Thursday, 28 September 2017

Breakthrough In Understanding Of Cell's Powerhouse

Scientists provide new insight in the mitochondrial protein-lipid interactions.

By Ratneshwar Thakur Published in The Hawk

(Dr. Nathan N. Alder with his team Members, Image: Ketan Malhotra) 

Mitochondria are cell's powerhouses, which catalyze the conversion of the energy stored in nutrients into the production of ATP, the chemical energy currency of the cell. When mitochondrial function is compromised, it can lead to various complications related to the functioning of organs with high metabolic rates such as the brain and heart. This study has provided clues as to how deregulation of mitochondrial lipid homeostasis can contribute to mitochondrial diseases such as Barth syndrome.

The research labs at the University of Connecticut led by Prof. Nathan N. Alder from the Department of Molecular and Cell Biology with his team members, including Dr. Ketan Malhotra, Dr. Arnab Modak and many others- have identified precise roles of cardiolipin in the initial stages of mitochondrial protein import – namely, mediating crucial interactions between the protein substrate receptor and the protein import channel.  

The results of this study were published in the scientific journal Science Advances.

Among the many roles of mitochondria, they are the primary producers of the “energy currency” of the cell; therefore, the proper functioning of these organelles is important for many cellular processes. Most mitochondrial proteins are made outside the organelle and are transported via the coordinated action of a set of molecular machines residing on its two membranes.

“Mitochondrial lipids – specifically cardiolipin – play a central role in maintaining cellular energy homeostasis, but their importance in mediating mitochondrial protein transport remains underappreciated. This study aimed to bridge that gap and understand how cardiolipin aids the process of protein transport into mitochondria,” said Dr. Ketan Malhotra, first author of this paper.

“Perhaps the most formidable challenge in coordinating this work was the highly multidisciplinary nature of this study, which included analyses that spanned from molecular biophysics up to the level of the cell,” said Dr. Alder.

This study has important implications in the area of medical research since it demonstrates how lipid homeostasis is important for mitochondrial biogenesis. This study has shown that patients suffering from Barth syndrome can have a deficient mitochondrial protein transport system. This new study has opened new perspectives to look deeper inside the protein transport system to develop better understanding and control measures for such complications.

Scientists Identify Potential Metastasis Biomarker For Early Stage Tongue Tumors

The study identifies MMP10 as a novel candidate biomarker to help accurately identify those likely to develop cancer metastases.

By Ratneshwar Thakur Published in The Hawk

(Dr. Amit Dutt with his team members, Image Credit: Dr. Amit Dutt)

Tobacco-associated cancer of the lung, head, and neck forms about 40% of all cancers observed in India. In spite of such alarming increase, effective development of targeted therapeutics remains at large - due to lack of our understanding of the molecular changes that drive the formation of tumours in these cancers.

In a study published in the “Oral Oncology”- an official journal of the European Association of Oral Medicine, International Association of Oral Pathologists, Dr. Amit Dutt (Shanti Swarup Bhatnagar Prize (SSB) for Science and Technology 2017 in Medical Sciences), Wellcome Trust/ DBT India Alliance Int. Fellow, Tata Memorial Centre-ACTREC, and his team present a comprehensive landscape of genetic alterations that underlie an early stage tongue tumors. Their study led to the identification of a gene, Matrix Metalloproteinase (MMP10), as a potential prognostic biomarker to identify those likely to develop cancer metastases- i.e. spread of cancer from one organ to another from an early on stage.

In this study, total 57 patients were studied. Majority of the patients were in an early stage of tongue tumors with tobacco/nut chewing habits. High-throughput genomics and computational analysis were performed to identify MMP10 as a potential biomarker in these patients. "Integrative genomics analysis revealed that about 50 % of the patients indicated altered expression of MMP10 gene," says Dr. Pratik Chandrani, one of the authors and a post-doctoral researcher.

