In a brain affected by Alzheimer's Disease (AD), dementia sets in mainly as a consequence of synaptic decay (among other factors). As time progresses, the disease gets worse as indicated by deteriorating physiological and behavioural symptoms.
It is well known that synaptic dysfunction at the micro scale, caused by Amyloid beta, leads to dysfunction and hypo metabolism at the network level. However, there is a dearth of modelling efforts that bridge the gap between micro and whole brain levels. This recent work attempts to fill this gap and is the first reported work along these lines.
The research findings come from active collaborations among the research groups of Prof. G. Ambika (Indian Institute of Science Education and Research, Tirupati) and Prof Vijayalakshmi Ravindranath(Centre for Neuroscience, Indian Institute of Science, Bangalore) along with Prof G Rangarajan( Department of Mathematics, Indian Institute of Science, Bangalore) and Prof R E Amritkar(Physical Research Laboratory, Ahmedabad)
( Synapse loss and progress of Alzheimer’s disease- A network model -G. Kashyap, D. Bapat, D. Das, R. Gowaikar, R.E. Amritkar, G. Rangarajan, Ravindranath V., and G. Ambika , Scientific Reports (2019) 9:6555)
The decrease in neurite length and healthy spines observed in primary cortical cultures from APPSwe/PS1?E9 (APP/PS1) mice, provides clear evidence for loss of functional synapses. This micro-scale behaviour is directly derived from careful in vitro experiments on cultured neurons from a transgenic amyloid beta mouse model in research lab of Prof Ravindranath.
In the network model developed by Prof Ambika and collaborators, the loss in the synapses observed, is correlated to loss of connection strengths or weights of the network resulting in decrease in efficiency of transmission of signals. The number of multiple paths of high efficiency also decreases rapidly as the disease progresses, indicating loss of structural plasticity and inefficiency in choosing alternate paths or desired paths for any pattern of activity. The study is extended to human brain network data and shows how beyond a critical time, the brain network undergoes rapid deterioration.
Most network science approaches in this area have not utilized direct experimental evidence in formulating network model. That is what makes this research very novel. The conclusion that a critical phase transition can be predicted from this simple model, is very important in future clinical explorations.
For more details, please see https://rdcu.be/byyCY;
The research group under Prof. G Ambika focusses on understanding complexity of natural nonlinear systems using nonlinear dynamics and complex networks. The measures of multifractal analysis and recurrence networks derived from time series or observational data, help to detect the nature of the underlying dynamics in complex systems. Some of the recent contributions from this group are multiple time scale phenomena on dynamics of complex networks, loss of connectivity in directed networks and classification of pulsating variable stars and binary stars based on their recurrence network measures. Their results highlight several applications including synapse loss and progress of Alzheimer’s disease, multifractal nature of heart dynamics derived from ECG, to distinguish healthy heart and abnormalities.
|Recurrence networks constructed from the light curves of four pulsating variable stars belonging to the RRc Lyrae category, displayed against background of variable star AG Carinae from Hubble Legacy Archive. (Background image credits: Judy Schmidt [CC0], from Wikimedia Commons).|
|Multifractal parameters of ECG from normal heart (green) differentiated from that of abnormal heart data.|
You may observe various patterns of liquids, particles and objects around you. One everyday example is the ring-like patterns of dried coffee drops on table. Physicists go further to ask the question ‘how such stains are formed’. This intriguing phenomenon was first explained in 1997 by Deegan. In short, there is a tiny flow of liquid from the centre of the drop towards the edge. This flow carries the coffee particles to the edge and deposits them there forming a ring-like stain upon drying.
The whole scenario is different when a drop wets and spreads on a surface that contains dispersed powder. The spreading of a drop occurs in a blink of an eye. When the drop spreads, its edge pushes on the powder particles and forms rings. Here, physics of drop spreading and imbibition into the powder layer plays a role. We study these effects and look at the resulting patterns formed.
The scenario is further different when the drop impacts on a powder layer with some kinetic energy. Here, the drop, as it impinges on the surface, can entrap a layer of air. This forms a bubble inside the drop. The dynamics of this bubble displaces the powder layer in particular manner.
Physics behind such everyday phenomena are studied in Microfluidics Group of Dr. Dileep Mampallil.
Rings formed on a soot layer upon spreading of an ethanol drop. See Phys. Rev. E. 98, 043107, (2018).
