three groups: Group A (aerobics), Group B (chen tai chi), and Group C (control). Exercise sessions were held four days per week over a period of four weeks. Evaluations included the Montreal Cognitive Assessment for cognition, a one-leg stand test for static balance, a Timed Up and Go Test for dynamic balance, a six-minute walk test for cardiopulmonary fitness, and a health-related quality-of-life scale. Assessments were conducted at baseline, immediately after the intervention, and at follow-up was taken after eight weeks.ResultsPost-intervention, improvements were observed in cognition and static balance across all groups. Within-group analysis revealed that the aerobics group experienced statistically significant enhancements in cognition (p = 0.0001) and static balance (p = 0.01). Although no statistically significant differences were found between groups in terms of dynamic balance, cardiopulmonary fitness, and quality of life, the within-group analysis showed significant improvements in the aerobics group in dynamic balance (p = 0.0009), cardiopulmonary fitness (p = 0.03), and quality of life (p = 0.0001).ConclusionCompared to chen tai chi and no intervention, the study concludes that aerobic exercise has a more pronounced effect on improving cognition, balance, cardiopulmonary fitness, and quality of life in older adults. Aerobic exercise is recommended as an effective method to prevent frailty and promote independence among the elderly.
Introduction: Scores are available to predict the probability of contrast-induced nephropathy (CIN) after cardiac interventions, but not many scores are available for non-cardiac interventions and ...there are none for intravenous exposure to contrast. We designed this study to develop a simplified score to determine the probability of developing CIN in patients exposed to the parenteral contrast medium. Methods: This was a prospective study of patients who received parenteral contrast. Of 1300 patients, the first 1000 comprised the derivation cohort and the next 300 comprised the validation cohort. The patient variables in the development cohort were studied using univariate analysis. Statistically significant individual variables were used as independent variables, and CIN was used as the dependent variable in the final multivariate logistic regression model. Then, the risk score was obtained and validated. Results: The incidence of CIN was 3.8%. The risk factors, namely the presence of diabetes mellitus, e-GFR, and route and volume of contrast material were significantly associated with the risk of CIN (P < 0.05). The developed risk score had a sensitivity of 90.4% and specificity of 98.78%. The overall accuracy was 97.8%. The values of AUC of ROC in the development and validation datasets were high. This indicated that the predicted CIN risk score correlated well with the calibration and discriminative characteristics. Conclusions: The route and volume of contrast administered, low e-GFR, and diabetes mellitus were the significant risk factors. The developed risk score exhibited very good sensitivity and specificity and excellent accuracy in predicting the probability of CIN.
Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation-induced necrosis, but its function and substrates remain unclear. Herein, we show ALKBH7 regulates ...dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find
mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in
mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from
mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.
Temporomandibular joint (TMJ) is a bicondylar joint. Various conditions have the same clinical presentation as TMJ dysfunction, which requires a thorough assessment of active and passive movements ...and palpation of the joints surrounding the joint. Many times, TMJ dysfunction occurs due to an alteration in the cervical spine. The patient complains of clicking or popping sound at the jaw and a reduced maximum mouth opening. The conditions that lead to TMJ dysfunction include bruxism, arthritis, stress, injury to the jaw, and overuse. The trend of the available literature has changed from 1972 to 2021 to assess changing trends in the publication on TMJ about authors, country, collaboration of the institutes, and the journal. We have done this bibliometric assessment. The articles were collected from the PubMed database; the keywords used were temporomandibular dysfunction (TMD), neck pain, physiotherapy, and rehabilitation. A total of 437 articles were found from 1975 to 2021, which were then converted into pictorial forms using the CiteSapce R software, and the data were interpreted. The analysis of the bibliometrics of publications on TMD, neck pain, and functional disability between the years 1975 and 2021 shows a total of 437 articles were published. The articles were from 196 sources; the highest number of publications were seen from 2014 until 2021, with the highest number of published papers by author Yoo WG and the highest number of articles published by the Journal of Physical Therapy Science. This bibliometric analysis depicts that the quantity of literature on TMD and the forward head has increased, as has the effectiveness of physical therapy interventions on the forward head in terms of correcting temporomandibular dysfunction.
PDF
