Why babies need to move in the womb

Formation of joints in the developing embryo and their maintenance after birth is sensitive to mechanical movement. Now, researchers at Indian Institute of Technology (IIT) Kanpur have deciphered the molecular mechanism underlying this phenomenon. They have demonstrated how permanent cartilage is formed in an embryo due to mechanical movement. They also found out how permanent cartilage is lost and temporary or transient cartilage is formed in its place in the absence of movement.

While permanent cartilage lines the joint, the transient cartilage is a bone-forming one. Earlier this group demonstrated that during embryonic development, a bipotential cartilage population gives rise to both permanent and transient cartilage. BMP and Wnt are two major signals regulating this process. While BMP promotes transient cartilage formation, Wnt promotes permanent cartilage formation.

In patients with osteoarthritis, the permanent cartilage acquires all the characteristics of a temporary cartilage, which affects joint function. Currently, in people with osteoarthritis, it is not possible to reverse the fate of permanent cartilage that has become a temporary-like cartilage. The work done by a team led by Prof. Amitabha Bandyopadhyay from the Department of Biological Sciences and Bioengineering at IIT Kanpur suggests that it might be possible to prevent osteoarthritis from worsening if intervened at an early stage. The results were published in the journal Development. The work was carried out in collaboration with the laboratory of Prof. Paula Murphy of Trinity College Dublin.

Transient cartilage

BMP signalling — which helps in the formation of transient cartilage — is normally not present in permanent cartilage cells in a joint. That transient cartilage forms in the place of permanent cartilage due to joint immobilisation was already known. And independently, the team had shown that BMP signalling promotes transient cartilage formation. “So we wanted to find out if immobilising the joints in a chick embryo allows the BMP signalling to come up in the joint cartilage cells. We did find that happening,” Prof. Bandyopadhyay says.

The investigation into what causes the BMP signalling to be present in future permanent cartilage cells when the joint is immobilised led them to a surprise finding. The lead author, Pratik Singh, found out that an inhibitor of BMP signalling (Smurf1) is absent in the joint that is immobilised resulting in increased BMP signalling. “The role of the Smurf1 inhibitor is to maintain a BMP-free area thereby enabling the progenitor cells to become permanent cartilage. But due to increased BMP signalling the permanent cartilage gets converted into transient-like cartilage,” says Prof. Bandyopadhyay.

The Smurf1 inhibitor is not directly involved in joint cartilage formation but creates an environment that permits the formation of permanent cartilage by keeping the BMP signalling under check.

Toggle switch

Mechanical movement seems to act like a toggle switch. In the presence of it, Wnt – the signal that promotes joint cartilage – is on and BMP signalling is off in the joint cartilage cells. The opposite is true when the joint is immobilized. This is the reason why immobilisation of joints causes greater disturbance to permanent cartilage than even inhibition of Wnt signalling. “We are now investigating if osteoarthritis is also associated with appearance of BMP signalling in the wrong place. If so, we can block the BMP signalling in these cells during the early-stage of osteoarthritis to possibly prevent the condition from worsening,” he says.

The last new neurons were observed in 13 year olds

The human brain may not be as pliant as was believed, a recent study shows. In this study, bound to provoke argument, researchers observe that the latest neurons form in the brain when the subject is about 13 years old and no later. This finding, published in Nature, contradicts earlier experiments, according to which neurons in the hippocampal region of the brain could be formed even late in adulthood.

Hippocampus

The hippocampus is a region which is believed to be the abode of long-term memory and emotional responses. This was also believed to be true in other mammals such as chimpanzees and rodents.

In the study, the researchers took advantage of the fact that specific antibodies could bind to proteins of interest and indicate their locations in tissue. They thereby identified the locations of the neural precursor cells, proliferating cells and immature neurons in samples from 59 human subjects and traced the development from the foetal stage to old age. Up to 14 weeks of gestation, the three cell types migrated from their point of genesis to the region within the hippocampus – the dentate gyrus – where they stayed and developed. The oldest individual they observed with immature neurons was 13 years old.

The researchers observe that a lack of neurogenesis in the hippocampal region has been suggested in the case of some aquatic mammals like dolphins, porpoises and whales. This is interesting because these mammals are known for their intelligence, longevity and complex behaviour, too. They also offer a reason for why humans appear to differ so drastically from other mammals studied.

Open source record of plants with “druggable” chemicals will help validate traditional systems.

he use of Indian medicinal plants for drug discovery and therapeutics just received a boost. A database of such plants has been built by a Chennai-based team led by Areejit Samal of the Institute of Mathematical Sciences.