During the examination of patients by doctors, the presence of regional lymph node metastasis, if so any, plays a conclusive role in the choice of treatment. About 70% of patients with early T1 or T2 stage tumours may not harbor any nodal metastasis in the neck. This study identifies MMP10 as a novel candidate biomarker to help accurately identify these 70% patients, who could thus be spared from unnecessary surgery with known harmful effects.

“I anticipate the outcome of validated novel therapeutic targets from this study to profoundly inform the designing of successful clinical trials,” said Dr. Amit Dutt.

In spite of all the technological developments in radiology, preoperative estimation of metastatic nodal status among early tongue cancer patient is highly inaccurate. Therefore, routine physical neck dissection and conventional pathological estimation of the entire dissected nodes still remains the gold standard in staging neck nodal status in patients with tongue cancers.

“Accurate prediction of metastases in tongue cancers— as MMP10 expression level appears as a promising candidate-- would have an immediate clinical impact through avoidance of unnecessary treatment of patients at low risk with appropriate direction of resources toward aggressive treatment of patients at high risk of having metastatic disease,” said Dr. Sudhir Nair (Clinician Scientist - Head & Neck).

“The finding from our study provides a roadmap to validate the MMP10 as a potential prognostic biomarker to stratify those likely to develop metastases in tongue cancer patients. However, further clinical and functional validation in a large number of patient and cells would be required,” said Dr. Pawan Upadhyay, first author of this paper.

Thursday, 21 September 2017

Scientists Are Learning Lessons Of Regeneration From Tiny Organism

The study opens up a new possibility to discover the role of non-stem cells in the skin regeneration.

BY Ratneshwar Thakur                 Published in India Science Wire
Also appeared in BioTechTimes BusinessLine APN NetIndian BioVoiceNews 

(Dr. Dasaradhi Palakodeti with his team members at inStem)

In an ideal world, one would like to live with no deformities. How often you think about being able to re-grow limbs after an amputation or any injury. Imagine being able to regenerate your spinal cord after an accident has left you paralyzed. Nature has many examples of some tiny organisms completely re-growing from their small pieces. Scientists are studying such organisms to learn important lessons in regeneration.

Researchers at the Bangalore-based Institute for Stem Cell Biology and Regenerative Medicine have reported that deformities in the epidermis of an organism called planaria cause the defect in their stem cell function and regeneration. This is significant because epidermal cells are not stem cells.

Planaria are flatworms that live in fresh water and have the ability to regenerate from almost any pieces to form a completely new animal with all functional organ systems. Researchers used planaria as a model organism to understand the mechanism behind its immense regenerative ability.

“Our study has shown how the organization of epidermal cells during planarian regeneration is crucial for regulating stem cell function,” said Dr. Dasaradhi Palakodeti, a scientist at the Bangalore based Institute, and a co-author of the study published in the journal Development.

Regeneration is often synonymous with stem cells and most of the studies focus on understanding factors essential for ‘stemness’. “Here, for the first time we show how planarian epidermis (non- stem cell) plays a critical role in wound healing and stem cell function,” said Dhiru Bansal, first author of this paper.

However, it is still unclear how the environment surrounding stem cells regulates their function. Researchers believe stem cells are instructed by surrounding cells to make right decisions to proliferate and differentiate for regeneration, to give rise missing tissues. The team is working to understand the role of a specific protein called PABPC2 (cytoplasmic poly A binding protein) in regeneration.

“Our report about a crosstalk between stem cells and epidermis in planaria opens new possibilities that can be addressed in other systems as well,” said Jahnavi Kulkarni, one of the authors of this paper.

The study opens up a new possibility to discover the role of non-stem cells in the skin regeneration. Skin is often well-thought-out for its protective function but this new study highlights other potential roles of the skin. 

The research team included Dhiru Bansal, Jahnavi Kulkarni, Kavana Nadahalli, Vairavan Lakshmanan, Srikar Krishna, Vidyanand Sasidharan, Shilpa Dilipkumar, Akash Gulyani, Srikala Raghavan and Dasaradhi Palakodeti (Institute for Stem Cell Biology and Regenerative Medicine, Bangalore); Jini Geo and Renu Pasricha (National Centre for Biological Sciences, Bangalore).

