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Myotendinous junctions (MTJs) are specialized sites on the muscle surface where forces generated by myofibrils are transmitted across the sarcolemma to the extracellular matrix. At the ultrastructural level, the interface between the sarcolemma and extracellular matrix is highly folded and interdigitated at these junctions. In this study, the effect of exercise and growth hormone (GH) treatments on the changes in MTJ structure that occur during muscle unloading, has been analyzed. Twenty hypophysectomized rats were assigned randomly to one of five groups: ambulatory control, hindlimb unloaded, hindlimb unloaded plus exercise (3 daily bouts of 10 climbs up a ladder with 50% body wt attached to the tail), hindlimb unloaded plus GH (2 daily injections of 1 mg/kg body wt, i.p.), and hindlimb unloaded plus exercise plus GH. MTJs of the plantaris muscle were analyzed by electron microscopy and the contact between muscle and tendon was evaluated using an IL/B ratio, where B is the base and IL is the interface length of MTJ's digit-like processes. After 10 days of unloading, the mean IL/B ratio was significantly lower in unloaded (3.92), unloaded plus exercise (4.18), and unloaded plus GH (5.25) groups than in the ambulatory control (6.39) group. On the opposite, the mean IL/B ratio in the group treated with both exercise and GH (7.3) was similar to control. These findings indicate that the interaction between exercise and GH treatments attenuates the changes in MTJ structure that result from chronic unloading and thus can be used as a countermeasure to these adaptations.

Primates are an important and unique animal resource. We have developed a nonhuman primate model of spinal cord injury (SCI) to expand our knowledge of normal primate motor function, to assess the impact of disease and injury on sensory and motor function, and to test candidate therapies before they are applied to human patients. The lesion model consists of a lateral spinal cord hemisection at the C7 spinal level with subsequent examination of behavioral, electrophysiological, and anatomical outcomes. Results to date have revealed significant neuroanatomical and functional differences between rodents and primates that impact the development of candidate therapies. Moreover, these findings suggest the importance of testing some therapeutic approaches in nonhuman primates prior to the use of invasive approaches in human clinical trials. Our primate model is intended to: 1) lend greater positive predictive value to human translatable therapies, 2) develop appropriate methods for human translation, 3) lead to basic discoveries that might not be identified in rodent models and are relevant to human translation, and 4) identify new avenues of basic research to "reverse-translate" important questions back to rodent models. [ABSTRACT FROM AUTHOR]

The lumbosacral spinal cord of mammals contains the neural circuitry capable of generating full weight-bearing locomotion of the hind limbs without any supraspinal input. One or more interventions, for example, pharmacological, epidural stimulation, and/or locomotor training, however, are necessary to gain access to and modulate the properties of this circuitry and to facilitate recovery of full weight-bearing locomotion after spinal cord injury. [ABSTRACT FROM AUTHOR]

This article reviews several tools we have developed to improve the understanding of locomotor training following spinal cord injury (SCI), with a view toward implementing locomotor training with robotic devices. We have developed (1) a small-scale robotic device that allows testing of locomotor training techniques in rodent models, (2) an instrumentation system that measures the forces and motions used by experienced human therapists as they manually assist leg movement during locomotor training, (3) a powerful, lightweight leg robot that allows investigation of motor adaptation during stepping in response to force-field perturbations, and (4) computational models for locomotor training. Results from the initial use of these tools suggest that an optimal gait-training robot will minimize disruptive sensory input, facilitate appropriate sensory input and gait mechanics, and intelligently grade and time its assistance. Currently, we are developing a pneumatic robot designed to meet these specifications as it assists leg and pelvic motion of people with SCI. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the triggers and maintenance of atrial fibrillation (AF) are not fully understood. One potential unproved mechanism is that gastroesophageal reflux disease (GERD), in which acid reflux induces local and systemic inflammation, may increase triggered activity in the myocardium and pulmonary veins and increase AF risk. A self-report questionnaire was mailed to a random sample of 5,288 residents of Olmsted County, Minnesota, aged 25 to 74 years to assess the presence and frequency of GERD from 1988 to 1994. The long-term risk for AF over a period of 11.4 +/- 5.0 years was determined through review of clinical evaluations and the electrocardiographic database in those without previous AF. The average age was 53 +/- 17 years, and 2,571 subjects (49%) were man. Of these patients, 741 developed AF (cumulative probability of AF at 18 years 20%, 95% confidence interval [CI] 17% to 22%). Age (hazard ratio [HR] 1.09, 95% CI 1.08 to 1.10, p <0.001), male gender (HR 