Junction Defects Research Articles

Mitochondrial disorders are associated with morphological neuromuscular junction defects

We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders.Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p=0.0001), neoformed (p=0.0049) and dilated (p=0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p=0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy.This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.

ESCRT-III-dependent adhesive and mechanical changes are triggered by a mechanism detecting alteration of septate junction integrity in Drosophila epithelial cells.

Barrier functions of proliferative epithelia are constantly challenged by mechanical and chemical constraints. How epithelia respond to and cope with disturbances of barrier functions to allow tissue integrity maintenance is poorly characterised. Cellular junctions play an important role in this process and intracellular traffic contribute to their homeostasis. Here, we reveal that, in Drosophila pupal notum, alteration of the bi- or tricellular septate junctions (SJs) triggers a mechanism with two prominent outcomes. On one hand, there is an increase in the levels of E-cadherin, F-actin, and non-muscle myosin II in the plane of adherens junctions. On the other hand, β-integrin/Vinculin-positive cell contacts are reinforced along the lateral and basal membranes. We found that the weakening of SJ integrity, caused by the depletion of bi- or tricellular SJ components, alters ESCRT-III/Vps32/Shrub distribution, reduces degradation and instead favours recycling of SJ components, an effect that extends to other recycled transmembrane protein cargoes including Crumbs, its effector β-Heavy Spectrin Karst, and β-integrin. We propose a mechanism by which epithelial cells, upon sensing alterations of the SJ, reroute the function of Shrub to adjust the balance of degradation/recycling of junctional cargoes and thereby compensate for barrier junction defects to maintain epithelial integrity.

C2 Superior Facetal Osteotomy: A Novel Technique in Complex Craniovertebral Junction Surgery for C1 Lateral Mass Screw Placement.

Complex craniovertebral junction (CVJ) defects account for a considerable proportion of CVJ diseases. Given the heavily assimilated C1, an unfavorable C1-C2 joint orientation, an overriding C2 superior facet, a low-hanging occiput, and an abnormal vertebral artery course with a high-riding vertebral artery, placement of C1 lateral mass screws might be difficult. To address this, a novel technique for placing C1 lateral mass screws that avoid vertebral artery injury, low-hanging occiput, and overriding C2 superior facet was developed in this study. This approach enables firm fixation of C1-C2 even in difficult situations where the placement of the C1 lateral mass is challenging.

Endothelial cell SMAD6 balances Alk1 function to regulate adherens junctions and hepatic vascular development.

BMP signaling is crucial to blood vessel formation and function, but how pathway components regulate vascular development is not well-understood. Here, we find that inhibitory SMAD6 functions in endothelial cells to negatively regulate ALK1-mediated responses, and it is required to prevent vessel dysmorphogenesis and hemorrhage in the embryonic liver vasculature. Reduced Alk1 gene dosage rescued embryonic hepatic hemorrhage and microvascular capillarization induced by Smad6 deletion in endothelial cells in vivo. At the cellular level, co-depletion of Smad6 and Alk1 rescued the destabilized junctions and impaired barrier function of endothelial cells depleted for SMAD6 alone. Mechanistically, blockade of actomyosin contractility or increased PI3K signaling rescued endothelial junction defects induced by SMAD6 loss. Thus, SMAD6 normally modulates ALK1 function in endothelial cells to regulate PI3K signaling and contractility, and SMAD6 loss increases signaling through ALK1 that disrupts endothelial cell junctions. ALK1 loss-of-function also disrupts vascular development and function, indicating that balanced ALK1 signaling is crucial for proper vascular development and identifying ALK1 as a 'Goldilocks' pathway in vascular biology that requires a certain signaling amplitude, regulated by SMAD6, to function properly.

PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity

The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7.

Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort.

Congenital myasthenic syndromes (CMS) are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and β2 adrenergic receptor agonists. In this study, we identified and genetically characterized the largest cohort of CMS patients from India to date. Genetic testing of clinically suspected patients evaluated in a South Indian hospital during the period 2014-19 was carried out by standard diagnostic gene panel testing or using a two-step method that included hotspot screening followed by whole-exome sequencing. In total, 156 genetically diagnosed patients (141 families) were characterized and the mutational spectrum and genotype-phenotype correlation described. Overall, 87 males and 69 females were evaluated, with the age of onset ranging from congenital to fourth decade (mean 6.6 ± 9.8 years). The mean age at diagnosis was 19 ± 12.8 (1-56 years), with a mean diagnostic delay of 12.5 ± 9.9 (0-49 years). Disease-causing variants in 17 CMS-associated genes were identified in 132 families (93.6%), while in nine families (6.4%), variants in genes not associated with CMS were found. Overall, postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found to cause neuromuscular junction defects (DES, TEFM) in our cohort accounted for 2.8%. Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%), followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort, including DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative CMS genes and underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects.

