Functional consequences of familial ALS-associated SOD1L84F in neuronal and muscle cells.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1L84F variation in a familial ALS case. In this study, we examined the functional consequences of SOD1L84F overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1L84F showed increased oxidative stress and increased cell death. Interestingly, SOD1L84F destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1L84F also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1L84F altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1L84F hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines.

Clinical and Genetic Analysis of A Father-Son Duo with Monomelic Amyotrophy: Case Report.

Monomelic Amyotrophy (MMA) is a rare neurological disorder restricted to one upper limb, predominantly affecting young males with an unknown aetiopathogenesis. We report a familial case of father-son duo affected by MMA. Whole exome sequencing identified genetic variations in SLIT1, RYR3 and ARPP21 involved in axon guidance, calcium homeostasis and regulation of calmodulin signaling respectively. This is the first attempt to define genetic modifiers associated with MMA from India and advocates to extend genetic screening to a larger cohort. Deciphering the functional consequences of variations in these genes will be crucial for unravelling the pathogenesis of MMA.

Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS.

Giant Extra-Ordinary Near Infrared Transmission from Seemingly Opaque Plasmonic Metasurface: Sensing Applications.

In the present study, we report giant extra-ordinary transmission of near infrared (NIR) light, more than 90%, through a seemingly opaque plasmonic metasurface, which consists of two metal nano-slits arrays (MNSAs) with alternate opening arrangements. By using perfect coupling of the plasmonic modes formed between the sharp edges of the upper and lower MNSAs of silver, a giant, wavelength selective transmission could be obtained. The study is accompanied by optimization of electromagnetic (EM) field coupling for different interlayer spacings and lateral overlap between the two MNSAs to understand their significance in light transmission through the metasurface. The interlayer spacing between the MNSAs works as the transmitting channel for light. The optimization of performance with different fill factors and plasmonic metals was performed as well. Because of the excitation of extended surface plasmons (ESPs) generated at both the MNSAs, the metasurface can be used for refractive index (RI) sensing as one of its applications by using a transparent and flexible polymer, such as polydimethylsiloxane (PDMS), as substrate. The maximum sensitivity which could be achieved for the optimal configuration of the metasurface was 1435.71 nm/RIU, with a figure of merit (FOM) of 80 RIU-1 for 90.45% optical transmission of light for the refractive index variation of analyte medium from 1.33 to 1.38 RIU. The present study strengthens the concept of light funneling through subwavelength structures due to plasmons, which are responsible for light transmission through this seemingly opaque metasurface and finds use in highly sensitive, flexible, and cost-effective EOT-based sensors.

Implications of oxidative stress in chronic kidney disease: a review on current concepts and therapies.

Moderate levels of endogenous reactive oxygen species (ROS) are important for various cellular activities, but high levels lead to toxicity and are associated with various diseases. Levels of ROS are maintained as a balance between oxidants and antioxidants. Accumulating data suggest that oxidative stress is a major factor in deterioration of renal function. In this review, we highlight the possible mechanism by which oxidative stress can lead to chronic kidney disease (CKD). This review also describes therapies that counter the effect of oxidative stress in CKD patients. Numerous factors such as upregulation of genes involved in oxidative phosphorylation and ROS generation, chronic inflammation, vitamin D deficiency, and a compromised antioxidant defense mechanism system cause progressive detrimental effects on renal function that eventually lead to loss of kidney function. Patients with renal dysfunction are highly susceptible to oxidative stress, as risk factors such as diabetes, renal hypertension, dietary restrictions, hemodialysis, and old age predispose them to increased levels of ROS. Biomolecular adducts (DNA, proteins, and lipids) formed due to reaction with ROS can be used to determine oxidative stress levels. Based on the strong correlation between oxidative stress and CKD, reversal of oxidative stress is being explored as a major therapeutic option. Xanthine oxidase inhibitors, dietary antioxidants, and other agents that scavenge free radicals are gaining interest as treatment modalities in CKD patients.

Integrating deep learning CT-scan model, biological and clinical variables to predict severity of COVID-19 patients.

The SARS-COV-2 pandemic has put pressure on intensive care units, so that identifying predictors of disease severity is a priority. We collect 58 clinical and biological variables, and chest CT scan data, from 1003 coronavirus-infected patients from two French hospitals. We train a deep learning model based on CT scans to predict severity. We then construct the multimodal AI-severity score that includes 5 clinical and biological variables (age, sex, oxygenation, urea, platelet) in addition to the deep learning model. We show that neural network analysis of CT-scans brings unique prognosis information, although it is correlated with other markers of severity (oxygenation, LDH, and CRP) explaining the measurable but limited 0.03 increase of AUC obtained when adding CT-scan information to clinical variables. Here, we show that when comparing AI-severity with 11 existing severity scores, we find significantly improved prognosis performance; AI-severity can therefore rapidly become a reference scoring approach.

Analysis of C9orf72 repeat expansion in amyotrophic lateral sclerosis patients from North India.

Pathogenic expansion of a hexanucleotide repeat in C9orf72 is associated with ~30% of familial ALS and ~7% of sporadic ALS patients amongst different populations. This repeat expansion was screened in 75 ALS patients and 115 healthy individuals from North India. On analysis by repeat-primed PCR, pathogenic expansion was not observed either in ALS patients or healthy controls. These observations are similar to the findings in most of the Asian populations.