1.81, 95% CI 1.53 to 2.14, p <0.001), hypertension (HR 1.36, 95% CI 1.14 to 1.61, p = 0.0006), and heart failure (HR 1.74, 95% CI 1.16 to 2.60, p = 0.007) were independently associated with the risk of AF. The presence of any GERD was not associated with risk for AF (HR 0.81, 95% CI 0.68 to 0.96, p = 0.014) after adjustment for other risk factors. The frequency of GERD did not significantly affect the risk for AF, although patients with more frequent GERD had a slightly higher AF risk. Esophagitis increased the risk for AF (HR 1.94, 95% CI 1.35 to 2.78, p <0.001), but the association did not persist when accounting for other risk factors (p = 0.72). In conclusion, in this large population-based study of patients surveyed for GERD, no association was found with the presence or frequency of symptoms and AF. Patients with esophagitis were more likely to develop AF, although this association requires further study. [ABSTRACT FROM AUTHOR]

Nanotube porins form transmembrane nanomaterial-derived scaffolds that mimic the geometry and functionality of biological membrane channels. We report synthesis, transport properties, and osmotic energy harvesting performance of another member of the nanotube porin family: boron nitride nanotube porins (BNNTPs). Cryo-transmission electron microscopy imaging, liposome transport assays, and DNA translocation experiments show that BNNTPs reconstitute into lipid membranes to form functional channels of ~2-nm diameter. Ion transport studies reveal ion conductance characteristics of individual BNNTPs, which show an unusual C 1/4 scaling with ion concentration and pronounced pH sensitivity. Reversal potential measurements indicate that BNNTPs have strong cation selectivity at neutral pH, attributable to the high negative charge on the channel. BNNTPs also deliver very large power density up to 12 kW/m 2 in the osmotic gradient transport experiments at neutral pH, surpassing that of other BNNT-based devices by two orders of magnitude under similar conditions. Our results suggest that BNNTPs are a promising platform for mass transport and osmotic power generation.

The molecular underpinnings and consequences of cycles of whole-genome duplication (WGD) and subsequent gene loss through subgenome fractionation remain largely elusive. Endogenous drivers, such as transposable elements (TEs), have been postulated to shape genome-wide dominance and biased fractionation, leading to a conserved least-fractionated (LF) subgenome and a degenerated most-fractionated (MF) subgenome. In contrast, the role of exogenous factors, such as those induced by environmental stresses, has been overlooked. In this study, a chromosome-scale assembly of the alpine buckler mustard (Biscutella laevigata; Brassicaceae) that underwent a WGD event about 11 million years ago is coupled with transcriptional responses to heat, cold, drought, and herbivory to assess how gene expression is associated with differential gene retention across the MF and LF subgenomes. Counteracting the impact of TEs in reducing the expression and retention of nearby genes across the MF subgenome, dosage balance is highlighted as a main endogenous promoter of the retention of duplicated gene products under purifying selection. Consistent with the "turn a hobby into a job" model, about one-third of environment-responsive duplicates exhibit novel expression patterns, with one copy typically remaining conditionally expressed, whereas the other copy has evolved constitutive expression, highlighting exogenous factors as a major driver of gene retention. Showing uneven patterns of fractionation, with regions remaining unbiased, but with others showing high bias and significant enrichment in environment-responsive genes, this mesopolyploid genome presents evolutionary signatures consistent with an interplay of endogenous and exogenous factors having driven gene content following WGD-fractionation cycles., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The present study aims at ideating a quantitative protocol to evaluate effectiveness of training programmes especially meant for farmers, farm women, and rural youth. The specific objective was to develop a robust framework for measuring the effectiveness of rural training programmes organized by the Farmers Training Centres (FTCs) of India. Kirkpatrick's training evaluation model provides us the foundation to design a four-dimensional composite framework based on range-based indicator normalization, principal component analysis based indicator weight estimation, and rank correlation based framework sensitivity testing. We used cross-sectional primary data generated through household survey and personal interviews with randomly selected one thousand trainees to test and validate our proposed protocol. Applying it on our evaluation target we find that the degree of effectiveness of the training programmes varies; one in every four training programmes may not be effective. Trainees' reactions on various aspects of the training programmes may have positive and significant influence on learning. Training outcomes may be linked with the trainees' post-training changes in behaviour. A sensitivity test confirms that the proposed framework is not susceptible to changes in weighting schemes, implying robustness of indicator selection. The findings offer dissection of individual training programmes guiding policy decisions for a training organization. The proposed framework