Cellular processes associated with LRRK2 function and dysfunction.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) encoding gene are the most common cause of monogenic Parkinson's Disease (PD). The identification of LRRK2 polymorphisms associated with increased risk for sporadic PD, as well as the observation that LRRK2-PD has an almost indistinguishable pathological phenotype from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic PD cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with PD reside within the enzymatic core of LRRK2, suggesting the modification of its activity greatly impacts disease onset and progression. Although progress has been gained since its discovery in 2004, there is still much to be understood regarding LRRK2's physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review will discuss the state of current knowledge for the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. As well, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function shall also be discussed. This article is protected by copyright. All rights reserved

Improvement of environmental performance of integrated steel sector through process integration & optimisation measures and innovative waste management practices

The metallurgical and mineral processing industries are always known to be major contributors to environmental pollution. Amongst them, the iron & steel sector finds predominance simply because of the significant volume of effluents, emissions and solid wastes generated from the various process streams. Over the last decade efforts have been made to reduce cnvironmetital pollution from the integrated steel sector through various process integration and optimisation measures as well as cleaner technology development. In addition, a large number of innovations in waste management have resulted in implementation of integrated waste management plans in the steel sector as well as development of ninny value-added products. This paper takes an overview of some of these developments that have contributed significantly to improved environmental performance of the integrated steel sector in India

A Reappraisal of the Eruptive History and Recent (1991-2009) Volcanic Eruptions of the Barren Island, Andaman Sea

The Barren Island volcano in the Western Sunda Arc has displayed explosive Strombolian eruptions for more than two decades. This recent explosive event, together with the historic and prehistoric volcanic landforms, present reliable information about explosive Strombolian eruptions and the volcanological evolution of the Barren Island volcano. This study is a re-evaluation of existing knowledge and incorporates new information and interpretations of the recent and past volcanic activity on Barren Island. Direct observations of explosive eruptions since 1991 showed discrete events of bursting and ballistic transport of blocks and formation of sustained ash plumes, indicating Strombolian and violent Strombolian eruptions. Active lava flows were not seen during the observations which, instead, reveal intact preservation of the historic lava flows. A prehistoric mafic stratocone with a central depression (caldera), a central scoria cone with summit crater and abundant basaltic lava flows of historic eruptions and the scoria cones of the recent activity are the major volcanic landforms. They bear evidence of alternating effusive and explosive activity during prehistoric times accompanied by caldera forming activity; scoria cone Strombolian activity switches over to effusive events during the historic period and exclusively Strombolian activity during recent times. The results of this study differ from previous studies that interpreted several episodes of active lava flows and Hawaiian, Plinian and Vulcanian styles of the recent eruptions. It also provides new insights into the volcanological evolution of the Barren Island volcano which is crucial in understanding the future behaviour of the volcano and risk assessment

Performance Studies on the Crushing and Screening Circuit at South Bank Treatment Plant of Hindustan Copper Ltd.

The global energy crisis, inflation and financial diffi-culties, spiralling increase in operating costs against non-remunerative prices of the finished products are generally the constraints for expansion and modernisat- ion of any mineral processing plant today.However, a very careful look is warranted for before taking any investment decision and a prudent justification for evaluation of the full potential of any plant. The Treatment Plant at South Bank (TPSB) is a typical old plant of HCL/ICC and is the subject of present study

In silico comparative analysis of LRRK2 interactomes from brain, kidney and lung

Mutations in LRRK2 are the most frequent cause of familial Parkinson’s disease (PD), with common LRRK2 non-coding variants also acting as risk factors for idiopathic PD. Currently, therapeutic agents targeting LRRK2 are undergoing advanced clinical trials in humans, however, it is important to understand the wider implications of LRRK2 targeted treatments given that LRRK2 is expressed in diverse tissues including the brain, kidney and lungs. This presents challenges to treatment in terms of effects on peripheral organ functioning, thus, protein interactors of LRRK2 could be targeted in lieu to optimize therapeutic effects. Herein an in-silico analysis of LRRK2 direct interactors in brain tissue from various brain regions was conducted along with a comparative analysis of the LRRK2 interactome in the brain, kidney, and lung tissues. This was carried out based on curated protein–protein interaction (PPI) data from protein interaction databases such as HIPPIE, human gene/protein expression databases and Gene ontology (GO) enrichment analysis using Bingo. Seven targets (MAP2K6, MATK, MAPT, PAK6, SH3GL2, CDC42EP3 and CHGB) were found to be viable objectives for LRRK2 based investigations for PD that would have minimal impact on optimal functioning within peripheral organs. Specifically, MAPT, CHGB, PAK6, and SH3GL2 interacted with LRRK2 in the brain and kidney but not in lung tissue whilst LRRK2-MAP2K6 interacted only in the cerebellum and MATK-LRRK2 interaction was absent in kidney tissues. CDC42EP3 expression levels were low in brain tissues compared to kidney/lung. The results of this computational analysis suggest new avenues for experimental investigations towards LRRK2-targeted therapeutics

