Aggregation of E121K mutant D-amino acid oxidase and ubiquitination-mediated autophagy mechanisms leading to amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a terminal adult-onset neuromuscular disorder. Our group has been studying this illness and previously reported novel mutations and rare mutations in a study using next-generation sequencing of DNA samples from Indian ALS patients. In this paper, we focus on the E121K mutation in the DAO gene to understand how it leads to ALS.

Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.

The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation.

Role of ALS-associated OPTN-K489E mutation in neuronal cell-death regulation.

Optineurin (OPTN) gene is a marker of amyotrophic lateral sclerosis (ALS). However, the role of optineurin protein (OPTN) in ALS pathology is unclear, even though it is known to regulate autophagy, apoptosis, and other survival-death cellular processes. Genetic analysis of Indian ALS patients by our group ascertained a novel mutation K489E in the OPTN gene.

Characterization of E121K mutation of D-amino acid oxidase - Insights into mechanisms leading to amyotrophic lateral sclerosis.

D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing study by our group, E121K mutation in DAO was associated with amyotrophic lateral sclerosis (ALS) in patients from India. However, variations in molecular mechanisms caused by this mutation which leads to ALS have not been studied.

A distant angiogenin variant causes amyotrophic lateral sclerosis through loss-of-function mechanisms: Insights from long-timescale atomistic simulations and conformational dynamics.

Amyotrophic Lateral Sclerosis (ALS) is a progressive and incurable neurodegenerative disorder characterized by the degeneration of motor neurons leading to severe muscle atrophy, respiratory failure and death within 3-5 years of disease onset. Missense mutations in Angiogenin (ANG) cause ALS through loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions. Although loss-of-function mechanisms of several rare and ALS-causing ANG variants have been studied before, the structure-function relationship and subsequent functional loss mechanisms of certain novel and uncharacterized rare variants have not been deciphered hitherto.

Comparison and implementation of different control strategies for improving production of rHSA using Pichia pastoris.

Recombinant protein production by various host organisms is strictly regulated, which is determined mainly by host cell genetics and maintenance of process variables within desirable limits in a reactor. Since the process dynamics typically exhibit nonlinear interactions amongst the critical process variables, the commonly employed controllers are suboptimal for control of most bioprocesses. In this article, we present the implementation of an augmented controller for improving the production of recombinant human serum albumin (rHSA) using Pichia pastoris.

A molecular dynamics based investigation reveals the role of rare Ribonuclease 4 variants in amyotrophic lateral sclerosis susceptibility.

Missense mutations in certain genes of the Ribonuclease (RNASE) superfamily cause amyotrophic lateral sclerosis (ALS) through loss of either ribonucleolytic or nuclear translocation or both of these activities. While rare ANG/RNASE5 variants have been previously shown to be ALS causative, it is not yet known if any of the reported rare RNASE4 variants can also trigger ALS. The study aims to understand whether rare variants of RNASE4 can manifest ALS through similar loss-of-function mechanisms.

Targeted next-generation sequencing reveals novel and rare variants in Indian patients with amyotrophic lateral sclerosis.

Studies on genetic aberrations among Indian amyotrophic lateral sclerosis (ALS) patients are limited to C9orf72 and ATXN2 repeat expansions and mutations in the SOD1 gene. In this study, we used targeted next-generation sequencing to analyze 25 ALS-associated genes in a cohort of 154 Indian ALS patients. We identified known pathogenic mutations in SOD1 (G148D; H44R), TARDBP (M337V; N267S), DAO (R199Q), and ANG (K41I).

In silico identification of genetically attenuated vaccine candidate genes for Plasmodium liver stage.

Genetically attenuated parasites (GAPs) that lack genes essential for the liver stage of the malaria parasite, and therefore cause developmental arrest, have been developed as live vaccines in rodent malaria models and recently been tested in humans. The genes targeted for deletion were often identified by trial and error. Here we present a systematic gene - protein and transcript - expression analyses of several Plasmodium species with the aim to identify candidate genes for the generation of novel GAPs.

Maximizing biomass concentration in baker's yeast process by using a decoupled geometric controller for substrate and dissolved oxygen.

Biomass production by baker's yeast in a fed-batch reactor depends on the metabolic regime determined by the concentration of glucose and dissolved oxygen in the reactor. Achieving high biomass concentration in turn is dependent on the dynamic interaction between the glucose and dissolved oxygen concentration. Taking this into account, we present in this paper the implementation of a decoupled input-output linearizing controller (DIOLC) for maximizing biomass in a fed-batch yeast process.

Production of monoclonal antibodies for breast cancer by HB8696 hybridoma cells using novel perfusion system.

Perfusion culture using spinfilters have been used for the production of health-care products using mammalian cells culture. However, available spinfilters are either highly prone to clog and/or are disposable and hence affects product formation. To address these problems, a novel non-woven Bombyx mori silk screen based spinfilter module for clog-free extended perfusion culture of hybridoma cells has been designed.