enriches the Kirkpatrick's training evaluation model by offering standardized indicators for training effectiveness evaluation., Competing Interests: Declarations of Competing interest We, the authors of the present article do hereby declare that we have no financial and personal relationships with other people or organizations that could inappropriately influence or bias the present work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 μM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bradyarrhythmias, characterized by heart rates of <60 bpm due to conduction issues, carry risks of sudden cardiac death and falls. Pacemaker implantation is a standard treatment, but the interplay between bradyarrhythmias, coronary artery disease (CAD), and patient attributes requires further exploration. This study was a retrospective hospital record-based study that analyzed data from 699 patients who underwent pacemaker implantation for symptomatic bradyarrhythmias between February 2019 and February 2022. Clinical parameters, coronary angiography (CAG) findings, ejection fraction, and indications for pacemaker implantation were documented. The relationship between CAD severity, specific bradyarrhythmias, and ejection fraction was explored. Statistical analysis included chi-squared tests and t tests. The mean age of the study population (n = 699) was 66.75 years (male:female ratio, 70:30), with 77.2% having type 2 diabetes and 61.6% being hypertensive. The majority of patients had minor or non-obstructive CAD (61.8%), followed by normal CAG findings (25.75%) and obstructive CAD (12.45%). Complete heart block (CHB) was the primary indication for pacemaker implantation (55.2%), followed by sick sinus syndrome (22.3%). The results did not show any association between ejection fraction and CAG findings. Patients who presented with CHB had a higher incidence of obstructive CAD, indicating greater severity. This study sheds light on the intricate interplay between severe bradyarrhythmias, CAD, and patient characteristics. Our analysis revealed no statistical significance between obstructive CAD and the need for a permanent pacemaker. This makes us question our practice of maintaining a low threshold for coronary angiography during pacemaker implantation. The observed low yield and anticoagulation protocol reassure us of the choice to delay this diagnostic intervention. These insights can guide tailored management strategies, enhancing clinical care approaches for patients with severe bradyarrhythmias necessitating pacemaker implantation., Competing Interests: The authors report no conflicts of interest for the published content. No funding information was provided., (Copyright: © 2024 Innovations in Cardiac Rhythm Management.)

Background: The pandemic of SARS-CoV-2 was a novel situation, there was no conclusive knowledge, particularly concerning its effect on pregnant women and infants. Eminent obstetric organizations have introduced an array of guidelines to assist clinicians in countering this prior unknown outbreak. The primary objective of this study was to summarize the clinical characteristics, complications, and maternal and neonatal outcomes of COVID-19 during pregnancy and puerperium., Methods: This was a cross-sectional observational study conducted in the Outpatient/Emergency/Inpatient or COVID ward in the Department of Obstetrics and Gynaecology, of a tertiary hospital in Nadia district, West Bengal, India, from 1.7.2020 to 30.6.2021 including 104 pregnant or puerperal mothers with laboratory-confirmed, i.e., RT-PCR or Rapid Antigen Test positive reports after informed consent. The obstetric outcome, modes of delivery, and neonatal status including any complications or SNCU admission within six weeks postpartum were recorded., Results: The majority were in the ≥ 20-24 years age group, primigravida, residents of Nadia with no significant travel or contact history. 73.08% were affected in the third trimester and the comorbidities detected were chiefly anemia (15.38%), hypertensive or chronic liver diseases, and hypothyroidism. 45.19% of the mothers were asymptomatic while the other complaints were fever (18.27%), cough (11.55%), anosmia and/or ageusia (10.58%), sore throat (9.61%), respiratory distress, loose stools, and chest pain. The medical complications were predominantly low SpO2, convulsions, pneumonitis, and two maternal deaths. The obstetric complications were preterm birth (26.9%), pre-eclampsia/eclampsia (17.3%), antepartum (3.9%) and postpartum hemorrhage (4.4%), and sepsis (5.8%). Fourteen mothers had first-trimester termination, 63 had vaginal deliveries, and the rest had cesarean section. Out of 90 neonates, most were in the range of ≥ 2-2.5 kg birth weight and normal 1-min APGAR score. None tested positive for COVID-19 RTPCR and no detectable congenital anomaly or neonatal death was recorded., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Skin cancer, including the highly lethal malignant melanoma, poses a significant global health challenge with a rising incidence rate. Early detection plays a pivotal role in improving survival rates. This study aims to develop an advanced deep learning-based approach for accurate skin lesion classification, addressing challenges such as limited data availability, class imbalance, and noise. Modern deep neural network designs, such as ResNeXt101, SeResNeXt101, ResNet152V2, DenseNet201, GoogLeNet, and Xception, which are