The team studied a large family with many affected members and identified the relevant gene variations linked to the disorder
A study by researchers from the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) and the National Institute of Mental Health and Neurosciences (NIMHANS), in Bengaluru, identifies two specific genes which may be related to bipolar disorder, a neuropsychiatric disorder that has been studied widely.
While there are strong indications that genetics plays a role in it, the specific genes whose mutations result in the individual being affected are difficult to identify. In a paper published recently in the journal Bipolar Disorders, the team describes their decade-long work studying four generations of a family with several members in each generation affected. In all, 28 members of one family were genotyped, and of these 11 were affected by bipolar disorder.
Genes and psychiatry
When asked about the challenges involved in carrying out the study, Prof. Anuranjan Anand, from JNCASR, an author of the paper, says in an email to The Hindu, “A variety of genetic parameters and models of the disorder needed to be tested. Further, disease-gene mapping is very sensitive to genetic parameters and defining this in a psychiatric disorder like BPD is a challenge.”
Bipolar disorder is an illness that affects about 0.8% of the global population. Also known as manic-depressive illness, it is characterised by mood swings, irrational behaviour and phases of mania or extreme highs, and at other times, phases of depression. The figures in India are not definitely known due to lack of reporting and diagnosis and poor documentation. However, judging by the global estimate, a significant number of Indians could be affected by this disease.
“If in a family there are multiple members with the disorder, then what is shared among the ill members, and not shared by the unaffected members may help identify the gene,” says Dr Sanjeev Jain from NIMHANS, one of the authors of the paper. “However, since the human genome is over three billion base pairs [long], we use a number of markers to identify which region of the genome is shared, and look up the gene in that region.” He is quick to clarify that with psychiatric genetics, not all those at risk may develop the disease.
“The experiment involves doing thousands of genotyping reactions and a large amount of sequencing of reactions for a large family with several affected members,” says Prof. Anand.
The group identified regions within chromosome 1 and chromosome 6 and, subsequently, found that variants of two genes (KANK4 and CAP2) were the likely candidates.
“We sequenced all the genes in the region, compared them to databases of the world, and of south Asians, and control samples from here, as well as other patients from here, and then zeroed in on the two variants,” says Dr Jain.
KANK1, one of the KANK family of genes, has been implicated in cerebral palsy, spastic quadriplegia-2 and steroid resistant nephritic syndrome, according to the authors of the paper. “Other genes in the KANK family have been linked to diseases, so it is likely that this variant in KANK4, too, may be linked to disease,” says Dr Jain.
The authors also describe that these mutations in KANK4 and CAP2 are rare variants. These occur in less than 1% of the population, often fewer than one in a thousand. As Prof. Anan puts it, “Today there are nearly 150 families across the world with structures like this. These give us a toe-hold into biology, illuminating clinical molecular mechanisms involved.”
The study suggests understanding the consequences of this variation in biological processes in the brain and further analysis of these two genes in people with bipolar disorder will be beneficial and help understand the biological aspects of the disease.
Curcumin also helps in the activation of innate immune cells known as macrophages and dendritic cells
Simple strategy: Increasing the number of central memory cells leads to better vaccine efficacy. NIAID NIAID
A study carried out on mice models has found that curcumin in nanoparticle form has the potential to enhance the efficacy of BCG vaccine such that it confers protection against adult pulmonary TB. The researchers found that injecting curcumin nanoparticles soon after vaccinating the mice with BCG produced an appreciable enhancement of immune memory cells (T central memory cells) responsible for long-term protection against TB infection.
BCG vaccine is effective against disseminated and meningeal TB in young children. But the protection does not last for long as the host-protective immune responses that the vaccine induces diminishes over time. Thus the vaccine is not protective in adults.
The team led by Gobardhan Das and Anand Ranganathan from the Special Centre for Molecular Medicine at the Jawaharlal Nehru University (JNU) demonstrated in mice models that curcumin nanoparticles enhance vaccine efficacy in two important ways. The work was done in collaboration with KIIT University, Bhubaneswar. The results were published in the journal Infection and Immunity.
In children, the vaccine induces two types of immune cells — effector memory T cells and central memory T cells. While the effector memory T cells play a crucial role in mounting an immediate immune response against virulent TB bacteria and kill them, the central memory T cells help in long-term protection in children from childhood TB. After persisting for some time, the central memory cells ultimately diminish. As a result, the protection does not last beyond childhood and adults become vulnerable to TB infection despite BCG vaccination.
