Biology subjects

Rai, N.

Publications and source records attributed to Rai, N..

3 recordsLinked to original sources

bioRxiv2018

A network-based model for drug repurposing in Rheumatoid Arthritis

BackgroundThe identification of drug repositioning targets through computational methods has the potential to provide a fast, inexpensive alternative to traditional drug discovery process. Diseases where complicated pathophysiology evolves over time are excellent targets for such methods. One such disease is Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune disease, where the drug survival at 5-years is less than 50% for patients treated with disease-modifying anti-rheumatic drugs (DMARDs).\n\nMethods and FindingsWe have developed a network-based approach for drug repositioning that takes into account the human interactome network, proximity measures between drug targets and disease-associated genes, potential side-effects, genome-wide gene expression and disease modules that emerge through pertinent analysis. We found that all DMARDs, except for hydroxychloroquine (HCQ), were found to be significantly proximal to RA-related genes. Application of the method on anti-diabetic agents, statins and H2 receptor blockers identified anti-diabetic agents - gliclazide, sitagliptin and metformin - that have similar network signatures with the DMARDs. Subsequent in-vitro experiments on mouse fibroblast NIH-3T3 cells validated the findings and the down regulation of six key RA-related inflammatory genes. Our analysis further argues that the combination of HCQ and/or sulfasalazine with methotrexate (MTX) is predicted to have an additive synergistic effect in treatment based on network complementarity. Similarly, leflunomide and tofacitinib were found to be suitable alternatives upon chemoresistance to MTX-based double/triple therapy, given the complementary network signatures and overlapping critical target hubs.\n\nConclusionsOur results corroborate that computational methods that are based on network proximity, among other contextual information can help narrow down the drug candidates for drug repositioning, as well as support decisions for combinatorial drug treatment that is tailored to patients needs.\n\nAuthor summaryThe network-based proximity between drug targets and disease genes can provide novel insights on the repercussion, interplay, and reposition of drugs in the context of disease. Disease-modifying anti-rheumatic drugs (DMARDs) located significantly close to rheumatoid arthritis (RA)-associated genes and RA-relevant pathways. Three anti-diabetic agents were identified to have an anti-inflammatory effect like DMARDs. We built RA disease module encompassing the emerging small-molecule targets and functional neighbors, which better explained the RA pathophysiology. By proximity and network robustness, tofacitinib and tocilizumab were the most potent for RA disease module as a single agent, and this is consistent with clinical observation. Side effects of clinical importance are predictable by measuring network-based proximity between drug targets and side effect protein. Network-based drug-disease proximity offers a novel and clinically actionable information about drugs and opens the new possibility to drug combination and reposition.

systems biology↗

bioRxiv2018

The Genomic Formation of South and Central Asia

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia--consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC--and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.\n\nOne Sentence SummaryGenome wide ancient DNA from 357 individuals from Central and South Asia sheds new light on the spread of Indo-European languages and parallels between the genetic history of two sub-continents, Europe and South Asia.

genomics↗

bioRxiv2017

Like Sugar in Milk: Reconstructing the genetic history of the Parsi population

BackgroundThe Parsis, one of the smallest religious community in the world, reside in South Asia. Previous genetic studies on them, although based on low resolution markers, reported both Iranian and Indian ancestries. To understand the population structure and demographic history of this group in more detail, we analyzed Indian and Pakistani Parsi populations using high-resolution autosomal and uniparental (Y-chromosomal and mitochondrial DNA) markers. Additionally, we also assayed 108 mitochondrial DNA markers among 21 ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.\n\nResultsOur extensive analyses indicated that among present-day populations, the Parsis are genetically closest to Middle Eastern (Iranian and the Caucasus) populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred [~]1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement.\n\nConclusionsWe show that the Parsis are genetically closest to the Neolithic Iranians, followed by present-day Middle Eastern populations rather than those in South Asia and provide evidence of sex-specific admixture from South Asians to the Parsis. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7thcentury and in agreement with their assimilation into the Indian sub-continents population and cultural milieu \"like sugar in milk\". Moreover, in a wider context our results suggest a major demographic transition in West Asia due to Islamic-conquest.

evolutionary biology↗