Scorpion is known for its painful sting. Relatively less known fact is that the scorpion venom, world’s most expensive liquid (~10 million USD/Litre), is enriched with many important natural products, which can fight cancer and autoimmune disorders. Recent study by Shibdas Banerjee et al. has reported a new alkaloid from the scorpion venom, while most venom components identified in past are peptidic or proteinic in nature. This news has surprised the world and recently mentioned in Chemical and Engineering News (C&EN). The study was conducted in collaboration with the laboratories of Prof. Richard N. Zare, Stanford University, and Prof. Lourival D. Possani, UNAM, Mexico. Scorpions use their venom to paralyze their prey. However, this alkaloid was not found to have insecticidal activity. The exact role of this alkaloid in the venom is still a mystery. A chemical method of synthesizing the alkaloid has also been developed. Authors suggest that this venom alkaloid might be of potential interest for evaluating its medicinal effect.
Original article: Banerjee et al. Journal of Natural Products, 2018, DOI:10.1021/acs.jnatprod.8b00527
A mechanistic understanding of cancer growth is critical to identify new therapeutic approaches to combat human cancers. Our research work in cancer biology centres around understanding the roles of NF-kB and MAPK signalling in the regulation of oncogenes, tumor-immune system cross-talk and the link between inflammation and cancer. One of the major questions addressed is how cross-talk between different signal transduction pathways fine-tunes the gene expression signatures of cancerous and healthy immune cells. V Siva Kumar's research group focuses primarily on identifying molecules or molecular complexes to which cancer cells are addicted for survival, regardless of the causative oncogenic mutations.
At IISER Tirupati, the cancer group also focuses on understanding the molecular mechanisms of signal transduction, gene regulation and the functionality of oncogenes/ co-regulators in the development of human cancers and metastasis. Recent work has identified the vital roles of Metastasis Associated Protein 1 (MTA1) in epithelial - mesenchymal transitions, metastasis and several other new physiological functions in DNA damage, inflammatory responses and infection. Pakala Suresh Babu's research group focuses on understanding the emerging roles of MTA1, which in turn would lead to development of MTA1 - targeted therapy for combating not only cancer but also for inflammation and pathogen-driven pathologic conditions.
An aptamer based tumor targeted drug delivery approach is underway in the research group of Ashwani Sharma (Ash Lab). Aptamer is a single stranded DNA or RNA (15 to 70 base length), which has high affinity and specificity for its target and is an oligonucleotide-based substitute to protein antibodies and has been shown to overcome the weaknesses of antibodies. Utilizing state-of-the-art RNA nanotechnology platforms decorated with aptamers and oligotherapeutics such as siRNA, Ash lab focuses on the target specific delivery to different cancers such as breast, colon and lung cancers. The lab also focuses on designing detection and diagnostic platforms for early detection of cancer utilizing target specific recognition of DNA/RNA aptamers.
In addition to new therapeutic approaches, the institute is also involved in developing methods for early diagnosis of cancer using modern techniques. Shibdas Banerjee's group focuses especially on clinical mass spectrometry imaging, coupled with discovery of new disease biomarkers.
Our research on tuberculosis revolves around understanding the biology of Mycobacterium tuberculosis with the objective to develop strategies for shortening treatment time and also to enable early diagnosis of this sub-clinical disease. We concentrate on two interconnected areas-improving drug permeation and enhancing drug efficacy. We focus on identifying key outer membrane channel forming proteins that are essential for nutrient and antibiotic uptake in order to understand factors which allow permeation of new chemical entities (NCEs) across the otherwise impermeable mycobacterial outer membrane. Raju Mukherjee's research group employs both proteomic and chemical genomic tools to identify such channel proteins and other factors (intrinsic resistome) that mitigate the efficacy of current drugs leading to anti-microbial resistance. In addition, we are aiming to develop a diagnostic tool to detect the sub-clinical asymptomatic manifestation of the disease by exploiting the strong cell-cell interaction mediated by glycolipids and cell surface carbohydrates.
According to the WHO-UNICEF Report 2015, India stands third in the number of deaths due to malaria. This increased mortality is associated with 67% rise in falciparum cases in the last decade. Further, recent clinical reports from Orissa and Karnataka show high severity among blood group B patients. The severity of malaria is caused by formation of clumps of parasitized RBC with uninfected RBCs in the microvasculature leading to blockage of blood flow resulting into organ failure and deaths. Since one-third of the Indian population has blood group B, it is imperative to identify the parasite molecule that binds to blood group B to cause increased agglutination. This will have direct implication towards development of therapeutics against severe malaria, specifically in the Indian perspective.
Besides agglutination, blockage of blood flow is also mediated by binding of parasites to various host endothelial cell surface proteins such as ICAM-1, CD31, EPCR, CD36 and gC1qR expressed on endothelial cell surface. However, these proteins are expressed at low levels and need to highly up-regulate to achieve the levels of sequestration observed during severity. Recently it was shown that Extracellular Vesicles (EVs) from Mycobacterium could up-regulate the expression of ICAM-1. Suchi Goel's research group aims to understand if parasite-derived EVs affect global expression profile of host receptors and hence sequestration. EVs are also being examined as a biomarker for early detection of severe malaria, as they are present in high density.
