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MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson’s diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a “governator” sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC’s flow of metabolites.

BackgroundBystander cardiopulmonary resuscitation (CPR) rates remain fairly low through most communities despite multiple interventions through the years. Understanding the attitudes and fears behind CPR training and performance would help target education and training to raise the rates of bystander CPR and consequently survival rates of victims. 7909 participants at a single-day mass CPR training session in Singapore were given survey questionnaires to fill out. 6473 people submitted completed forms upon the conclusion of the training session. Some issues looked at were the overall level of difficulty of CPR, difficulty levels of specific skills, attitudes towards refresher training, attitudes towards performing CPR, and fears when doing so.ResultsThe mean level of difficulty of CPR was rated 3.98 (scale of 1–10), with those with previous CPR training rating it easier. The skills rated most difficult were performing mouth-to-mouth breathing and chest compressions, while the easiest rated was recognizing non-responsiveness. A majority (69.7%) would agree to go for refresher training every 2 years and 88.7% felt everyone should be trained in CPR. 71.6% would perform full CPR for a member of the public in cardiac arrest and only 20.7% would prefer to only do chest compressions. The most cited fear was a low level of confidence, and fears of acquiring infections or aversion to mouth-to-mouth breathing were low.ConclusionsThe survey results show that most participants in Singapore are keen to perform conventional CPR for a member of the public and can help to target future CPR training accordingly.

Scoliosis is one of the most common pediatric spinal diseases that leads to a three-dimensional deformity of the spine and has a high risk of progression during growth. Regular clinical monitoring and follow-up X-rays are needed to providing proper treatment at that time. Repetitive X-rays can results in an increased risk of radiation related health problems. We present a non-invasive, ionizing radiation-free method for assessing scoliosis and its progression from the 3D images of the body torso, captured by a body scanner. A new concept is introduced based on a mathematical method in polar coordinate system to quantify and characterize the deformities in the torso from 2D transverse cross-sections of the 3D torso images at example cases for a healthy individual and for two patients with scoliosis. To capture quantitatively the characteristics of scoliosis, and to verify them at the example cases two asymmetry parameters and a linear fitting parameter are calculated: a) back side area asymmetry, b) left right area asymmetry, and c) coefficient of determination (R2). Within the analyzed patients, both the area asymmetries are maximum at the apex of scoliosis, and increase with the severity of scoliosis. R2 values are smaller in the case of patients compared with the healthy. Furthermore, the parameters show a trend when compared with the Cobb angle from the X-ray and the findings match with clinical examination. Therefore, the quantities are able to capture, certain characteristics associated with scoliosis. These quantities can be compared as a measure of deformities of torso, during the follow-up examinations in the future, without ionizing radiations.

Scoliosis is one of the most common pediatric spinal diseases that leads to a three-dimensional deformity of the spine and has a high risk of progression during growth. Regular clinical monitoring and follow-up X-rays are needed to providing proper treatment at that time. Repetitive X-rays can results in an increased risk of radiation related health problems. We present a non-invasive, ionizing radiation-free method for assessing scoliosis and its progression from the 3D images of the body torso, captured by a body scanner. A new concept is introduced based on a mathematical method in polar coordinate system to quantify and characterize the deformities in the torso from 2D transverse cross-sections of the 3D torso images at example cases for a healthy individual and for two patients with scoliosis. To capture quantitatively the characteristics of scoliosis, and to verify them at the example cases two asymmetry parameters and a linear fitting parameter are calculated: a) back side area asymmetry, b) left right area asymmetry, and c) coefficient of determination ( R 2 ). Within the analyzed patients, both the area asymmetries are maximum at the apex of scoliosis, and increase with the severity of scoliosis. R 2 values are smaller in the case of patients compared with the healthy. Furthermore, the parameters show a trend when compared with the Cobb angle from the X-ray and the findings match with clinical examination. Therefore, the quantities are able to capture, certain characteristics associated with scoliosis. These quantities can be compared as a measure of deformities of torso, during the follow-up examinations in the future, without ionizing radiations.

Piper nigrum L. also called black pepper is popular for its numerous uses. The present research is designed to investigate the pharmacological potential of methanol extract of Piper nigrum (MEPN). The antidepressant investigation was performed by using both in vivo forced swimming test (FST) and tail suspension test (TST) methods while the anxiolytic research by hole‐board test (HBT) method. Again, the antipyretic analysis was conducted through yeast‐induced pyrexia method, whereas clot lysis activity was employed by the thrombolytic method. Furthermore, in silico studies followed by molecular docking analysis of several secondary metabolites, pass prediction, and ADME/T were evaluated with AutoDock Vina, Discovery Studio 2020, UCSF Chimera software PASS online, and ADME/T online tools. The plant extract demonstrated dose‐dependent potentiality in antidepressant, anxiolytic, antipyretic, and thrombolytic activities. Induction of MEPN produced a significant (p < .5, p < .001) increase of mobility in FST and TST, and increased the head dipping and decreased the latency of time (p < .01, p < .001) in HBT. MEPN 400 (mg/kg; b.w.; p.o.) lowered the rectal temperature of yeast‐induced pyrexia substantially (p < .001). Besides, MEPN produced promising (p < .001) clot lysis activity. In the computational approach, among all the proteins, a docking score was found ranging from −1.0 to −7.90 kcal/mol. Besides, all the compounds were found safe in ADME/T study. The results of our scientific research validate the suitability of this plant as an alternative source of novel therapeutics. The methanolic extract of the plant Piper nigrum has promising biological activities that are supported by computational approaches. So, this plant can be considered as an alternative source of therapeutics.