Monday, 18 September 2017

Researchers Identify Role of Cellular Communications To Fight Against The Bacterial Infections

Host organism counter-acts against the pathogen by regulating the levels of occluding junctions.

(Dr. Guy Tanentzapf with Dr. Rohan J. Khadilkar, Image Credit: Dr. R.J. Khadilkar)

When it comes to survival against the evils either in our society or inside our body- communication plays an important role in all facets of life. Inter-cellular communication allows millions of cells to connect well and work together in coordination to perform important bodily processes for survival. However, very little is known about how local environment of stem cells changes, and communicates, upon a situation like the infection.

A Research team led by Dr. Guy Tanentzapf at University of British Columbia, Canada- has identified how cells talk to each other through their membrane junctions to fight against bacterial infections.

Dr. Guy Tanentzapf’s lab is working on to understand how cells interact with each other and respond to their environment. In particular, what are the roles of cell junctions at the cellular membrane that allow them to interact with each other and communicate with their environment?

The results of this study were published in the journal eLife.

In this study, Drosophila (Flies) has been used as the model organism. Flies are an excellent model organism for research due to the ease with which genetic manipulation can be achieved. The researchers said most of the molecules are highly conserved in flies; hence studies on flies can be applied to the mammalian system.

In animals, stem cells are essential for development, maintenance, and regeneration of tissues. Stem cells live with other non-stem cells in a particular microenvironment, known as stem cell niche. The cells in the stem cell niche play an instructive role for the stem cells to make highly specialized cells or to renew their population.

“In this study, we define a novel role for occluding junctions in the blood stem cell niche in Drosophila. We show that the occluding junctions form a permeability barrier that regulates the flow and transport of molecules across cells. The permeability barrier maintains a distinct micro-environment at the stem cell niche which helps in making the decision between stem cell renewal and differentiation,” said Dr. Rohan J. Khadilkar, Post-Doctoral researcher and first author of this paper.

According to this study, when the bacterial infection occurs, this permeability barrier gets disrupted due to a down-regulation of occluding junctions at the stem cell niche. This down-regulation triggers the rapid formation of different types of blood cells that primarily act as immune cells. These blood cells mount the cellular immune response in flies.

“Our study for the first time shows how the stem cell niche environment changes as a response to infection by bacteria and how does the host organism use this to fight against the attack of the pathogen. Since this mechanism helps in boosting the immune response of the host, it holds a lot of promise even in the case of humans,” said Dr. Khadilkar.

Journal Reference:

This news article was published in The Hawk:

Wednesday, 13 September 2017

Indian Researchers Explored How An Embryo Implants In To The Mother’s Womb

A new study suggests for the first time about the existence of cross-talk between the mother’s womb and an embryo to initiate a pregnancy.

(Dr. Deepak Modi at ICMR-National Institute for Research in Reproductive Health)

Reproduction is fundamental to all life forms and in humans initiation of pregnancy requires the embryo to adhere in the mother’s womb. As the embryo enters the mother’s womb, it has to rapidly find a suitable place to attach and then invade to get nutrition. This marks the initiation of pregnancy in humans. How the embryo decides where to implant and how the mother prepares her womb to initiate pregnancy is unknown.

In a collaborative effort, research teams led by Dr. Deepak Modi- Scientist at ICMR-National Institute for Research in Reproductive Health-Mumbai, Dr. Satish K. Gupta- Emeritus Scientist at National Institute of Immunology- New Delhi, and Dr. Asgerally Fazleabas, Professor at Michigan State University, USA- have shed light on how the mother prepares her womb to initiate pregnancy.

The results of the study were published in the Journal Endocrinology.

“My lab is working on to dissect the mechanisms by which the embryo and mother talk to each other to initiate the pregnancy. This is a joint team effort of three different laboratories. Here I would like to highlight that it’s only by networking we can make major breakthroughs,” said Dr. Modi.