Medium-Chain Fatty Acids Rescue Motor Function and Neuromuscular Junction Degeneration in a Drosophila Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.

Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2.

Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.

Combined Tripier and V-Y Advancement Flaps for Reconstruction of Large Lid-cheek Junction Defects

Reconstruction of lid-cheek junction defects has a known risk of ectropion. Cervicofacial flaps require significant dissection and can still be prone to ectropion. V-Y advancement flaps have been described as less morbid, but their use is limited to moderate-size defects that do not involve the lid margin. The authors present a technique of combined Tripier and V-Y advancement flaps for reconstruction of large defects of the lid-cheek junction involving the lower eyelid. A retrospective review of patients undergoing the authors' technique was performed. A facial artery perforator flap was designed in a V-Y fashion and advanced into the cheek. An orbicularis oculi myocutaneous flap (Tripier flap) was elevated from the upper eyelid and rotated into the lower eyelid/upper cheek to meet the superior edge of the V-Y flap. A separate review of patients undergoing cervicofacial flap reconstruction was also performed. Demographics, operative details, and complications were recorded and compared. This technique was applied to five patients with large-size (19.9 ± 5.6 cm2) defects of the lid-cheek. In all cases, healing was achieved without ectropion, hematoma, infection, dehiscence, flap necrosis, or facial nerve injury. Twenty-four patients separately underwent cervicofacial flap reconstruction for defects of comparable size (15.8 ± 10.7 cm2). Two patients developed ectropion, one patient developed a hematoma, and two patients developed an infection. Combined Tripier and V-Y advancement flaps is a useful technique to reconstruct lid-cheek junction defects. This method allows for the reconstruction of large lid-cheek junction defects that involve the lid margin.

Прогнозирование динамики пробега локомотивов с учетом влияния неисправностей и модернизаций узлов

Purpose: To improve planning system for depot and factory repairs and for locomotive up-grades in the conditions of new rolling stock delivery on the basis of life-cycle contract by the way of the development and application of mathematical model for prognosing average daily and linear runs given the impact on run of technical-technological, seasonal and random fac-tors as well as defects, limiting junctions, and their upgrading. Methods: To achieve the set goal realization, the impact assessment for non-productive downtime of new locomotives at repairs as a result of clearing of junction defects and an equipment and of downtime in wait-ing for planned repairs on dynamics of average daily and linear runs was carried out. Based on the method of multidimensional spectral singular analysis and the prognosis of time series Multi-Channel Singular Spectrum Analysis, the mathematical model on run prognosis which algorithm for, has been embodied in integrated programming environment Visual Studio (2019) on C++ programming codes. Results: Run determination method given junction and equipment possible defects and given being planned upgrading has been proposed. Practical importance: In the conditions of life-cycle contract application which frames in, the participa-tion of locomotives and their components manufacturers in the technical support of supplied products throughout their entire service-life is implied, the usage of the proposed model at re-pair program monthly, quarterly and annual planning, would reduce the downtime in waiting for putting into a repair position on account of more accurate forecast, rationally distributed repairs, materials, stock of linear equipment between service manufactures.

Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature.

ObjectivesCongenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders characterized by neuromuscular junction defects. Mutations in GFPT1 have been shown to underlie CMS. An increasing number of patients with CMS due to mutations in GFPT1 have been reported. However, a comprehensive review of clinical and genetic analyses of GFPT-related CMS worldwide is lacking, especially, given that the common or hotspot mutations in GFPT1 have not been reported. Here, we described the clinical and genetic findings of three patients with GFPT1 mutations from southwestern China and reviewed the clinical and genetic features of patients with GFPT1-related CMS worldwide.MethodsClinical, laboratory, electrophysiological, myopathological, and genetic analyses of three patients with GFPT1-related CMS from southwestern China were conducted, and a review of previously published or reported cases about congenital myasthenic syndrome with GFPT1 mutations in the PubMed database was made.ResultsThe clinical, laboratory, electrophysiological, and myopathological features by muscle biopsy of three patients with GFPT1-related CMS were consistent with those of previously reported patients with GFPT1 mutations. Additionally, an abnormal decrement in high-frequency RNS was found. Two different homozygous missense mutations (c.331C>T, p.R111C; c.44C>T, p.T15M) were detected by whole-exome sequencing (WES) or targeted neuromuscular disorder gene panels.ConclusionA distinct decremental response to high-frequency RNS was found in three patients with GFPT1-related CMS from southwestern China, which has never been reported thus far. In addition, the location and degree of tubular aggregates (TAs) seemed to be associated with the severity of clinical symptoms and serum creatine kinase levels, further expanding the phenotypic spectrum of GFPT1-related CMS. Lastly, some potential hotspot mutations in GFPT1 have been found in GFPT1-CMS worldwide.

Emerging cellular themes in leukodystrophies.

Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.

Changes in the Ultrastructure of the Bladder Urothelium in Patients with Interstitial Cystitis after Intravesical Injections of Platelet-Rich Plasma.

Urothelial dysfunction is considered a key pathological mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS). Intravesical platelet-rich plasma (PRP) injections might be effective for treating IC/BPS. This prospective study investigated the changes in electron microscopic findings among IC/BPS patients after intravesical PRP injections. Twenty-six patients with refractory non-ulcer IC/BPS underwent monthly intravesical PRP injections for 4 months. Changes in clinical symptom scores and video urodynamic study parameters were assessed from baseline to after the PRP injections. A post-treatment Global Response Assessment (GRA) score ≥ 2 was considered a successful outcome. The mean GRA score was significantly higher after 4 PRP injections than at baseline. Approximately 42% of patients experienced successful outcomes after PRP treatment. Urothelial ultrastructural defects showed no significant differences between baseline and after the PRP injections. However, patients showed variable improvements in different urothelial defects (grade improvements: urothelium cell layers, 31%; umbrella cell integrity, 42%; umbrella cell surface uroplakin plaque, 54%; tight junctions between adjacent umbrella cells, 46%; lysed organelles, 58%; inflammatory cell infiltration, 31%). Patients with successful treatment outcomes showed significant improvements in urothelial tight junction defects. Repeated intravesical PRP injections are effective for improving IC/BPS symptoms as they promote urothelial ultrastructural defect recovery.

Functional loss of ubiquitin-specific protease 14 may lead to a novel distal arthrogryposis phenotype.

Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.

The rhinopharyngeal flap for reconstruction of lower clival and craniovertebral junction defects.

The endoscopic endonasal approach (EEA) to the lower clivus and craniovertebral junction (CVJ) has been traditionally performed via resection of the nasopharyngeal soft tissues. Alternatively, an inferiorly based rhinopharyngeal (RP) flap (RPF) can be dissected to help reconstruct the postoperative defect and separate it from the oropharynx. To date, there is no evidence regarding the viability and potential clinical impact of the RPF. The aim of this study was to assess RPF viability and its impact on clinical outcome. A retrospective cohort of 60 patients who underwent EEA to the lower clivus and CVJ was studied. The RPF was used in 30 patients (RPF group), and the nasopharyngeal soft tissues were resected in 30 patients (control group). Chordoma was the most common surgical indication in both groups (47% in the RPF group vs 63% in the control group, p = 0.313), followed by odontoid pannus (20% in the RPF group vs 10%, p = 0.313). The two groups did not significantly differ in terms of extent of tumor (p = 0.271), intraoperative CSF leak (p = 0.438), and skull base reconstruction techniques other than the RPF (nasoseptal flap, p = 0.301; fascia lata, p = 0.791; inlay graft, p = 0.793; and prophylactic lumbar drain, p = 0.781). Postoperative soft-tissue enhancement covering the lower clivus and CVJ observed on MRI was significantly higher in the RPF group (100% vs 26%, p < 0.001). The RPF group had a significantly lower rate of nasoseptal flap necrosis (3% vs 20%, p = 0.044) and surgical site infection (3% vs 27%, p = 0.026) while having similar rates of postoperative CSF leakage (17% in the RPF group vs 20%, p = 0.739) and meningitis (7% in the RPF group vs 17%, p = 0.424). Oropharyngeal bacterial flora dominated the infections in the control group but not those in the RPF group, suggesting that the RPF acted as a barrier between the nasopharynx and oropharynx. The RPF provides viable vascularized tissue coverage to the lower clivus and CVJ. Its use was associated with decreased rates of nasoseptal flap necrosis and local infection, likely due to separation from the oropharynx.

Preferential vertically oriented nanopillar perovskite induced by poly(9-vinylcarbazole) field-effect transistor

Organic-inorganic hybrid perovskite could potentially be used to create field-effect transistors (FETs) with high field-effect mobility. However, the energy level mismatch at the deep valence band maximum perovskite-contact junction and morphological defects greatly limit the charge transport in the thin film. In this work, we demonstrated charge injection can be improved by introducing Nafion as a surface modifier on top of the Indium tin oxide. Incorporating poly (9-vinylcarbazole) PVK into a quasi-one-dimensional precursor solution induced preferential vertically orientated nanopillars as revealed by synchrotron-based two-dimensional grazing incident X-ray diffraction. This simultaneously reduced the grain boundaries and improved pin-hole free films. As a result, maximum hole mobility of 0.012 cm2/Vs was achieved with a reduction in the hysteresis. Our work demonstrated the dependence of FETs performance on the injection barrier and perovskite nanopillar microstructure.

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.40 Neuromuscular junction defects in ACTA1-related nemaline myopathy

Nemaline myopathies (NMs) are a clinically heterogenous group of non-dystrophic congenital muscle diseases caused by mutations in at least 13 genes. NMs are characterised by muscle weakness, hypotonia and respiratory insufficiency, with presence of cytoskeletal protein aggregates (rods) in skeletal muscle fibers. In the present study we investigated whether neuromuscular junctions (NMJ) are affected in ACTA1-related nemaline myopathy, which accounts for about 50% of severe cases of NMs. For this purpose, we analysed the morphology and function of NMJs in the Acta1(H40Y) knock-in mouse model of the disease.

NEW GENES AND DISEASES: EP.301 The alpha2-subunit of the AP2 clathrin adaptor as the causal gene in an atypical myopathy with granulofilamentous inclusions

Clathrin-mediated endocytosis is the best characterized process for the entry of proteins and lipids at the plasma membrane of eukaryotic cells. We have previously shown that at costameres, muscle adhesion and force transmission sites, clathrin recruited by the AP2 adaptor forms flat plaques required for actin and desmin intermediate filament organization. Here, we describe a patient presenting a progressive muscular atrophy with loss of ambulation, complete tetraplegia, ophthalmoplegia, severe scoliosis and lower limb contractures and no cardiac involvement. Electron microscopy of muscle biopsy revealed inclusions composed of filamentous material, vacuoles, honeycomb structures and thin granular material surcharge. This case was classified as a myofibrillar myopathy with granulofilamentous inclusion bodies despite no mutation in DES, FHL1, CRYAB and other usual suspect genes. Whole exome sequencing identified two compound heterozygote single-nucleotide variants in the AP2A2 gene encoding the AP2 a2-subunit. Immunofluorescent labeling on muscle sections displayed intracellular aggregates positive for AP2, clathrin and desmin. Depletion of total AP2 in mouse muscle induced a dystrophic phenotype with severe force loss, subsarcolemmal disorganization, vacuoles and neuromuscular junction defects while specifically depleting AP2 a2-subunit induced small subsarcolemmal disorganization and light neuromuscular junction defects. Lastly, transferrin uptake assays of endocytosis function in the patient fibroblasts showed a decrease in endocytosis rates compared to fibroblasts from his healthy parents. Altogether, our results suggest that AP2A2 could be the causal gene in this family and AP2A2 mutations leading to a severe but atypical myopathy. Mutations in AP2A2 could represent the first case in a wider family of atypical myopathies with desmin inclusions caused by mutations in genes encoding proteins of the endocytosis machinery.

Fully transparent InZnSnO/β-Ga2O3/InSnO solar-blind photodetectors with high schottky barrier height and low-defect interfaces

Ultra-wide bandgap β-Ga2O3 photodiodes have received great attention due to transparent solar-blind deep ultraviolet photodetectors. We demonstrated an all oxide-based single-crystal β-Ga2O3 photodiode incorporated with transparent conductive InZnSnO and InSnO as Schottky and Ohmic contacts, respectively. High work function and low resistivity of InZnSnO allow for clear rectifying characteristics with a low dark current (<0.1 nA) of up to −100 V of reverse bias. The Schottky barrier height and junction defects at the Schottky interface were modified using post-annealing treatment, thereby influencing the deep ultraviolet photoresponse. The responsivity of the annealed device was 9.6 mA/W, decreasing the Schottky barrier height engineering, while the photo responding speed was degraded and caused a persistent photocurrent effect due to the generation of defect states.

Beneficial Effects of Quercetin on Microcystin-LR Induced Tight Junction Defects.

Quercetin has numerous functions including antioxidant and anti-inflammatory effects. The beneficial effect of quercetin against microcystin-LR (MC-LR)-induced testicular tight junctions (TJs) defects in vitro and in vivo were investigated. Significant reductions in transepithelial electrical resistance, occludin, and zonula occludens-1(ZO-1) levels were detected in the MC-LR-treated TM4 cells, and quercetin attenuated these effects. Interestingly, quercetin suppressed MC-LR-induced phosphorylation of protein kinase B (AKT). It effectively inhibited the accumulation of reactive oxygen species (ROS) in cells stimulated by MC-LR. In addition, ROS inhibitors blocked the TJ damage that is dependent on the AKT signaling pathway induced by MC-LR. In conclusion, our results suggest that alleviates MC-LR-impaired TJs by suppressing the ROS-regulated activation of the AKT pathway.