used in the study and ze optimised using the SGD technique. The dataset comprises diverse skin lesion images from the HAM10000 and ISIC datasets. Noise and artifacts are tackled using image inpainting, and data augmentation techniques enhance training sample diversity. The ensemble technique is utilized, creating both average and weighted average ensemble models. Grid search optimizes model weight distribution. The individual models exhibit varying performance, with metrics including recall, precision, F1 score, and MCC. The "Average ensemble model" achieves harmonious balance, emphasizing precision, F1 score, and recall, yielding high performance. The "Weighted ensemble model" capitalizes on individual models' strengths, showcasing heightened precision and MCC, yielding outstanding performance. The ensemble models consistently outperform individual models, with the average ensemble model attaining a macro-average ROC-AUC score of 96 % and the weighted ensemble model achieving a macro-average ROC-AUC score of 97 %. This research demonstrates the efficacy of ensemble techniques in significantly improving skin lesion classification accuracy. By harnessing the strengths of individual models and addressing their limitations, the ensemble models exhibit robust and reliable performance across various metrics. The findings underscore the potential of ensemble techniques in enhancing medical diagnostics and contributing to improved patient outcomes in skin lesion diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introgression is an important source of genetic variation that can determine species adaptation to environmental conditions. Yet, definitive evidence of the genomic and adaptive implications of introgression in nature remains scarce. The widespread hybrid zones of Darwin's primroses (Primula elatior, Primula veris, and Primula vulgaris) provide a unique natural laboratory for studying introgression in flowering plants and the varying permeability of species boundaries. Through analysis of 650 genomes, we provide evidence of an introgressed genomic region likely to confer adaptive advantage in conditions of soil toxicity. We also document unequivocal evidence of chloroplast introgression, an important precursor to species-wide chloroplast capture. Finally, we provide the first evidence that the S-locus supergene, which controls heterostyly in primroses, does not introgress in this clade. Our results contribute novel insights into the adaptive role of introgression and demonstrate the importance of extensive genomic and geographical sampling for illuminating the complex nature of species boundaries., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

The midpoint potential of the [Fe 2 S 2 ]-Cys 4 -cluster in proteins is known to vary between -200 and -450 mV. This variation is caused by the different electrostatic environment of the cluster in the respective proteins. Continuum electrostatics can quantify the impact of the protein environment on the redox potential. Thus, if the redox potential of a [Fe 2 S 2 ]-Cys 4 -cluster model compound in aqueous solution would be known, then redox potentials in various protein complexes could be calculated. However, [Fe 2 S 2 ]-Cys 4 -cluster models are not water-soluble, and thus, their redox potential can not be measured in aqueous solution. To overcome this problem, we introduce a method that we call Virtual Model Compound Approach (VMCA) to extrapolate the model redox potential from known redox potentials of proteins. We carefully selected high-resolution structures for our analysis and divide them into a fit set, for fitting the model redox potential, and an independent test set, to check the validity of the model redox potential. However, from our analysis, we realized that the some structures can not be used as downloaded from the PDB but had to be re-refined in order to calculate reliable redox potentials. Because of the re-refinement, we were able to significantly reduce the standard deviation of our derived model redox potential for the [Fe 2 S 2 ]-Cys 4 -cluster from 31 mV to 10 mV. As the model redox potential, we obtained -184 mV. This model redox potential can be used to analyze the redox behavior of [Fe 2 S 2 ]-Cys 4 -clusters in larger protein complexes.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been used as a tool for diagnosis, severity assessment and prognostication of congestive heart failure (CHF) in adults, with specific cut off values for diagnosis and denoting points of intervention. However, there is scarcity of paediatric literature regarding role of NT-proBNP as a marker of heart failure severity and prognostication. So, this study was done to assess the utility of NT-proBNP as a marker of severity of heart failure in children with congenital heart diseases. Single centre, prospective observational study. Children (1 month to 5 years), with congenital heart disease, admitted in the paediatric wards with varying severity of CHF were enrolled. Heart failure severity grading was done according to Laer modification of Ross Classification at the time of presentation to hospital and children were classified as having no/grade I CHF (score: 0-2); mild/grade II CHF (score 3-6); moderate/grade III CHF (score 7-9) or severe/grade IV CHF (score 10-12). NT-proBNP levels were measured within 24 h of admission. Eighty children with congenital heart disease were enrolled in this study. As per modified