The study is exciting as it has given some important insights in very early life events that happen inside the mother’s womb. What makes the discovery remarkable is that researchers have uncovered the mechanism by which the mother’s womb tells the embryo about where to implant to initiate the pregnancy.

According to this study, a protein called as HOXA10 present in the mother's endometrial cells and another protein called STAT3 in the cells of the embryo (the trophoblast cells) talk to each other. Researchers have observed that the signals sent by HOXA10 from the endometrial cells are sensed by STAT3 in the embryo which makes the trophoblast cells invade into the endometrium to establish the pregnancy.

The study had been technically challenging as it is neither ethical nor clinically justifiable to collect human tissue at early stages of pregnancy. “In-vitro data (study in laboratory set-up) needs to be proven in any In-vivo system (study in living system). To overcome this challenge, we did our studies in monkeys (which are closer to humans). We were happy our data in the lab dish turned out to be true even in the womb of monkeys,” said Dr. Geeta Godbole, the first author of this paper.

In the present form, the study is very fundamental where Dr. Modi and his team members are trying to explore secrets of nature. However, there are several long-term implications. Firstly, for infertile couples, the IVF (test tube baby) is the only treatment option, but the success rates of IVF are very low (less than 30%). “We feel that the results of our study in long term will help in devising strategies to improve success rates of IVF,” said Dr. Modi.

“In converse, our data may help in devising drugs that would help in blocking pregnancy and hence may act as contraceptives. Although far-fetched, the process of trophoblast invasion is synonymous to cancer metastasis; it is possible that our study would help in devising a treatment to prevent metastasis in cancers,” said the study leader about the other future perspectives of this finding. 

Journal Reference:

This news article was published in The Hawk:

Sunday, 10 September 2017

inStem Researchers Shed Light On Planarian’s Epidermis Role In Its Regeneration

A new report from the Institute for Stem Cell Biology and Regenerative Medicine chronicles breach in planarian’s epidermis cause defect in stem cell function and regeneration, providing a new insight into the Planarian’s regenerative abilities.

By Ratneshwar Thakur Published in The Hawk

(Dr. Dasaradhi Palakodeti with his team members, Image Credit: Dhiru Bansal)

Planaria are flatworms that live in fresh water and has the ability to regenerate which is incomparable among different living organisms. Interestingly, if you cut apart an adult planaria into pieces; not to be surprised, almost any piece can form a completely new animal with all organ systems. These entire regeneration events are orchestrated through adult somatic stem cells called as Neoblasts.

A Research group led by Dr. Dasaradhi Palakodeti at the Institute for Stem Cell Biology and Regenerative Medicine (InStem), Bangalore- has reported that breach in epidermis cause defect in stem cell function eventually leading to defect in regeneration. The discovery by inStem biologists was published in the journal Development.

“It would be ideal if we human beings could regenerate our lost tissue or limbs. This could tremendously boost human health. For the same, it is of paramount importance to understand the process of regeneration,” said Dhiru Bansal, Ph.D. student and first author of this paper.

Dr. Palakodeti’s lab is working on to understand the role of RNA binding proteins in regeneration. Interestingly, his group came across a protein PABPC2 during analysis, which drew their attention to study this protein for two main reasons. First, PABPC is a universal protein present in eukaryotes. It is important for protein synthesis, however, their mechanism and role in regeneration is not known. Secondly, it was a novel protein not reported so far in planaria.

To study the role of pabpc2 gene in regeneration, inStem researchers performed knockdown (a way to make gene non-functional) experiment. They fed the planarians with dsRNA specific to pabpc2 to knock down (KD) the gene. Planarians with pabpc2 KD showed the defect in wound closure and stem cell function due to epidermal defects compared to wild-type.

“In the current study, we have shown the role of the epidermis in providing instructive cues essential for Neoblasts function critical for planarian regeneration. These events essential for wound healing in planaria, such as epidermal migration to cover the wound surface is also observed during the cutaneous wound healing in mammals. Similarly, mobilization of proliferating stem cells (Neoblasts) to the site of injury, which is critical for planarian regeneration, has also been shown to be essential for tissue regeneration in mammals,” said the study leader.

