Towards a new tuberculosis drug: pyridomycin - nature's isoniazid

Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl(Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development

Catalytic Function of PLA2G6 Is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but Not Dystonia-Parkinsonism

Mutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia-parkinsonism. These clinical syndromes display two significantly different disease phenotypes. NBIA and INAD are very similar, involving widespread neurodegeneration that begins within the first 1-2 years of life. In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A(2), which has previously been shown to hydrolyze the sn-2 acyl chain of phospholipids, generating free fatty acids and lysophospholipids.We produced purified recombinant wildtype (WT) and mutant human PLA2G6 proteins and examined their catalytic function using in vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. Mutations associated with different disease phenotypes have different effects on catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme activity, with mutant proteins exhibiting less than 20% of the specific activity of WT protein in both lysophospholipase and phospholipase assays. In contrast, mutations associated with dystonia-parkinsonism do not impair catalytic activity, and two mutations produce a significant increase in specific activity for phospholipid but not lysophospholipid substrates.These results indicate that different alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and provides a mechanistic explanation for the accumulation of membranes in neuroaxonal spheroids previously observed in histopathological studies of INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly impair catalytic function, but may modify substrate preferences or regulatory mechanisms for PLA2G6

Primary cerebral alveolar rhabdomyosarcoma in adult

Primary cerebral rhabdomyosarcomas are very rare and malignant tumors that occur predominantly in the posterior fossa of pediatric patients. We report a rare case of primary cerebral rhabdomyosarcoma located in the supratentorial compartment of a 51 year-old woman together with a review of the pertinent Literature especially regarding the histological diagnosis and pitfalls

Does ligament balancing technique affect kinematics in rotating platform, PCL retaining knee arthroplasties?: A prospective randomized study

The goal of this prospective, randomized, blinded trial was to determine if ligament balancing techniques for rotating platform TKA affect postoperative knee kinematics. Sixteen patients with unilateral rotating platform TKA consented to participate in this institutional review board approved study. Eight patients were randomly selected to receive ligament balancing with an instrumented joint spreader device and eight patients received ligament balancing using fixed thickness spacer blocks. A single plane shape matching technique was used for kinematic analysis of static deep knee flexion and dynamic stair activities. There were no differences in knee kinematics between groups during static deep flexion activities. The spreader group demonstrated kinematics more similar to the normal knee during the ascending phase of the dynamic stair activity. Knee kinematics in static knee flexion were unaffected by ligament balancing technique, while knees balanced with the spreader demonstrated a medial pivot motion pattern during stair ascent. This medial pivot motion pattern may improve long-term results by more closely replicating normal knee kinematics

Role of Interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression

Background: The use of TNF inhibitors has been a major progress in the treatment of chronic inflammation. However, not all patients respond. In addition, response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL-17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. Therefore we studied the capacity of IL-17 to regulate synoviolin, an E3 ubiquitin ligase implicated in synovial hyperplasia in human rheumatoid arthritis (RA) FLS and in chronic reactivated streptococcal cell wall (SCW)-induced arthritis.<p></p> Methodology/Principal Findings: Chronic reactivated SCW-induced arthritis was examined in IL-17R deficient and wild-type mice. Synoviolin expression was analysed by real-time RT-PCR, Western Blot or immunostaining in RA FLS and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17-RC) or synoviolin inhibition were achieved by small interfering RNA (siRNA) or neutralizing antibodies. IL-17 induced sustained synoviolin expression in RA FLS. Sodium nitroprusside (SNP)-induced RA FLS apoptosis was associated with reduced synoviolin expression and was rescued by IL-17 treatment with a corresponding increase in synoviolin expression. IL-17RC or IL-17RA RNA interference increased SNP-induced apoptosis, and decreased IL-17-induced synoviolin. IL-17 rescued RA FLS from apoptosis induced by synoviolin knockdown. IL-17 and TNF had additive effects on synoviolin expression and protection against apoptosis induced by synoviolin knowndown. In IL-17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL-17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre-like structures.<p></p> Conclusion/Significance: IL-17 induction of synoviolin may contribute at least in part to RA chronicity by prolonging the survival of RA FLS and immune cells in germinal centre reactions. These results extend the role of IL-17 to synovial hyperplasia.<p></p&gt

Bedforms and sedimentary structures related to supercritical flows in glacigenic settings

Upper-flow-regime bedforms, including upper-stage-plane beds, antidunes, chutes-and-pools and cyclic steps, are ubiquitous in glacigenic depositional environments characterized by abundant meltwater discharge and sediment supply. In this study, the depositional record of Froude near-critical and supercritical flows in glacigenic settings is reviewed, and similarities and differences between different depositional environments are discussed. Upper-flow-regime bedforms may occur in subglacial, subaerial and subaqueous environments, recording deposition by free-surface flows and submerged density flows. Although individual bedform types are generally not indicative of any specific depositional environment, some observed trends are similar to those documented in non-glacigenic settings. Important parameters for bedform evolution that differ between depositional environments include flow confinement, bed slope, aggradation rate and grain size. Cyclic-step deposits are more common in confined settings, like channels or incised valleys, or steep slopes of coarse-grained deltas. Antidune deposits prevail in unconfined settings and on more gentle slopes, like glacifluvial fans, sand-rich delta slopes or subaqueous (ice-contact) fans. At low aggradation rates, only the basal portions of bedforms are preserved, such as scour fills related to the hydraulic-jump zone of cyclic steps or antidune-wave breaking, which are common in glacifluvial systems and during glacial lake-outburst floods and (related) lake-level falls. Higher aggradation rates result in increased preservation potential, possibly leading to the preservation of complete bedforms. Such conditions are met in sediment-laden jökulhlaups and subaqueous proglacial environments characterized by expanding density flows. Coarser-grained sediment leads to steeper bedform profiles and highly scoured facies architectures, while finer-grained deposits display less steep bedform architectures. Such differences are in part related to stronger flows, faster settling of coarse clasts, and more rapid breaking of antidune waves or hydraulic-jump formation over hydraulically rough beds. © 2020 The Authors. Sedimentology published by John Wiley & Sons Ltd on behalf of International Association of Sedimentologist