Adolescent idiopathic scoliosis, is a three-dimensional spinal deformity characterized by lateral curvature and axial rotation around the vertical body axis of the spine, the cause of which is yet unknown. The fast progression entails regular clinical monitoring, including X-rays. Here we present an approach to evaluate scoliosis from the three-dimensional image of a patient’s torso, captured by an ionizing radiation free body scanner, in combination with a model of the ribcage and spine. A skeletal structure of the ribcage and vertebral column was modelled with computer aided designed software and was used as an initial structure for macroscopic finite element method simulations. The basic vertebral column model was created for an adult female in an upright position. The model was then used to simulate the patient specific scoliotic spine configurations. The simulations showed that a lateral translation of a vertebral body results in an effective axial rotation and could reproduce the spinal curvatures. The combined method of three-dimensional body scan and finite element model simulations thus provide quantitative anatomical information about the position, rotation and inclination of the thoracic and lumbar vertebrae within a three-dimensional torso. Furthermore, the simulations showed unequal distributions of stress and strain profiles across the intervertebral discs, due to their distortions, which might help to further understand the pathogenesis of scoliosis.

The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.

Background: Mismatch negativity (MMN), an event-related potential (ERP) component occurring at specific recording sites and latency, is associated with an automatic change detection response, generally elicited using oddball paradigms wherein infrequent stimuli are embedded in repeated, frequent stimuli. To verify the presence of mismatch-related ERP responses to somatosensory stimulation in individuals with cerebral palsy (CP), we conducted a preliminary study involving healthy participants and patients with CP. Methods: Both groups underwent ‘frequent’ and ’infrequent’ stimulation applied to the ring finger and thumb of their left hand, respectively. ERPs were recorded at frontal, central, and parietal scalp locations using electroencephalography. A healthy cohort tested the experimental protocol and showed evidence that mismatch-related ERP responses were observable. Subsequent analysis focused on the patient group. Results: Statistically significant differences between the two types of stimuli were observed on the frontocentral and parietal channels between 150 and 250 ms after the stimulus onset in the patient group. Furthermore, a late discriminative response was observed in the frontal and parietal channels. Conclusion: The results demonstrate the presence of mismatch-related ERP responses in individuals with CP.

Motivated by several recent experimental observations that vitamin-D could interact with antigen presenting cells (APCs) and T-lymphocyte cells (T-cells) to promote and to regulate different stages of immune response, we developed a coarse grained but general kinetic model in an attempt to capture the role of vitamin-D in immunomodulatory responses. Our kinetic model, developed using the ideas of chemical network theory, leads to a system of nine coupled equations that we solve both by direct and by stochastic (Gillespie) methods. Both the analyses consistently provide detail information on the dependence of immune response to the variation of critical rate parameters. We find that although vitamin-D plays a negligible role in the initial immune response, it exerts a profound influence in the long term, especially in helping the system to achieve a new, stable steady state. The study explores the role of vitamin-D in preserving an observed bistability in the phase diagram (spanned by system parameters) of immune regulation, thus allowing the response to tolerate a wide range of pathogenic stimulation which could help in resisting autoimmune diseases. We also study how vitamin-D affects the time dependent population of dendritic cells that connect between innate and adaptive immune responses. Variations in dose dependent response of anti-inflammatory and pro-inflammatory T-cell populations to vitamin-D correlate well with recent experimental results. Our kinetic model allows for an estimation of the range of optimum level of vitamin-D required for smooth functioning of the immune system and for control of both hyper-regulation and inflammation. Most importantly, the present study reveals that an overdose or toxic level of vitamin-D or any steroid analogue could give rise to too large a tolerant response, leading to an inefficacy in adaptive immune function.

Background/Objectives: Patients with physical disabilities, like cerebral palsy, the most common movement disorder in childhood, can benefit from instrumental therapy using piano. Playing the piano promotes the interaction between different brain regions and integrates motor skills, sensory skills, musical hearing, and emotions. A pilot music study examined the effects of six months of piano lessons on hand motor skills and musical hearing in groups of children with motor disabilities. Methods: The allocation to the group was not randomized. Various tests, including the standardized Box and Block Test (BBT) and piano tests, assessed hand motor skills. Musical hearing was evaluated, and a questionnaire was used to determine the participants’ enjoyment and experience with the piano lessons. The regularity, tempo of keystrokes, and synchronization between the two hands were assessed and compared to evaluate the effects of six months of piano training. Results: After six months of piano training, statistically significant improvements were observed in the BBT, as well as in the regularity and tempo of the non-dominant hand. The children showed significant improvement in hand-motor control, moving 27.3% more cubes in the BBT. Regularity and tempo in piano playing, especially in the non-dominant hand, also improved. Moreover, 55% of the children better recognized the correct pitches of notes. Conclusions: Thus, this study supports the concept that piano lessons are an effective form of physical therapy for the development of hand motor skills and musical hearing.