It is unclear in the stem cell field how the environments surrounding the stem cell, which constitute non-stem cells, regulate stem cell function. “Our study uncovered how the organization of the epidermal cells during planarian regeneration is crucial for regulating the stem cell function,” said Dr. Palakodeti.

“Regeneration is often synonymous to stem cells and most of the studies focus on understanding factors responsible for stemness. This study is unique as we identified how a non-stem cell regulates stem cell function. Non-stem cells direct stem cells to respond based on cues,” said Dhiru Bansal.

Dr. Palakodeti’s team have also explored how an ubiquitously (most of the tissues) expressed protein could specifically affect only certain cell types establishing the varied role of the protein in different cell types -critical for some while redundant for other cell types.

This study opens up a new possibility to explore the new role of non-stem cells in regulating stem cells. Skin is often considered for its protective function but this study highlights a much more important role skin can play. It will be interesting to see if these features are also conserved in other organisms. 

Journal Reference:

Tuesday, 5 September 2017

NIPGR Researchers Have Identified A Novel Broad Spectrum Antifungal Molecule From Bacteria

Burkholderia bacteria recruit a prophage tail-like protein to feed on fungi.

By Ratneshwar Thakur Published in The Hawk

(Dr. Gopaljee Jha with his team members)

Across the world, fungal infections are emerging as a major problem for sustainable agriculture and farming. They are also responsible for death and disability in humans, and extinction of wildlife. Currently, worldwide researchers have been trying to find various measures to control the fungal infections.

A research group at National Institute of Plant Genome Research (NIPGR), New Delhi (An autonomous institute of Department of Biotechnology, Govt. of India) -led by Dr. Gopaljee Jha, has recently identified a novel broad-spectrum antifungal protein. The study was published in the journal Nature Communications.

Group of researchers from Dr. Jha’s lab has quarantined a novel bacterium Burkholderia gladioli strain NGJ1 from healthy rice seedling which demonstrates fungal eating property, a phenomenon known as mycophagy.

When the researchers allowed the bacterium to grow on the plates containing fungal cells, dramatically bacterium killed fungal cells to utilize fungal metabolites for its own growth.

“On this observation, we expected that NGJ1 would prove to be a better biocontrol agent than other antifungal bacteria. Due to its mycophagous property, the bacterium can not only prevent fungal growth but can eradicate fungal biomass as it utilizes them as a source of nutrients,” said Dr. Jha.

According to this study, it was found that treatment of NGJ1 was able to prevent the disease-causing ability of Rhizoctonia solani, which is responsible for sheath blight disease of rice. It is certainly a unique observation that a small size bacterium killing relatively large size fungi.

From previous studies, it is believed that phages are bacterial predators and upon induction, they can kill bacterial cells. Through series of experimentation, Dr. Jha’s group has reported that NGJ1 has made its phage inactive (prophage) and appoint one of the prophage tail-like proteins (Bg_9562) to forage over fungi.

They also observed that the purified Bg_9562 protein demonstrates broad spectrum anti-fungal activity against several economically important pathogens, such as Rhizoctonia solani (rice sheath blight pathogen), Fusarium oxysporum (pathogenic to various plants), Chickpea blight pathogen, Apple scab pathogen and Candida albicans (causes Candidiasis in humans) and others.

This Bg_9562 gene could be a new perspective for further research against fungal infections. It can be used as a transgene to develop broad-spectrum fungal disease resistant plants, which is need of the hour.

“Considering broad-spectrum antifungal activity of this protein, it is being proposed that the protein could be utilized to control fungal diseases of plants as well as humans/animals. Moreover, the current study opens up various translational applications in controlling fungal diseases,” said Dr. Durga Madhab Swain, research fellow and one of the first authors.

Dr. Jha appreciates his team members (Durga, Sunil, Isha, Rahul, Rajeev, Srayan, Joyati) for this accomplishment. He says that all team members have worked day and night to find the molecular basis of bacterial mycophagy.

Journal Reference: