Tech

Dynamic full-field optical coherence tomography: 3D live-imaging of retinal organoids

image: a, Colour bar of the D-FFOCT images with a consistent colormap for (b,c). b, Image of a D29 retinal organoid, showing multiple cells with different dynamic profiles. c, Image of a D51 retinal organoid, where precursors of photoreceptors begin to appear in a rosette formation (red dotted line). High-temporal-resolution imaging performed on a D147 retinal organoid. d, Part of the retinal organoid revealed fusiform structures corresponding to emerging photoreceptor outer segments in the centre of the rosette. e, Magnified view of nuclei in three different states around the rosette: (i) a nucleus in a normal state with a compact, uniform shape and is very bright (i.e., exhibiting a high activity); (ii) an seemingly dying, inflated nucleus, exhibiting almost no activity; and (iii) a nucleus undergoing division with no defined nuclear membrane in the cytoplasm, and two distinct parts (white arrows) of the content of a nucleus (suggesting mitosis of the nucleus with chromosomes already divided, with the same subcellular activity level as the "normal" nucleus). f, Magnified image of the photoreceptor outer segment-like structures imaged side-on; three of them are marked with a white line. Scale bar: 20 μm.

Image: 
by Jules Scholler, Kassandra Groux, Olivier Goureau, José-Alain Sahel, Mathias Fink, Sacha Reichman, Claude Boccara and Kate Grieve

Current modalities for imaging living tissues and 3D cell cultures are invasive, slow or lacking in spatial resolution. Dynamic full-field optical coherence tomography (D-FFOCT) is a label-free, non-invasive, quantitative technique allying high spatial and temporal resolutions. This technique relies on low coherence interferometry to amplify the phase and amplitude fluctuations, created by moving scattering structures inside biological samples, yielding a motility contrast. D-FFOCT opens up the possibility of following the development of complex 3D multicellular structures, such as retinal organoids.

In a new paper by Jules Scholler, Kassandra Groux, et al., published in Light: Science & Applications, a team of optics experts (Institut Langevin, Paris, France) led by Dr Kate Grieve from the Quinze-Vingts National Eye Hospital (Paris, France), in collaboration with cell biologists (Institut de la Vision, Paris, France), have developed and applied a new imaging modality for the imaging of in-development retinal organoids.

These scientists summarize the operational principle of their microscope:

"We use the interferometric amplification of a full field optical coherence tomography device and study the fluctuation of the interferometric signal to quantitatively construct tomographic volumes with a metabolic contrast. Owing to our high sensitivity, we are able to reconstruct highly contrasted images of almost transparent samples without using any exogenous labels."

"Owing to the full field configuration and the high sensitivity, our method is faster and requires much lower illumination intensity than nonlinear microscopy techniques that can damage the sample irreversibly. This allows us to study the development of the same sample over periods of several weeks" they added.

"D-FFOCT will have many potential applications for in vitro living tissue including disease modeling, cancer screening, and drug screening" the scientists forecast.

Credit: 
Light Publishing Center, Changchun Institute of Optics, Fine Mechanics And Physics, CAS

NUS-led study considers potential and constraints of reforestation for climate mitigation

image: Nursery seedlings beginning to flourish in Sungai Tohor, Riau, after a community-based peatland restoration project.

Image: 
Assistant Professor Janice Ser Huay Lee

Reforestation is a promising nature-based climate solution. However, there are practical considerations beyond the suitability of land for planting trees, such as financial, land-use and operational constraints, which can limit its outcomes and thus need to be taken into account. A recent study led by researchers from the National University of Singapore (NUS) found that these constraints could limit the climate mitigation potential of reforestation in the Southeast Asian context. Understanding how these constraints operate helps inform the prioritisation of cost-effective reforestation and investment opportunities.

Their findings were published in the journal Nature Climate Change on 17 August 2020.

Reforestation and climate change mitigation

During the annual meeting in Davos in January this year, the World Economic Forum launched an ambitious initiative to plant one trillion trees worldwide to restore biodiversity and fight climate change.