By documenting 1,742 Indian medicinal plants and 9,596 chemicals that plants use to thrive and ward off threats (phytochemicals), this database has the distinction of being the largest so far. This is a first step towards validating and developing traditional systems of medicine that use plant extracts.

For the repository, the scientists sourced information from several texts including those that documented tribal medicine. With supporting studies in the form of well-planned lab tests, this work has the potential to improve health care and enhance drug discovery.

Plants secrete various special chemicals to ward off predators, fight pathogens and survive in difficult situations. Some of these so-called phytochemicals have been used to prepare traditional medicines and also poisons. While there are extensive databases of phytochemicals of Chinese herbs, there has no similar work in India.

The new database, named IMPPAT (Indian Medicinal Plants, Phytochemistry And Therapeutics) brings together not just the Indian medicinal plants and their associated phytochemicals, but also the latter’s 2D and 3D chemical structures, the therapeutic use of the plants and the medicinal formulations.

Among the many challenges in building IMPPAT was in removing redundancy and standardising names and spellings that varied across the several books and documents they have referred to.

From previous work we know that natural products are made of highly complex molecules, which therefore are more likely to bind to very specific proteins unlike commercial (or synthesised) drug molecules.

“We show that phytochemicals in IMPPAT also have high stereochemical and shape complexity similar to natural product library of Clemons et al, and thus, IMPPAT phytochemicals are also expected to be specific protein binders,” says Areejit Samal. Drug molecules which are specific protein binders are likely to have fewer side-effects as they will bind specifically to their target protein.

Quest for druggability

The team analysed the features of the phytochemical structures using established “druggability” criteria.

This identified 960 potentially druggable phytochemicals of which only a small percentage showed similarities to existing FDA-approved drugs. “This offers immense potential for drug discovery,” says Dr Samal. Of the 960 phytochemicals, 14 have the highest druggability score, and one of these is Skullcapflavone I – This is produced by two plants, one of which is Andrographis paniculata, commonly known as Nilavembu or Siriyanangai. Another interesting topper is Kumatakenin, which is made by three plants including Artemisia capillaris. This plant is a close relative of Artemisia annuafrom which Nobel laureate Youyou Tu extracted the drug artemisinin which has saved the lives of many malaria patients.

“We hope to expand the links between phytochemicals of Indian medicinal plants and their target proteins, enabling application of systems biology... Our resource will help future efforts render Indian medicine evidence-based rather than experience-based,” says Dr Samal.

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The biomolecules that bind to cancer cells give a green fluorescence

New fluorescent nanoparticles created from simple biomolecules can now help light up cancer cells for better imaging.

Scientists from Indian Association for the Cultivation of Sciences (IACS), Kolkata have created nanoparticles from folic acid, riboflavin and lactose and tuned the molecules to give a green fluorescence to help in cell imaging using bright-field microscopy.

“The cadmium selenium quantum dots currently used for imaging purposes are highly toxic to the human cells. But we have used simple molecules which are found within the human body as basic ingredients to do the same work,” says Dr. Nikhil R Jana, Professor and corresponding author of the paper published in MRS Advances.

The newly created nanoparticles are mixed with the cell culture medium, kept for 2-3 hours, washed and then viewed under the microscope. The nanoparticles label the cancer cells alone and are seen with a green fluorescence under the microscope.

The nanoparticles exhibit specific labelling properties. Since oral cancer cells have folate and riboflavin receptors, the nanoparticles prepared from folic acid and riboflavin bind to these receptors. Folic acid nanoparticles bind to ovary cancer cells, while nanoparticles made from lactose bind to galactose receptors found on liver cancer cells.

They found that the green fluorescence depended mainly on the temperature at which they were treated. “We used a wide range of temperature for cooking the molecules (90-340 degree C). The broadness of the fluorescence spectra increased with the lowering of the reaction temperature,” says Hayder Ali, PhD scholar and first author of the paper. “These new nanoparticles are less than 10 nanometre in size and can also be used for targeted drug delivery as they seem to have specific labelling abilities.”

Preliminary in vivo studies using a mouse model show no toxicity, and the researchers are currently working on getting a red emission so that bioimaging can be done with low background signal.

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The oil risk — on the rise in international prices

As international oil prices head higher, India will have to brace itself for the economic risks of expensive energy. Brent crude oil futures were trading at about $70 a barrel on Friday, marking a four-year high and a price increase of close to 6% since the start of the year. The rise in international prices has been particularly sharp given that oil had been selling at below $45 in June. This is a rally of about 55% in a matter of just months. Oil price dynamics have often been explained by changes in the supply outlook influenced by the decisions of major oil producers. Oil trading at $70 should offer some respite to traditional oil producers like the OPEC members, which have suffered the onslaught of U.S. shale producers. According to the IMF, last year, for instance, Saudi Arabia would break even on its budget with oil at $70. The recent spurt in oil prices, however, seems to be more the result of a weakening of the U.S. dollar than anything else. The dollar has been gradually weakening against major global currencies since the beginning of last year. But the trend was given a new push following comments by U.S. Treasury Secretary Steven Mnuchin in favour of a weak-dollar policy. At Davos this week, Mr. Mnuchin noted that a weaker dollar would be good for American trade. However, given that the U.S. is right in the middle of a monetary tightening cycle, it is unlikely that the dollar will continue to boost oil prices, unless the Federal Reserve slows the projected pace of interest rate increases.

Consumers in India are already beginning to feel the pinch as petrol and diesel prices have hit multi-year highs. The retail selling price of both petrol and diesel in Delhi, for instance, has risen by close to ₹3 a litre since the beginning of 2018. The rise in domestic fuel prices is on expected lines given the policy of dynamic daily pricing of petrol and diesel adopted by the Centre. But as rising oil prices put pressure on domestic consumers, the government will have to desist from resorting to subsidies to ease the pain. It should work towards rationalising taxes on petrol and diesel to bring down retail prices. This will help consumers without imposing an undue burden on the oil marketing companies. An even bigger risk posed by higher oil prices is to the government’s fiscal management. With the fiscal windfall from low oil prices likely to end for now, the government should think for the long term and make crucial tweaks to its hydrocarbon exploration and licensing policy to expedite oil discovery and production. Simultaneously, it must take a leaf from China’s book and actively support Indian energy firms’ bids for overseas oilfields. Self-reliance is ultimately the best hedge.

ASEAN rising — on India-Southeast Asia cooperation

As leaders of the 10 countries of the Association of Southeast Asian Nations gathered in New Delhi this week, India’s ties with ASEAN got a dose of both symbolism and substance. The ASEAN-India Commemorative Summit, followed by their attendance at the Republic Day parade as joint chief guests, underlined the new consensus on the need for Southeast Asia and India to boost cooperation. First, as the demand for goods in Western economies comes down, the region needs to look deeper within to grow markets and increase trade. Second, continuing tensions between the “great powers” — between the U.S. and Russia, or the U.S. and China — are forcing the unaligned countries of ASEAN and India to forge a common understanding. China’s moves in particular, both its naval forays in the Indo-Pacific and its Belt and Road Initiative connectivity project, have the potential to change equations in the region. Third, as Singapore’s Prime Minister and the Chairman of ASEAN, Lee Hsien Loong, reminded the world in an editorial, and Prime Minister Narendra Modi said in his speech at the summit, India’s cultural and trade ties with Southeast Asia go back 2,000 years — and with Southeast Asia having come out of the overhang of Cold War divisions, India and ASEAN have a unique opportunity to reap the potential of their geographic proximity. The Delhi Declaration they signed articulated their urgent concerns as ASEAN and India called for measures to deepen security, economic and socio-cultural cooperation, and connectivity. These include joint mechanisms for maritime transport, trade and a “code of conduct” for the South China Sea.

But it must not be forgotten that when ASEAN-India leaders last gathered together in New Delhi in 2012 to mark the 20th anniversary of the dialogue partnership, they had made a similar commitment to trade and maritime security, and several promises are yet to be realised. With trade with ASEAN at $76 billion, India ranks lower than not just the U.S. and China, but also South Korea, Japan and Australia. The Regional Comprehensive Economic Partnership negotiations launched in 2012 have been held up, largely because of Indian concerns over unfettered access to Chinese goods and ASEAN resistance to movement of Indian services and labour. The other big unfulfilled promise is on connectivity, between ASEAN countries and India, as well as India’s connectivity through its Northeast to Myanmar and beyond. Work on the extension of the India-Myanmar-Thailand Trilateral Highway, the Kaladan multimodal highway, and Tamu-Kalay rail link to Myanmar has lagged behind deadlines. Border trade posts and infrastructure in the Northeast need much improvement to attract investment in the region. India and the ASEAN countries have much to gain from each other — but heavy-lifting is required to integrate India into the ASEAN equation. Else, shared history and culture and political leaderships in sync may only yield rousing summitry.