Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10^-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer’s disease, 6 genes with Parkinson’s disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.     

Anti-bacterial and anti-biofilm properties of green synthesized copper nanoparticles from Cardiospermum halicacabum leaf extract

Bioprocess and Biosystems Engineering - In the present study, a copper nanoparticle (Cu NPs) was synthesized by a green synthesis method with Cardiospermum halicacabum leaf extract. The surface...     

Hesperidin modulates the rhythmic proteomic profiling in Drosophila melanogaster under oxidative stress

The circadian clock regulates vital aspects of physiology including protein synthesis and oxidative stress response. In this investigation, we performed a proteome-wide scrutiny of rhythmic protein accrual in Drosophila melanogaster on exposure to rotenone, rotenone + hesperidin and hesperidin in D. melanogaster. Total protein from fly samples collected at 6 h intervals over the 24 h period was subjected to two-dimensional gel electrophoresis and mass spectrometry. Bioinformatics tool, Protein ANalysis THrough Evolutionary Relationships classification system was used to the determine the biological processes of the proteins of altered abundance. Conspicuous variations in the proteome (151 proteins) of the flies exposed to oxidative stress (by rotenone treatment) and after alleviating oxidative stress (by hesperidin treatment) were observed during the 24 h cycle. Significantly altered levels of abundance of a wide variety of proteins under oxidative stress (rotenone treatment) and under alleviation of oxidative stress (rotenone + hesperidin treatment) and hesperidin (alone) treatment were observed. These proteins are involved in metabolism, muscle activity, heat shock response, redox homeostasis, protein synthesis/folding/degradation, development, ion-channel/cellular transport, and gustatory and olfactory function of the flies. Our data indicates that numerous cellular processes are involved in the temporal regulation of proteins and widespread modulations happen under rotenone treatment and, action of hesperidin could also be seen on these categories of proteins.     

Distribution Patterns of Slender Loris Subspecies (<Emphasis Type="Italic">Loris lydekkerianus</Emphasis>) in Kerala,Southern India

Gray slender lorises (Loris lydekkerianus) are 1 of 2 nocturnal primate genera occurring in India. Although the distribution and abundance of the species is known for some parts of southern India, the relative distribution of the 2 subspecies, Loris lydekkerianus lydekkerianus and L. l. malabaricus, and their comparative densities and extent of overlap between their distributions remains largely unknown. We investigated the distribution pattern and relative density of slender lorises in the Western Ghats mountain range in the state of Kerala in southern India. We surveyed 36 forest ranges in 17 forest divisions of northern and central Kerala from February to November 2009 for the presence of lorises. We sighted slender lorises in 22 forest ranges in a variety of vegetation types, and the relative abundance of the species ranged from 0.02 to 1.44 lorises/km. Our results confirm that both loris subspecies are present in Kerala: Mysore slender lorises have a narrow patchy distribution on the eastern edges of the Western Ghats mountain range, and Malabar slender lorises have a fairly contiguous distribution on the western slopes of the Western Ghats. We recommend more detailed surveys in southern Kerala to identify the distribution patterns of the subspecies in these areas.     

Monsoon-dependent breeding in the field crab Paratelphusa hydrodromous (Herbst)

The reproductive cycle of the field crab Paratelphusa hydrodromous (Herbst) was determined by direct field observations as well as by calculating the percentage of ovigerous females in a Madras population for a period of three years. The females breed annually in a single spawning. These observations, corroborated by histological studies on the nature of the ovary, indicate that gametogenic activity starts in December and vitellogenesis is completed during January-May. Spawning commences in the last week of June or first week of July with the release of brood in the month of September (1979), October (1978) or November (1980) during northeast monsoon. The smallest female crab showing spawning had a carapace width of 3.1 cm and the largest spawning crabs measured 5.5 mm. The mean number of eggs spawned in the smallest crab was 247 and that in the largest crab was 417. Mean incubation was 41 ± 12.388 days. Vitellogenesis and spawning occurred at peak temperature conditions. Though the time taken for vitellogenesis and commencement of spawning were constant for the study period, the duration of retention of the juveniles in the brood varied with the onset of monsoon.     

Understanding dynamics using sensitivity analysis: caveat and solution

Background  

Parametric sensitivity analysis (PSA) has become one of the most commonly used tools in computational systems biology, in which the sensitivity coefficients are used to study the parametric dependence of biological models. As many of these models describe dynamical behaviour of biological systems, the PSA has subsequently been used to elucidate important cellular processes that regulate this dynamics. However, in this paper, we show that the PSA coefficients are not suitable in inferring the mechanisms by which dynamical behaviour arises and in fact it can even lead to incorrect conclusions.     

Status of <Emphasis Type="Italic">Macaca silenus</Emphasis> in the Kudremukh Forest Complex,Karnataka, India

We assessed the population status of endangered lion-tailed macaques (Macaca silenus) in the rain forests of Kudremukh Forest complex (Kudremukh National Park, Someshwara Wildlife Sanctuary and Mookambika Wildlife Sanctuary), Western Ghats, Karnataka in January 2007. We performed a census of 20 groups in Kudremukh NP, 4 groups in Someshwara WS, and 6 groups in Mookambika WS. We estimated the population size as ca. 451 individuals in the 3 parks. The forests of Kudremukh NP and Someshwara WS are continuous, and the present finding of 24 groups in a single continuous forest confirms the existence of another significant population of lion-tailed macaques.     

The Role of Carboxy-Terminal Glycosaminoglycan-binding Domain of Vitronectin in Cytoskeletal Organization and Migration of Endothelial Cells

Vitronectin is a major cell adhesion molecule present in the subendothelial matrix that mediates the attachment and spreading of a variety of cells. The carboxy-terminal end of vitronectin has a consensus sequence for glycosaminoglycan-binding. To define the functional role of this domain, we generated fragments of vitronectin that lack the glycosaminoglycan-binding domain by formic acid cleavage of plasma-derived vitronectin. In addition, we also generated similar recombinant fragments of vitronectin as glutathione S-transferase fusion proteins in E. coll. These fragments were tested for their ability to support the adhesion of human umbilical vein endothelial cells. These fragments promoted endothelial cell adhesion, reaching half maximal activity at 2-5 μg/well compared to plasma-derived vitronectin which reached at 0.2 μg/well. However, the cells that adhered to these fragments did not develop well-formed focal adhesion plaques and actin stress fibers. In addition, these fragments were poorly chemotactic for endothelial cell migration when compared to intact plasma-derived vitronectin in a modified Boyden chamber assay. The present studies show that carboxy-terminal glycosaminoglycan-binding domain of vitronectin is essential for proper cytoskeletal organization and migration of endothelial cells on vitronectin substratum.