Tree planting, and reforestation in general, have often been touted as a cost-effective nature-based solution to address climate change. This is due to the ability of trees and other natural vegetation to convert atmospheric carbon dioxide (CO2) to biomass through the process of photosynthesis, which is nature's way of capturing and locking up carbon. However, broader considerations beyond where trees could be planted may have impacts on the effectiveness of reforestation as a climate solution.

Barriers to reforestation

In the study, the research team led by Professor Koh Lian Pin, who is from the NUS Department of Biological Sciences, estimated the climate mitigation potential of reforestation across Southeast Asia, and assessed the effects of biophysical, financial, land-use, and operational considerations on different constraint scenarios.

The researchers found that 121 million hectares of land across Southeast Asia are suitable for reforestation, and could potentially contribute to climate mitigation at a rate of 3.4 gigatonnes of CO2 per year.

"However, only a fraction of that mitigation potential may be achievable if practical constraints are taken into account," noted Prof Koh, who is also Director of the NUS Centre for Nature-based Climate Solutions.

One example is the many pockets of "barren land" in Southeast Asia that may actually be in use by farmers to grow crops for subsistence, or for sale in local markets. NUS postdoctoral research fellow Dr Zeng Yiwen, who is the first author of the paper, explained, "If we exclude these small farmlands, the available land for reforestation in Southeast Asia would be reduced to about 76 million hectares, and its climate mitigation potential would drop to 2.2 gigatonnes of CO2 per year."

The team noted that there may also be a need for reforestation sites to be near mature forests which could act as sources of seeds or seedlings that are critical for the reforestation process. Other considerations that the team took into account included the cost of reforestation and protection status.

"If we want to maximise the success of reforestation projects and restrict them to within two kilometres of existing intact forests, we would only be looking at about 33 million hectares of available land in the region, which would provide only 0.9 gigatonnes of CO2 sequestration potential per year," said Ms Tasya Sarira, the second author of the study who is from the University of Adelaide.

Reforestation: Balancing trade-offs

Prof Koh explained, "The barriers to reforestation we have identified are not insurmountable. For example, by involving smallholder farmers in the reforestation process, such as through agroforestry or tree planting on their farms, climate mitigation potential can be realised while balancing trade-offs with food security and local livelihoods."

Reforestation is an important nature-based solution, not only for climate mitigation, but also for the multiple co-benefits it provides, including biodiversity conservation, clean air and water, and poverty alleviation.

"A more complete and nuanced consideration of both the potential and limits of nature-based climate solutions is needed to inform climate policies and decisions that are scientifically sound, economically feasible and socially acceptable," he elaborated.

Credit: 
National University of Singapore

Further details revealed about a highly-efficient anticancer drug delivery system

image: Intracellular investigation of FRET NPDs.

Image: 
Tohoku University

The majority of drug delivery systems use nano carriers to transport drugs due to their small size and ability to distribute drugs to otherwise inaccessible sites of the body. The downside to this small size, however, is that large quantities are needed to match the required dosage.

Alternative carrier-free systems, known as nanoprodrugs (NPD), show immense promise for cancer treatment. For example, a SN-38 NPD has about 10 times higher anticancer efficiency than commercially available drugs. Now, researchers have, for the first time, developed a comprehensive study on the dynamics of SN-38 NPDs inside cancer cells, including their internalization rate, intracellular localization, and degradation, as well as their therapeutic efficiency.

"These innovative systems show high anticancer activity, but the knowledge fundamental for clinical translation, such as their interaction with cancer cells, was still lacking," said Professor Hitoshi Kasai, co-author of the study.

The research team evaluated the state of NPDs inside cancer cells using the Förster Resonance Energy Transfer (FRET) based microscopy technique. FRET relies on the energy transfer between two light-sensitive molecules. Taking advantage of the fluorescent property of the SN-38 along with the Bodipy FL fluorescence probe in the NPDs specifically designed for this study, FRET allowed the researchers to observe the state of NPDs from intact particle to the dissolved prodrug.

Confocal laser microscopy observation confirmed significant NPD degradation from intact state to a dissolved prodrug inside the cells over time. This means that NPDs were consistently absorbed by cells as intact particles before being transported into the lysosomes - a membrane bound organelle containing digestive enzymes. Once inside the lysosomes, the SN-38 prodrug dissolved from an intact particle (Figure 2) and performed its therapeutic effects on the cancer cells.