Ross Classification, 11 had grade I/No heart failure (13.7%), 32 children had grade II/mild heart failure (40%), 36 had grade III/moderate heart failure (45%) and only 1 had grade IV/severe heart failure (1.25%). The median NT-proBNP levels (IQR) in the above mentioned grades of heart failure were found to be 321.11 (211.1-411.78 pg/ml), 750.62 (474.62-995.2 pg/ml), 4159.61 (1440.59-11,857 pg/ml) and 11,320.34 pg/ml, respectively. Seven children (8.75%) expired. Median NT-proBNP value in seven children who died was significantly higher than those who survived [median (IQR): 11,681.01 pg/ml (10,092.72-14,754 pg/ml) vs 839.4 pg/ml (456.67-3288.09 pg/ml), p value < 0.001]. NT-proBNP level of 520.2 pg/ml predicted grade II (mild heart failure) or more severe grades of heart failure with Sensitivity, Specificity, Negative Predictive Value and Positive Predictive Value of 83%, 91%, 57.1% and 98%, respectively. NT-proBNP levels increase progressively with increasing severity of CHF and can be used as a marker of severity of heart failure in children with congenital heart disease presenting with CHF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long-term high-fat feeding results in intramyocellular lipid accumulation, leading to insulin resistance. Intramyocellular lipid accumulation is related to an energy imbalance between excess fat intake and fatty acid consumption. Alternating current electromagnetic field exposure has been shown to enhance mitochondrial metabolism in the liver and sperm. Therefore, we hypothesized that alternating current electromagnetic field exposure would ameliorate high-fat diet-induced intramyocellular lipid accumulation via activation of fatty acid consumption. C57BL/6J mice were either fed a normal diet (ND), a normal diet and exposed to an alternating current electromagnetic field (ND+EMF), a high-fat diet (HFD), or a high-fat diet and exposed to an alternating current electromagnetic field (HFD+EMF). Electromagnetic field exposure was administered 8 hrs/day for 16 weeks using an alternating current electromagnetic field device (max.180 mT, Hokoen, Utatsu, Japan). Tibialis anterior muscles were collected for measurement of intramyocellular lipids, AMPK phosphorylation, FAT/CD-36, and carnitine palmitoyltransferase (CPT)-1b protein expression levels. Intramyocellular lipid levels were lower in the HFD + EMF than in the HFD group. The levels of AMPK phosphorylation, FAT/CD-36, and CPT-1b protein levels were higher in the HFD + EMF than in the HFD group. These results indicate that alternating current electromagnetic field exposure decreases intramyocellular lipid accumulation via increased fat consumption., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nakanishi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Odontogenic keratocysts constitute 10%-20% of odontogenic cysts and exhibit a distinctive corrugated parakeratinized lining epithelium. Considering that cornified envelope formation is an important phenomenon during keratinocyte differentiation, this study aimed to clarify the characteristics of cornified envelope formation in odontogenic keratocysts., Methods: We investigated the cellular distribution of cornified envelope-related proteins (transglutaminases and their substrates), as well as the upstream regulatory protein c-Fos, by immunohistochemical analysis of the lining epithelium of 20 odontogenic keratocysts. We examined the corresponding mRNA levels by quantitative polymerase chain reaction. Ten dentigerous cysts served as control non-keratinized cysts., Results: The distributions of transglutaminase and their substrates except loricrin and small protein-rich protein 1a significantly differed between odontogenic keratocysts and dentigerous cysts. There was no significant difference in c-Fos expression between odontogenic keratocysts and dentigerous cysts. The mRNA levels of transglutaminases and their substrates were significantly higher in odontogenic keratocysts than in dentigerous cysts. However, c-Fos mRNA levels did not significantly differ between groups., Conclusion: Surprisingly, the overall appearance of cornified envelope-related proteins of odontogenic keratocysts was consistent with the characteristics of non-keratinized oral mucosa identified in previous studies. These findings indicate that the contribution of cornified envelope-related molecules in odontogenic keratocysts is similar to that in non-keratinized oral epithelium, rather than keratinized oral epithelium, suggesting that odontogenic keratocysts are not genuine keratinized cysts. The upregulation of cornified envelope-related genes in odontogenic epithelium could be an important pathognomonic event during odontogenic keratocyst development., (© 2023 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Introduction: The paralysis that occurs after a spinal cord injury, particularly during the early stages of post-lesion recovery (∼6 weeks), appears to be attributable to the inability to activate motor pools well beyond their motor threshold. In the later stages of recovery, however, the inability to perform a motor task effectively can be attributed to abnormal activation patterns among motor pools, resulting in poor coordination., Method: We have tested this hypothesis on four adult male Rhesus monkeys ( Macaca mulatta ), ages 6-10 years, by recording the EMG activity levels and patterns of multiple proximal and distal muscles controlling the upper