Integration of biocontrol agents with fungicide, weedicide and plant growth regulator for management of stem and root rot of jute

Combination of chemical fungicides (viz., Carbendazim 50 WP and Tebuconazole 250 EC) and biocontrol agents (viz., Pseudomonas fluorescens Psfl1, P. striata Pst1, Azotobacter chrococcum Azbc3, Bradyrhizobium japonicum Brj4, Trichoderma aureoviridae S12, T. harzianum JTV2, T. virens JPG1, Aspergillus niger AN15 strains respectively either singly or in consortium) were used to counteract Macrophomina phaseolina, the causal organism of stem and root rot of jute. In addition, suitable plant growth regulator viz., Indole-3-acetic acid (100-1.0 µg/ppm) and herbicide Quizalofop ethyl 5 % EC were used to augment the activity of Trichoderma. T. aureoviridae strain S12 was found to be the best among the eight isolates screened for tolerance against the two fungicides and herbicide at a concentration of 10000 - 500 µg respectively as well as against M. phaseolina (Inhibition=72.33 %) in-vitro. This strain showed best compatibility with other strains and highest tolerance to fungicide i.e., Carbendazim 50 % (up to 500 ?g). Highest number (13.7×106) of active spores was recorded at a concentration of 25 ppm of IAA under in-vitro condition. S12 recorded a biocontrol efficiency of 61.8 % against stem rot of jute along with significant plant growth promotion and fibre production. Plant biomass also increased up to 7.5-12.1 % and fibre production 37.0-39.9 % with fungal and bacterial consortium + carbendazim seed dressing and soil drenching. These biocontrol fungi and PGPR consortium with high tolerance to fungicide, weedicide and plant growth regulator up to certain extent may be potentially exploited in IDM which may be a low cost technology in jute and allied fibre crops

An operator-induced conformational change in the C-terminal domain of the λ repressor

4,4'-bis(1-anilino-8-naphthalenesulfonic acid (Bis-ANS), an environment-sensitive fluorescent probe for hydrophobic region of proteins, binds specifically to the C-terminal domain of λ repressor. The binding is characterized by positive cooperativity, the magnitude of which is dependent on protein concentration in the concentration range where dimeric repressor aggregates to a tetramer. In this range, positive cooperativity becomes more pronounced at higher protein concentrations. This suggests a preferential binding of Bis-ANS to the dimeric form of the repressor. Binding of single operator OR1 to the N-terminal domain of the repressor causes enhancement of fluorescence of the C-terminal domain bound Bis-ANS. The binding of single operator OR1 also leads to quenching of fluorescence of tryptophan residues, all of which are located in the hinge or the C-terminal domain. Thus two different fluorescent probes indicate an operator-induced conformational change which affects the C-terminal domain. The significance of this conformational change with respect to the function of λ repressor has been discussed

Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson’s disease and Multiple System Atrophy

Aggregated alpha-synuclein (a-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of a-synuclein exist, including phosphorylated and nitrated forms. It is unclear which a-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant a-synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three a-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology- affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 a-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 a- synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 a- synuclein in MSA. Quantification of the LB scores revealed that pS129 a-synuclein was the dominant and earliest a-synuclein PTM followed by nY39 a-synuclein, while lower amounts of pSer87 a-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments

Survival of Φ0/2\Phi_{0}/2 periodicity in presence of incoherence in asymmetric Aharonov-Bohm rings

Magneto conductance oscillations periodic in flux with periodicity $\Phi_{0}$ and $\Phi_{0}/2$ are seen in asymmetric Aharonov-Bohm rings as a function of density of electrons or Fermi wave vector. Dephasing of these oscillations is incorporated using a simple approach of wave attenuation. In this work we study how the excitation of the $\Phi_{0}/2$ oscillations and the accompanying phase change of $\pi$ are affected by dephasing. Our results show that the $\Phi_{0}/2$ oscillations survive incoherence, i.e., dephasing, albeit with reduced visibility while incoherence is also unable to obliterate the phase change of $\pi$.Comment: 4 pages, 3 figure

Characterization of fragment emission in ^{20}Ne (7 - 10 MeV/nucleon) + ^{12}C reactions

The inclusive energy distributions of the complex fragments (3 $\leq$ Z $\leq$ 7) emitted from the bombardment of ^{12}C by ^{20}Ne beams with incident energies between 145 and 200 MeV have been measured in the angular range 10$^{o} \leq \theta_{lab} \leq$ 50^{o}. Damped fragment yields in all the cases have been found to be the characteristic of emission from fully energy equilibrated composites. The binary fragment yields are compared with the standard statistical model predictions. Enhanced yields of entrance channel fragments (5 $\leq$ Z $\leq$ 7) indicate the survival of orbiting-like process in ^{20}Ne + ^{12}C system at these energies.Comment: 18 pages, 13 figure