Kasai adds that "Our works provides a comprehensive overview of the dynamics of prodrug nanoparticles inside cancer cells, allowing for further progress towards their application as next-generation anticancer drug delivery devices."

Credit: 
Tohoku University

RNA as a future cure for hereditary diseases

Short RNA molecules can be used as medication. Their effectiveness is based on the genetic information they carry: therapeutic RNA can bind to the body's own RNA and thus influence how it functions. However, only a handful of such drugs are available so far.

"That's mainly because it's tricky to get the RNA molecules to precisely the organ in the body where they need to take effect. Currently, that's the biggest hurdle in the development of RNA drugs," says Jonathan Hall, Professor of Pharmaceutical Chemistry at ETH Zurich. Together with Daniel Schümperli, Emeritus Professor from the University of Berne, and colleagues from ETH, University Hospital Zurich and Triemli Hospital Zurich, he has now succeeded in developing an RNA molecule that can compensate for the effect of gene mutations in bone marrow cells.

This therapeutic approach could one day be applied to a rare hereditary disease called erythropoietic protoporphyria (EPP), which affects people whose mother and father both have a genetic predisposition to the disease. Those who suffer from EPP experience a painful sensitivity to sunlight.

Gene mutations cause the body of these patients to produce less of a certain enzyme, ferrochelatase. Ferrochelatase is central to the production of haemoglobin, the protein that transports oxygen in the blood and makes it appear red. This ferrochelatase deficiency causes a metabolic molecule, protoporphyrin, to accumulate in the red blood cells. Protoporphyrin reacts to rays of visible light, forming molecules that attack tissue and can cause painful inflammation when the patient is exposed to sunlight or a strong artificial light.

Fusion molecule shown to be effective

Hall and his colleagues developed several short RNA molecules, which bind to the RNA copy of the ferrochelatase gene in the body's cells. In cell culture experiments, they identified certain molecules that were able to restore a sufficient production of the enzyme and thus compensate for the negative effects of the known EPP gene mutations.

However, developing the RNA molecule was only the first part of the task. "This molecule must also be able to reach the right organ in the body and from there penetrate the interior of the cells," Hall says. In the case of EPP, these are the blood stem cells in the bone marrow. To this end, the researchers fused one of the RNA molecules with various chemically active compounds, which they tested in a mouse model of EPP. They identified one fusion molecule - the RNA molecule fused with cholesterol - that was able to compensate for the gene mutation in this animal model.

Research not yet complete

Hall stresses that it is too early to label the molecule he has identified as an RNA drug. In demonstrating that such molecules can be used to increase the amount of functional ferrochelatase in mice, the researchers are at only an early stage of their work. "This is the first step and it shows that our approach holds promise," Hall says. Next, the researchers need to optimise the fusion molecule or identify other fusion molecules that are even more effective, he explains, adding that they also require additional, more refined mouse models for the EPP disease. Further research is essential to find an optimum drug candidate whose effect can then be investigated in humans.

Credit: 
ETH Zurich

Study debunks robocall myths, lays groundwork for stopping them

New research from North Carolina State University finds that the number of robocalls isn't going up, and that answering a robocall doesn't make you more likely to get additional robocalls. However, stories you've heard about individuals getting hundreds of back-to-back unsolicited calls? Those are true.

"These findings stem from a broader study that is the first step toward a more robust set of tools for reducing robocalls, if not eliminating them," says Brad Reaves, co-author of a paper on the work and an assistant professor of computer science at NC State. "We made some fundamental advances in tracking robocalls back to their source, and upended a lot of the conventional wisdom regarding robocalls."

"The COVID-19 pandemic has really highlighted the importance of this work, because robocalls have made people less likely to answer phone calls from unknown numbers - and that makes it more difficult for contact tracers to do their jobs," says Sathvik Prasad, a Ph.D. student at NC State and first author of the paper.

For this work, the researchers define robocalls as automated or semi-automated calls that play a recorded message. To address questions related to robocalls, the researchers worked with communications company Bandwidth Inc. to set up 66,606 phone lines that would be used exclusively to monitor for robocalls. The ultimate goal was to collect data on how robocalls and robocall campaigns worked. The researchers monitored the lines for 11 months, from early 2019 to early 2020.

To provide some sense of scale, the relevant phone lines received 1,481,201 unsolicited calls over the 11-month study period. The researchers used an automated system to answer more than 146,000 of those calls. The system also recorded the calls and analyzed the audio.

"One of our research questions was whether robocalls were getting worse, or becoming more frequent," Prasad says. "We found that the answer is no - the number of robocalls was virtually identical from month to month."

"We were also curious about whether answering a robocall made it more likely that a phone line would receive additional robocalls," Reaves said. "For years, messaging from government agencies and trusted nonprofit organizations has focused on reducing robocalls by not answering calls from unknown numbers. And while we encourage people to avoid engaging with robocalls, we found that answering a robocall has no effect on the number of robocalls you receive."

The researchers did, however, find that another widespread story about robocalls was true.

"Everyone on the research team had heard stories about a friend of a friend of a friend who had gotten so many unsolicited calls that they couldn't even use their phone for a day or two," Reaves says. "And we found that this is a rare, but real, phenomenon. We dubbed these high call-volume events 'storms,' and found that they happen when a robocaller identifies itself using a fake phone number - and that phone number actually belongs to someone else. If the robocaller makes hundreds of thousands of calls using the fake number, hundreds of people see it on their 'missed calls' list and call it back. The high volume of calls essentially makes it impossible for the person who actually has the relevant phone number to use their phone. However, because robocallers switch numbers fairly often, the inconvenience usually only lasts for a day or two."

But while those findings are interesting, some of the most important findings stem from the researchers' analysis of the robocall's audio recordings.

"First of all, about 62% of the unsolicited calls our numbers received included practically no audio at all - which was surprisingly high," Prasad says. "And only a little more than half of the remaining 38% contained enough audio data to allow for us to conduct a robust assessment."

"But what was exciting was that we were able to identify calls that were identical or nearly identical, allowing us to group calls into clusters that were clearly all affiliated with a single campaign," Reaves says.

"This is a big deal because tracing a call back through communication service providers is a manual process that takes time," Reaves explains. "We started with answering just over 146,000 calls - it would be impossible to trace them all back. But first we eliminated all the silent calls, that narrows it down considerably. Then we were able to cluster calls together into 2,687 specific campaigns. Most of the campaigns only made a few calls, but a handful of those campaigns made thousands of calls. So, effectively you can narrow down a big chunk of robocalls to only a few campaigns. And you can track those down. That's a subject we'll be discussing at greater length in the future."

Credit: 
North Carolina State University

Acidic niche keeps lymphatic system in check during immune response

TAMPA, Fla. -- In the fight against cancer, the immune system is the first line of defense. The lymphatic system specifically is essential to protecting the body against foreign invaders. Activation of immune cells in the lymph nodes leads to the production and release of antibodies, and activation of lymphocytes, including T cells, to battle infection. But little is known about how activation of immune cells in the lymph nodes can occur without enabling effector functions that could also damage the lymphatic system.

In a new article published in Nature Communications, Moffitt Cancer Center researchers describe a novel acidic niche within lymph nodes that plays an integral role in regulating T cell activation.

"Acidosis is a potent inhibitor of effector T cell functions," said Robert Gillies, Ph.D., chair of the Department of Cancer Physiology at Moffitt. "Oxygen levels are reported to be low in lymph nodes and that hypoxic tissue is acidic. We wanted to determine if lymph nodes were also acidic."

For this study, Moffitt researchers used fluorescence and magnetic resonance imaging to identify a naturally occurring acidic niche within lymph nodes. Upon further analysis, they discovered that the T cells were the source of that acidity. They say the results pinpoint localized acidosis as a critical component of the adaptive immune response.

The findings demonstrate the potential role for the lymph node microenvironment in shaping T cell biology. T cells activated by antigen-presenting cells, such as dendritic cells, produce an acidic environment that is balanced by the enhanced capacity to generate lactic acid.

"The low extracellular pH of lymph nodes does not impair the T cell's activation, but it does suppress the cytokine production, which is likely what protects lymph nodes from being attacked by the immune system," said Gillies.