One way of enhancing the efficacy of the BCG vaccine is by increasing the number of central memory cells so they last longer and confer protection for longer duration. In nature, dynamic balance exists between the two types of immune T cells — central memory cells and effector memory cells. Altering the ratio to increase the number of central memory cells will help in enhancing the efficacy of the BCG vaccine. “We were able to enhance the ratio of these two cell types by using curcumin nanoparticles,” says Prof. Das.
More memory cells
Increasing the number of central memory cells with respect to the effector memory cells was achieved through a simple process. The potassium ion channel (Kv1.3) is required for the differentiation of central memory cells into effector memory T cells. “In mice, the nanocurcumin blocks this channel and as a result the conversion of central memory cells into effector memory cells is under check. So the number of central memory cells increases leading to better vaccine efficacy,” says Shaheer Ahmad from JNU, the first author of the paper.
Curcumin also helps in the activation of innate immune cells known as macrophages and dendritic cells. TB bacteria reside and grow inside the macrophages. But once activated by curcumin nanoparticles, the macrophages and dendritic cells clear the bacteria and also enhance the level of TB-specific acquired immune cells (Th1 and Th17 cells).
“Curcumin nanoparticles not only increase the level of TB-specific acquired immune cells Th1 and Th17 but also simultaneously reduce the level of certain other cells (Th2 and Tregs) thus improving the efficacy of the BCG vaccine,” says Prof. Das. After TB infection, the levels of Th2 and Tregs cells increase and they inhibit the host-protective effect of Th1 and Th17 responses. So blocking or reducing the level of Th2 and Tregs cells enhances the vaccine efficacy.
The capacity of curcumin nanoparticles to modulate vaccine efficacy was tested in mice model. Following vaccination, the mice were treated with curcumin nanoparticles and then infected with TB bacteria. “We measured the bacterial burden in the lungs and spleen several times and observed that mice treated with curcumin nanoparticles had much less bacterial load than the controls,” says Ahmad.
“We are quite excited by this result and are hopeful further studies would take it to a stage where its application becomes a reality,” says Prof. Ranganathan.
Blackbuck ancestors came into India from the Saharo-Arabian region about two million years ago
Reason for divergence: The expansion of grasslands following blackbuck entry into Indian subcontinent could have facilitated the divergence.Ananya Jana Ananya Jana
A regular favourite with poachers and an animal that notoriously made headlines a few years ago, the blackbuck is once again in the limelight, this time, with its story of origin and evolution.
Researchers from the Indian Institute of Science (IISc), Bengaluru, studied four genera of ‘true antelopes’ — Gazella, Nanger, Eudorcas and Antilope — and found that the blackbuck’s (Antilope cervicapra) ancestors came into India from the Saharo-Arabian region about two million years ago and then evolved to its current form.
“If we compare the divergence dates of the blackbuck to the biogeographical conditions in India, we find that the antelopes were part of the fauna that came in through the northwest gateway into India. The very recent formation of the Thar desert could have a been a barrier to the back-dispersal of a grassland specialist like the blackbucks,” explains Ananya Jana, a Ph.D. student at the Centre for Ecological Sciences, and the first and corresponding author of the work published in Molecular Phylogenetics and Evolution.
Diverged in India
The paper states that the lack of blackbuck fossils outside India leads to the speculation that they diverged from their ancestors only after reaching India, long after the intensification of aridification in the Indian subcontinent. The expansion of grasslands following that period opened up new niches, which could have facilitated the divergence of many taxa.
Blackbucks have been confined to the scrubland regions of India, currently seen in most States, except for the Terai region, northeast and the Western Ghats. In the south, blackbucks can be seen up to the Tirunelveli district in Tamil Nadu.
Call for reclassifying
The team also noted that Antilope was not a sister of Gazella, as was previously believed, but was within the same genera. This would call for reclassifying the genus.
“We should probably reassign Antilope to be a species under Gazella. Members of the Gazella genus have certain morphological characters, which were not seen in Antilope, so they were put under a separate genus. Now, molecular studies have shown that the characteristics are not entirely different but have evolved differently,” explains Prof. Praveen Karanth, the team head and one of the authors of the paper.
Usually, researchers use mitochondrial DNA for genetic analysis. However, this team used nuclear DNA, which has genetic material from both parents. They used 12 different nuclear markers for the study.
“We have seen that there are differences in the mitochondrial-DNA and nuclear-DNA trees. Therefore, there are conflicts between molecular data also. We need to carefully look at and interpret the data. It is time that taxonomical studies combine use both molecular and morphological analysis,” adds Prof. Karanth.
Evolution of chinkara
Another interesting finding was that the chinkara (Gazella bennetti), another ‘true antelope’ of India, evolved much more recently about 7,00,000 years ago, probably after the establishment of the Thar desert. These are also found in the hilly terrains of Iran, and are known as Iranian Gazelle. Being facultative drinkers, they were better adapted to the drier, semi-arid region.
Genetics has now helped researchers tell two stories of origin and evolution. Though the blackbucks and chinkara look like sisters they actually may have very different evolutionary histories.
The sensor was able to detect multidrug-resistant leukaemia cells even when just 10 cells per ml were present
Stable device: The response of the sensor remains almost unchanged for three weeks, say S.S. Islam (left) and Payal Gulati.
A highly sensitive carbon nanotube-based sensor capable of detecting multidrug-resistant myeloid leukaemia cells even when present at very low concentration of 10 cells per ml has been fabricated by Delhi-based researchers.
Using chemical vapour deposition technique, the team led by Prof. S.S. Islam from the Centre for Nanoscience and Nanotechnology at the Jamia Millia Islamia produced vertically aligned multi-walled carbon nanotubes. The carbon nanotubes were grown on a silicon wafer substrate. In order to miniaturise the sensor and make it flexible, moisture-resistant and stable even at 180 degree C, the researchers transferred the carbon nanotubes to a flexible substrate made of polyethylene terephthalate (PET).
As a first step to converting the carbon nanotubes into a sensor, the researchers functionalised the nanotubes. Nanotubes that are functionalised have better ability to bind to a leukaemia antibody, which in turn binds to the leukaemia cells present in the sample.
“We used vertically aligned carbon nanotubes to increase the surface area available for the antibodies to bind to them,” says Payal Gulati from Jamia Millia Islamia and first author of a paper published in the journal Sensors and Actuators B: Chemical. “As more antibodies get bound to carbon nanotubes, the sensitivity improves.”
The portions of the functionalised nanotubes that do not contain the antibody are blocked with bovine serum albumin to prevent the leukaemia cells from binding there.
Compared with drug-sensitive leukemic cells, multidrug-resistant leukaemia cells have better ability to bind to the antibody found on the nanotubes. “The expression of P-glycoprotein transporter present on leukaemia cell surface gets enhanced when the cell becomes multidrug-resistant,” says Gulati. So to make the cells multidrug-resistant, the researchers treated them with chemotherapy drug doxorubicin
A solution containing six different leukaemia cell populations ranging from 150 cells per ml to 15 million cells per ml were tested to assess the sensitivity. The carbon nanotubes are allowed to stand in a solution containing leukaemia cells for three hours at room temperature to allow sufficient time for the cells to bind to the antibody found on the nanotube surface.
“We found the sensitivity of the sensor to be superior. It was able to detect multidrug-resistant leukaemia cells even when just 10 cells per ml were present,” says Prof. Islam.
The presence of leukaemia cells bound to the antibody is determined by measuring a drop in the conductivity of the carbon nanotubes. To measure changes in conductivity, three electrodes — carbon nanotubes as a working electrode, a counter electrode made of platinum and a reference electrode — are immersed in a electrolyte and a constant voltage is applied and a change in current is measured.
Leukaemia cells are insulating in nature. So the conductivity of carbon nanotubes reduces as the cells bind to the antibody. The more the concentration of cells bound to the antibody the greater is the reduction in the current flow.
“We were able to measure a change in current when just 10 leukaemia cells bind to the antibody present on the carbon nanotubes,” says Gulati.
The researchers found that there was negligible variation in current even after three weeks when the carbon nanotubes containing leukaemia cells are stored at 4 degree C in a buffer solution. “The response of the sensor remains almost unchanged for three weeks,” she says.
Reversing baldness in the future may be as simple as wearing a hat, thanks to a new noninvasive, low-cost hair-growth-stimulating technology tested successfully on mice, scientists say.
Based on devices that gather energy from a body’s day-to-day motion, the hair-growth technology, described in the journal ACS Nano, stimulates the skin with gentle, low-frequency electric pulses, which coax dormant follicles to reactivate hair production.
The devices don’t cause hair follicles to sprout anew in smooth skin. Instead they reactivate hair-producing structures that have gone dormant, researchers said.
The technology can be used as an intervention for people in the early stages of pattern baldness, but it would not bestow tresses to someone who has been bald for several years,they said.
Researchers noted that because the devices are powered by the movement of the wearer, they don’t require a bulky battery pack or complicated electronics.
Small devices called nanogenerators passively gather energy from day-to-day movements and transmit low-frequency pulses of electricity to the skin. That gentle electric stimulation causes dormant follicles to “wake up,” the researchers said.