Plant Biology and Agriculture
Roots are important to plants for sensing and transporting nutrients and water from the ground. In recent times, the plant root system has gained importance as an important but under-utilised tool to improve plant growth and yield. The architecture of a plant's root system is thought to increase tolerance to abiotic stresses acting on the root, such as nutrient deficiency, drought and salinity. Research at IISER Tirupati focuses on deciphering molecular mechanisms and regulatory systems (such as plant hormone cytokinin (CK) status) that enable plants to orchestrate the complex development of root system architecture. We aim at developing basic plant research discoveries into technologies that improve agriculture sustainability. This area of research has lots of scope and importance in our county as environmental and agricultural sustainability is a major focus that needs to be addressed. Eswar Rami Reddy has two international patents (US patent No.9187761B2; EU patent No. EP2121935;) to describe methods to increase the root system size, thereby improving crops.
Ecology and EvolutionDISCOVERING INDIA's HIDDEN GENETIC AND CULTURAL BIODIVERSITY
Although India hosts several global biodiversity hotspots, our recent research using modern genetic tools reveals that there are several species that have not yet been described from the Indian forests. Our research has described new bird species and genera, uncovering evolutionary patterns that reveal the role of mountain systems along with ancient climate in driving speciation. We also find that bird song, an indicator of cultural diversity, has undergone diversification not only across different mountains, but also across isolation created by deforestation. We collaborate with engineers to develop an automated system to identify and detect dialects of different bird songs. A parallel effort includes documenting the extent of landscape change using remote-sensing data. We continue to explore landscapes across India to describe evolutionary and biogeographic patterns using advanced genetic and genomic data.PREDICTING IMPACTS OF CLIMATE CHANGE
Multiple teams of researchers are working on documenting various impacts of climate change on the distribution and life history of birds and mammals across the Western Ghats and Himalayan landscapes, including Ladakh. Patterns of speciation and colonisation are unclear, and the use of genomic methods in addition to field observations can reveal broad scale patterns of colonisation as well as evolutionary patterns. We also work specifically on small mammals like squirrels, which though common, are often cryptic but respond to minor changes in habitat and the environment around them. Of particular interest are expansions of low-elevation species into higher elevations, and these species can modify their behaviours and adapt to changing conditions rapidly, sometimes within half a century. In these systems, we record impacts like demographic and genetic impacts of climate change, with a view to understanding microevolution within populations.
Robin VV's group largely works on bird systems in the Western Ghats, Andaman and Nicobar Islands and peninsular India. Nandini Rajamani's group works on small mammals in the Trans-Himalayas of Ladakh and in the Western Ghats, understanding behaviour and adaptations of species to changing environments.
With the excessive increase in global energy needs, some researchers and scientists forecast that fossil fuel, mainly oil, will be depleted in 2055, while others predict that this will happen around 2050. One solution to the impending energy crisis is the development of vehicles that use alternate sources of power, such as electric power. Li-ion batteries (LIB), which are currently considered the most promising electrochemical energy storage system, unfortunately cannot be used in electric vehicles. The success of the current LIB technology rests largely on the graphite anode, which, due to the limited Li-ion kinetics triggers dendrite formation on surfaces and causes subsequent short circuiting of batteries. Exploration of alternate anodes without compromising high power capability is warranted.
Research at IISER Tirupati is focussed on developing the recovery process of possible materials like Ni, Co, Mn, Li, and carbon and re-using them for same charge storage applications. As Li-deposits are highly limited globally, developing alternate storage devices like Na, K, Mg and Al battery chemistries is essential. Vanchiappan Aravindan's research group is exploring various new materials for energy storage technologies. In addition to batteries, super-capacitors are also considered a strong contender for electric vehicle applications, mostly based on high surface area carbons.
In addition to directed basic research projects above, basic research at IISER Tirupati covers a number of other areas of science:
Number theory and complex algebraic geometry, homotopy theory, differential geometry, harmonic analysis, algebraic and differential topology and theory of representations of p - adic groups.
Bio-organic chemistry of peptides and nucleic acids, antisense therapeutics, nucleic acid based nanoparticles for drug delivery, total synthesis of natural products, bio-inorganic chemistry and activation of small molecules, computational and quantum chemistry and carbene stabilized zero valent heterodiatomic compounds.
Modelling the structure and dynamics of galaxies and dark matter halos, experimental high energy physics, quantum chromodynamics, microfluidics, observational astrophysics (star formation), theoretical condensed matter physics (quantum magnetism), strongly correlated systems and atomically thin nanomaterials, non-linear dynamics, string theory, and atomic and molecular physics.
Cell adhesion in neuritogenesis and neurodegenaration.
EARTH AND CLIMATE SCIENCES
Minerology and ignesious petrology.