The researchers say this robust physiological mechanism can be exploited by cancers, resulting in evasion of immune surveillance by malignant tissue and tumors. They believe this could be managed by manipulating the acidity in combination with immunotherapies such as T-cell checkpoint blockade therapy. However, more research is needed to confirm.

Credit: 
H. Lee Moffitt Cancer Center & Research Institute

Women less likely to receive pay for college internships

The odds of women receiving pay for a college internship are 34% lower than for men, according to new research from Binghamton University, State University of New York.

A team of researchers led by Binghamton University Assistant Professor of Student Affairs Administration John Zilvinskis sought to find out whether women and other underserved groups were more or less likely to participate in paid or unpaid internships in college compared with their peers. They were prompted to examine this issue given that paid internships often lead to higher paying positions post-graduation and that women continue to earn less than men for the same position despite their level of education.

Using data from a 2018 experimental itemset of the National Survey of Student Engagement, the researchers examined the relationship between student identity and academic major to the outcome of receiving pay for an internship. Of the 2,410 seniors who participated in internships, 58% of men received pay during their internships, whereas only 35% of women received pay. After controlling for background and major, the odds of women receiving pay for their internship were almost 34% lower than for men.

"This finding aligns with general scholarship regarding inequity in compensation, and our findings demonstrate that discrepancies by gender can occur in the college internship process as well," said Zilvinskis.

Also contributing to this research from Binghamton University were Professor of Psychology Jennifer Gillis and Assistant Vice President for Student Success Kelli Smith.

"Although tremendous strides have been made for women in the workplace, we must continue to identify points of inequality," said Gillis.

To move toward equity in pay for college internships for female students, Smith recommends implicit bias training for those within university settings who advise students on career decision making, whether faculty or career advisors; having universities analyze and be transparent in sharing pay data disaggregated by gender; working with employers to ensure awareness; and providing educational sessions for students on internship seeking and salary negotiation.

"Since career advising and support is everyone's business within a university setting -- not just career centers -- it is important that all members directly serving students be informed of such findings to effect change," said Smith. "Career centers can play a leading role with both training for campus staff, faculty and employer partners, and designing relevant student educational content and programming."

Credit: 
Binghamton University

Swans reserve aggression for each other

image: Aggression among mute swans

Image: 
WWT

Swans display more aggression to fellow swans than other birds, new research shows.

The study examined three swan species - mute, whooper and Bewick's - and found all were most frequently aggressive to their own kind.

The findings suggest that similar individuals are the greatest competition for food and other resources such as shelter, which can lead to conflict.

The research, by the Wildfowl and Wetlands Trust (WWT) and the University of Exeter, was undertaken to better understand how swan behaviour affects other waterbirds over winter.

Dr Kevin Wood, Principal Research Officer at WWT, said: "We know that swans have a reputation for aggressiveness but some of us suspected that in reality a lot of the aggression was directed towards other swans rather than smaller birds such as ducks or geese.

"To test that idea, we recruited some great students who used the webcams at Slimbridge and Caerlaverock to collect behavioural data on aggressive interactions between the various waterbirds at those sites over the past two winters.

"Our suspicions were right.

"In fact, almost all of the waterbird species in our study were most aggressive to their own species, which makes ecological sense as the individuals that are most similar to you are your greatest competition for food and other resources.

"It's valuable to finally have the data to show that, and it's another rung on the ladder of better-informed judgement on swans."

The study was carried out by monitoring live-stream webcams on reserves at WWT Slimbridge Wetland Centre in Gloucestershire and WWT Caerlaverock Wetland Centre in Dumfries over the past two years.

It's one of the first studies that has relied completely on remotely collected data - and could be one of the solutions to continuing research with restrictions in place during the Covid-19 pandemic.

Dr Paul Rose, of Exeter's Centre for Research in Animal Behaviour, added: "This is a great example of how undergraduate projects can really help wild conservation action by allowing students to practice key research techniques but at the same time collecting data that is valuable to field scientists.

"We'd been thinking of using the WWT webcams for a while, to learn more about the swans' behaviour without disturbing them, and this project on aggression and species differences seemed to beneficial to the needs of WWT's conservation work and to the students fulfilling the requirements of their degrees."

Across whooper, Bewick's and mute swans, infighting between the same species accounted for up to 80% of negative interactions.

Bewick's swans in particular were more likely to behave aggressively with one another, which could reflect their extreme lifestyles which involve a 7,000km migration across a continent twice a year.

The number of wintering Bewick's swans in the UK declined by more than 50% between 1995 and 2015, with numbers continuing to fall.

Conservationists have theorised that this may be due to competing with mute and whoopers swans at their winter sites in Europe and at summer sites in Arctic Russia.

However, these findings show this is unlikely.

The study has also helped demonstrate how remotely-collected data can inform scientific research, without causing as much disturbance to birds and reducing carbon footprint in terms of travel.

It is likely to become an increasingly useful tool as conservationists try to carry out research while potential for field-work is limited.

The next step is to study other waterbirds to see how their behaviour alters depending on the presence and number of swans.

Credit: 
University of Exeter

Blocking copper uptake in tumor cells may be clue to boosting immune system

Australian researchers have discovered that removing copper from the blood can destroy some of the deadliest cancers that are resistant to immunotherapy using models of the disease.

While immunotherapy, a treatment that works through a patient's immune system to kill the cancers, has proven to be a breakthrough for many cancer patients, offering real hope and for some even a cure - some cancers camouflage themselves from current immunotherapies by expressing the aptly titled Programmed Death Ligand or PD-L1.

Dr Orazio Vittorio and his team from Children's Cancer Institute in Sydney and UNSW Sydney published the findings today in the prestigious Cancer Research, a journal of the American Association for Cancer Research.

It is known that cancer cells such as brain cancer "feed" on copper, often having up to six times the normal levels of the metal inside the tumour cells. Dr Vittorio and colleagues, including Professor Maria Kavallaris AM, studied tumour samples from more than 90 patients with neuroblastoma and 90 patients with gliomas. Both these cancers have high mortality rates and to date have not responded well to cancer immunotherapy. Neuroblastoma accounts for 15% of total childhood cancer deaths and only 50% of patients with high-risk neuroblastoma patient survive their disease. Glioblastoma has the worst survival rate of all cancers, with only 5% of patients surviving 5 years past their diagnosis.

According to Dr Vittorio, these two cancers express PD-L1 as a way to hide from the immune system, explaining why these two cancers are so deadly.

By looking at the human biopsies the researchers found a correlation between high levels of copper and increased expression of PD-L1. The researchers then showed for the first time that copper levels could control the expression of PD-L1 in cancer cells.

The researchers went on to use an analogue of a drug, called TETA, that is currently used in the treatment of Wilson's Disease, which is a rare genetic disorder characterized by excess copper stored in various body tissues. They used this drug in animal models of neuroblastoma and glioblastoma to reduce the amount to copper in the tumour cells, leading to a reduction in the expression of PD-L1.

"When these mice were given immunotherapy there was a significant reduction in the size of their tumours," Dr Vittorio said.

"Given that TETA is already in use in a number of clinical conditions and it is inexpensive and easy to manufacture, this may offer a viable treatment alternative for those cancers that are resistant to current immunotherapies."

Neuroblastoma claims more lives of children younger than five than any other cancer. Children like Luciano who was diagnosed at 14 months, endured three operations and eight rounds of chemotherapy. ''We are lucky because he responded well to treatment, but there were so many kids who have been lost. This research will help give hope to more families and children in the future'' his mother Maria said.

Credit: 
Children's Cancer Institute Australia

Biomedical scientists piece together how medication paralyzes parasitic worms

image: Researchers used video tracking to monitor parasitic worms exposed to diethylcarbamazine in a laboratory setting.

Image: 
Richard Martin

AMES, Iowa - For years, many scientists and medical professionals likely misunderstood how a commonly prescribed medication for elephantiasis battled the disease, but a new study sets the record straight.