limb of the Rhesus when performing three tasks requiring different levels of skill before and up to 24 weeks after a lateral hemisection at C7. During the recovery period the animals were provided routine daily care, including access to a large exercise cage (5' × 7' × 10') and tested every 3-4 weeks for each of the three motor tasks., Results: At approximately 6-8 weeks the animals were able to begin to step on a treadmill, perform a spring-loaded task with the upper limb, and reaching, grasping, and eating a grape placed on a vertical stick. The predominant changes that occurred, beginning at ∼6-8 weeks of the recovery of these tasks was an elevated level of activation of most motor pools well beyond the pre-lesion level., Discussion: As the chronic phase progressed there was a slight reduction in the EMG burst amplitudes of some muscles and less incidence of co-contraction of agonists and antagonists, probably contributing to an improved ability to selectively activate motor pools in a more effective temporal pattern. Relative to pre-lesion, however, the EMG patterns even at the initial stages of recovery of successfully performing the different motor tasks, the level of activity of most muscle remained higher. Perhaps the most important concept that emerges from these data is the large combinations of adaptive strategies in the relative level of recruitment and the timing of the peak levels of activation of different motor pools can progressively provide different stages to regain a motor skill., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Wai, Zdunowski, Zhong, Nielson, Ferguson, Strand, Moseanko, Hawbecker, Nout-Lomas, Rosenzweig, Beattie, Bresnahan, Tuszynski, Roy and Edgerton.)

Background: Patients with cervical/upper thoracic compressive myelopathy may have autonomic dysfunction. The composite autonomic severity score (CASS) is the gold standard test to detect autonomic dysfunction, and the self-rated composite autonomic system scale (COMPASS-31) questionnaire is a screening tool to diagnose autonomic dysfunction. This study compared the COMPASS-31 and modified CASS scores for the detection of autonomic dysfunction in patients with compressive myelopathy., Methods: Patients with cervical/upper thoracic compressive myelopathy scheduled for decompressive surgery completed a COMPASS-31 questionnaire and underwent autonomic function tests to calculate the modified CASS score before surgery., Results: Forty-two patients were included in the study; 19 (45.2%) had mild autonomic dysfunction, 5 (11.9%) had moderate autonomic dysfunction, and 18 (42.9%) had severe autonomic dysfunction. Median (interquartile range) of modified CASS and COMPASS-31 scores were 19 (6.33) and 3 (2.5), respectively. There was a positive correlation between modified CASS and COMPASS-31 scores ( r =0.43; P =0.004). Receiver operating characteristic curve analysis confirmed that COMPASS-31 had fair accuracy for prediction of moderate to severe autonomic dysfunction (area under the curve, 0.74; 95% confidence interval, 0.64-0.82; P =0.009). A cut-off of 30 for total COMPASS-31 score had a sensitivity of 52.2% and specificity of 89.5% to detect moderate to severe autonomic dysfunction, with positive and negative predictive values of 85.7% and 60.7%, respectively., Conclusion: Patients with cervical/upper thoracic compressive myelopathy had varying degrees of autonomic dysfunction based on the modified CASS. There was a positive correlation between the modified CASS and COMPASS-31 questionnaire. A COMPASS-31 score of >30 30 could be utilized to predict moderate to severe autonomic dysfunction in patients with compressive myelopathy., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The swallowing reflex is an essential physiological reflex that allows food or liquid to pass into the esophagus from the oral cavity. Delayed triggering of this reflex is a significant health problem in patients with oropharyngeal dysphagia for which no pharmacological treatments exist. Transient receptor potential channels have recently been discovered as potential targets to facilitate triggering of the swallowing reflex. However, the ability of transient receptor potential vanilloid 4 (TRPV4) to trigger the swallowing reflex has not been studied. Here, we demonstrate the involvement of TRPV4 in triggering the swallowing reflex in rats. TRPV4 immunoreactive nerve fibers were observed in the superior laryngeal nerve (SLN)-innervated swallowing-related regions. Retrograde tracing with fluorogold revealed localization of TRPV4 on approximately 25% of SLN-afferent neurons in the nodose-petrosal-jugular ganglionic complex. Among them, approximately 49% were large, 35% medium, and 15% small-sized SLN-afferent neurons. Topical application of a TRPV4 agonist (GSK1016790A) to the SLN-innervated regions dose-dependently facilitated triggering of the swallowing reflex, with the highest number of reflexes triggered at a concentration of 250 μM. The number of agonist-induced swallowing reflexes was significantly reduced by prior topical application of a TRPV4 antagonist. These findings indicate that TRPV4 is expressed on sensory nerves innervating the swallowing-related regions, and that its activation by an agonist can facilitate swallowing. TRPV4 is a potential pharmacological target for the management of oropharyngeal dysphagia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hossain, Ando, Unno, Roy and Kitagawa.)

