POMK regulates dystroglycan function via LARGE-mediated elongation of matriglycan

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetylglucosaminyltransferase-1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNac-β1,3-GlcNac-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy

The Influence of Natural Barriers in Shaping the Genetic Structure of Maharashtra Populations

BACKGROUND: The geographical position of Maharashtra state makes it rather essential to study the dispersal of modern humans in South Asia. Several hypotheses have been proposed to explain the cultural, linguistic and geographical affinity of the populations living in Maharashtra state with other South Asian populations. The genetic origin of populations living in this state is poorly understood and hitherto been described at low molecular resolution level. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue, we have analyzed the mitochondrial DNA (mtDNA) of 185 individuals and NRY (non-recombining region of Y chromosome) of 98 individuals belonging to two major tribal populations of Maharashtra, and compared their molecular variations with that of 54 South Asian contemporary populations of adjacent states. Inter and intra population comparisons reveal that the maternal gene pool of Maharashtra state populations is composed of mainly South Asian haplogroups with traces of east and west Eurasian haplogroups, while the paternal haplogroups comprise the South Asian as well as signature of near eastern specific haplogroup J2a. CONCLUSIONS/SIGNIFICANCE: Our analysis suggests that Indian populations, including Maharashtra state, are largely derived from Paleolithic ancient settlers; however, a more recent (∼10 Ky older) detectable paternal gene flow from west Asia is well reflected in the present study. These findings reveal movement of populations to Maharashtra through the western coast rather than mainland where Western Ghats-Vindhya Mountains and Narmada-Tapti rivers might have acted as a natural barrier. Comparing the Maharastrian populations with other South Asian populations reveals that they have a closer affinity with the South Indian than with the Central Indian populations

Effect of benzalkonium chloride-free latanoprost ophthalmic solution on ocular surface in patients with glaucoma

Tejaswini Walimbe,1 Vidya Chelerkar,2 Purvi Bhagat,3 Abhijeet Joshi,4 Atul Raut4 1Walimbe Eye Clinic, 2PBMA’s H.V. Desai Eye Hospital, Pune, 3Glaucoma Clinic, M and J Western Regional Institute of Ophthalmology, Civil Hospital, Ahmedabad, 4Clinical Research Department, Sun Pharma Advanced Research Company Ltd., Mumbai, India Introduction: Benzalkonium chloride (BAK), included as a preservative in many topical treatments for glaucoma, induces significant toxicity and alters tear breakup time (TBUT). BAK-containing latanoprost, an ester prodrug of prostaglandin F2a, can cause ocular adverse events (AEs) associated with BAK. The purpose of this study was to evaluate the efficacy and safety of BAK-free latanoprost. Patients and methods: A prospective, open-label, single-arm, multicenter, 8-week study in patients with primary open-angle glaucoma or ocular hypertension taking BAK-containing latanoprost for ≥12 months was performed. Patients were switched to BAK-free latanoprost ophthalmic solution 0.005% administered once daily, and eyes were assessed after 28 and 56 days. Primary efficacy and safety variables were TBUT and treatment-emergent AEs, respectively. Results: At day 56, 40 eyes were evaluable. Mean TBUT increased significantly from baseline (3.67±1.60 seconds) to 5.03±2.64 and 6.06±3.39 seconds after 28 and 56 days of treatment with BAK-free latanoprost (P<0.0001). Ocular Surface Disease Index© (OSDI©) score also decreased significantly to 12.06±13.40 and 7.06±10.75 at 28 and 56 days, respectively, versus baseline (18.09±18.61, P<0.0001). In addition, inferior corneal staining score decreased significantly to 0.53 from baseline (0.85, P=0.0033). A reduction in conjunctival hyperemia and intraocular pressure was observed at both time points. No treatment-related serious AEs were evident and 12 (26.08%) treatment-emergent AEs occurred in seven patients, with eye pain and irritation being the most frequent. No clinically significant changes in vital signs or slit lamp examinations were observed. Conclusion: Results indicate that switching from BAK-containing latanoprost to BAK-free latanoprost resulted in significant improvements in TBUT, OSDI© score, and inferior corneal staining score, and measurable reductions in conjunctival hyperemia score. Furthermore, BAK-free latanoprost was well tolerated with only mild-to-moderate and self-limiting AEs. BAK-free latanoprost appears to be effective in protecting ocular surface integrity in glaucoma patients but further studies are needed to confirm this beneficial effect. Keywords: tear breakup time, TBUT, Ocular Surface Disease Index, OSDI©, inferior corneal staining score, conjunctival hyperemia, intraocular pressure, glaucoma, ocular surfac

Prevalence and Phylogenetic Analysis of TT Virus DNA in Western India

In western India, TT virus (TTV) DNA positivity varied from 6.7% (5 of 75) in chronic hepatitis patients to 24.4% (10 of 41) in hemophiliacs; 7.4% (4 of 54) of voluntary blood donors had circulating TTV DNA. Phylogenetic analysis revealed a predominance of genotype 1a. In India, TTV is transmitted mainly by nonparenteral routes and is not an important cause of chronic liver diseases

Expanded clinical phenotype and untargeted metabolomics analysis in RARS2-related mitochondrial disorder: a case report

Abstract Background RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). Case presentation Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites. Conclusions Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction

Association of Diabetes Mellitus and Biomarkers of Abnormal Glucose Metabolism With Incident Radiographic Knee Osteoarthritis.

ObjectiveThe association of diabetes mellitus (DM) with increased risk of knee osteoarthritis (OA) is uncertain. We evaluated associations of DM and biomarkers of abnormal glucose metabolism with incident radiographic knee OA, controlling for body mass index (BMI).MethodsParticipants (mean ± SD age 60.6 ± 7.8 years; mean ± SD body mass index [BMI] 29.1 ± 4.9 kg/m2 ) were from the Multicenter Osteoarthritis Study and did not have radiographic knee OA at baseline (Kellgren/Lawrence [K/L] grade <2 bilaterally). A random sample (n = 987) was selected and stratified by BMI. Baseline serum fasting glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) were measured. Participants were categorized as having DM based on self-report, use of medication, or fasting glucose ≥126 mg/dl. Incident radiographic knee OA (K/L grade ≥2 or knee replacement) was assessed at 3 follow-up visits (30, 60, and 84 months). Knee-level pooled logistic regression analysis was performed to obtain odds ratios (ORs) (95% confidence interval [95% CI]) for associations of DM status and biomarkers of abnormal glucose metabolism with incident radiographic knee OA.ResultsAfter adjustment for BMI, the odds of incident radiographic knee OA were not associated with baseline DM status nor with levels of fasting glucose and HOMA-IR, overall and in men. In women, HOMA-IR was inversely associated with odds of incident radiographic knee OA (adjusted OR 0.80 [95% CI 0.69-0.94], P = 0.005).ConclusionDM and higher levels of biomarkers of abnormal glucose metabolism were not associated with increased odds of incident radiographic knee OA after adjusting for BMI in this cohort overall. A possible protective association of higher HOMA-IR with incident radiographic knee OA in women warrants further investigation