Viltolarsen is a phosphorodiamidate morpholino antisense oligonucleotide (PMO) designed to skip exon 53 of the DMD gene for the treatment of Duchenne muscular dystrophy (DMD), one of the most common lethal genetic disorders characterized by progressive degeneration of skeletal muscles and cardiomyopathy. It was developed by Nippon Shinyaku in collaboration with the National Center of Neurology and Psychiatry (NCNP) in Japan based on the preclinical studies conducted in the DMD dog model at the NCNP. After showing hopeful results in pre-clinical trials and several clinical trials across North America and Japan, it received US Food and Drug Administration (FDA) approval for DMD in 2020. Viltolarsen restores the reading frame of the DMD gene by skipping  exon 53 and produces a truncated but functional form of dystrophin. It can treat approximately 8-10% of the DMD patient population. This paper aims to summarize the development of viltolarsen from preclinical trials to clinical trials to, finally, FDA approval, and discusses the challenges that come with fighting DMD using antisense therapy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Giant axonal neuropathy (GAN) is a pediatric, hereditary, neurodegenerative disorder that affects both the central and peripheral nervous systems. It is caused by mutations in the GAN gene, which codes for the gigaxonin protein. Gigaxonin plays a role in intermediate filament (IF) turnover hence loss of function of this protein leads to IF aggregates in various types of cells. These aggregates can lead to abnormal cellular function that manifests as a diverse set of symptoms in persons with GAN including nerve degeneration, cognitive issues, skin diseases, vision loss, and muscle weakness. GAN has no cure at this time. Currently, an adeno-associated virus (AAV) 9-mediated gene replacement therapy is being tested in a phase I clinical trial for the treatment of GAN. This review paper aims to provide an overview of giant axonal neuropathy and the current efforts at developing a treatment for this devastating disease.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1 R206H by activin A induces heterotopic ossification. Since ACVR1 R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1 R206H expression at RNA levels, while ACVR1 WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1 R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.

Background: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies., Methods: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity., Results: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin , indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

Duchenne muscular dystrophy (DMD) is primarily caused by out-of-frame deletions in the dystrophin gene. Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) converts out-of-frame to in-frame mutations, producing partially functional dystrophin. Four single-exon skipping PMOs are approved for DMD but treat only 8 to 14% of patients each, and some exhibit poor efficacy. Alternatively, exons 45 to 55 skipping could treat 40 to 47% of all patients and is associated with improved clinical outcomes. Here, we report the development of peptide-conjugated PMOs for exons 45 to 55 skipping. Experiments with immortalized patient myotubes revealed that exons 45 to 55 could be skipped by targeting as few as five exons. We also found that conjugating DG9, a cell-penetrating peptide, to PMOs improved single-exon 51 skipping, dystrophin restoration, and muscle function in hDMDdel52; mdx mice. Local administration of a minimized exons 45 to 55-skipping DG9-PMO mixture restored dystrophin production. This study provides proof of concept toward the development of a more economical and effective exons 45 to 55-skipping DMD therapy., Competing Interests: Competing interest statement: T.Y. and R.M. are cofounders of OligomicsTx. The authors plan to file a patent application relevant to the technology described in this article.