The study, published in the peer-reviewed scientific journal Communications Biology, shows how the medication, diethylcarbamazine, paralyzes the parasites that cause lymphatic filariasis, also known as elephantiasis, upending the widely held belief the medication bolsters a patient's immune system but doesn't target the parasites directly. Richard Martin, a Distinguished Professor of biomedical sciences at Iowa State University's College of Veterinary Medicine and senior author of the study, said the findings could pave the way to better predict how resistance to the medication may develop in the parasites and allow medical professionals to understand how the medication may interact with other therapies.

Lymphatic filariasis causes the swelling and thickening of skin in the extremities. The disease is caused by parasitic worms transmitted into humans through the bite of insects such as mosquitoes. When the parasites reach their adult stage, they collect in the human lymphatic system. Lymphatic filariasis is most common in tropical regions of western Africa and South America, though similar disease arises in animals in other regions of the world, Martin said. The disease is a leading cause of permanent disability worldwide, according to the Centers for Disease Control and Prevention.

Diethylcarbamazine was discovered in 1947 and is used to treat a range of diseases caused by parasitic roundworms. Martin said the scientific consensus for most of the medication's existence suggested the therapy provoked a response in the host's immune system to which the parasites are susceptible. But Martin and his colleagues wanted to find out if there might be other factors influencing the efficacy of the medication.

"It's a drug that's not been extensively worked on for quite a number of years," Martin said. "People have just left it alone and assume that's how it works."

The new study indicates diethylcarbamazine directly targets the parasites with a temporary paralysis. The paralysis results when the medication causes pores, called transient receptor potential ion-channels, in the parasites' cellular membranes to open, allowing calcium to enter. The calcium triggers a retraction in the parasites' muscle cells, leading to paralysis. This paralysis allows the host's body to flush the parasites out of the lymphatic system.

"The parasites get displaced out of their local environment and end up getting stuck in liver cells and then they get gobbled up by the immune system," Martin said. "So the medication means the parasites are not able to stay in the place they want to."

Martin said previous studies may have missed this paralysis effect because it lasts for only a few hours, maybe four or five, before it wears off and the parasites resume their normal level of activity. The research team used computer-aided video tracking to monitor parasites exposed to diethylcarbamazine. They also measured electrical currents passing through muscle cells and used gene knock-down technology to analyze how the medication affects parasitic activity, he said.

A better understanding of how diethylcarbamazine works will allow doctors to anticipate how parasites might develop resistance to the therapy, Martin said. In addition, the new data could allow doctors to use diethylcarbamazine in concert with other therapies to lead to better outcomes for patients.

"If you know how this therapy works, you can start to select and develop better drugs that are maybe even more potent," Martin said.

Credit: 
Iowa State University

Species competition and cooperation influence vulnerability to climate change

image: Burying beetles, Nicrophorus Nepalensis, in motion.

Image: 
Shipher Wu (CC BY 4.0)

Organisms need to work together to adapt to climate change, especially in the presence of competitors, suggests a new study published today in eLife.

The findings show that some species can maximise their fitness in suboptimal environments by working together, highlighting how the pressing issue of habitat destruction affects the vulnerability of social organisms to climate change.

Organisms have a 'fundamental niche' - the ideal physical conditions they need to feed and reproduce (such as temperature and rainfall) - and a 'realised niche' - the actual conditions they live in, which includes biological influences such as competitor species and predators. Moreover, every species has a 'thermal performance curve' (TPC) which shows how temperature affects their physiological function and behaviours, such as breeding and movement. By combining these concepts for the first time, this study demonstrates how gaining a mechanistic understanding of within- and between-species social interactions can provide critical insights into how organisms might respond to global change.

"To the best of our knowledge, no study has ever distinguished between the fundamental and realised thermal performance curves of an organism, or quantified how this changes in the presence of competitor species," explains lead author Hsiang-Yu Tsai, Research Assistant at the Institute of Ecology and Evolutionary Biology, Taiwan University, and the Biodiversity Research Center, Academia Sinica, Taiwan. "Some studies have shown that cooperation within a species can help social organisms expand the environmental conditions they can thrive in, but little is known about how this is actually achieved."

The researchers sought to address this question in two ways: they first developed a theoretical model that predicts the width of thermal performance curves and how these change in response to competition with other species for resources. They then conducted a series of experiments to test the prediction of their model, using a species of Asian burying beetle - a social organism that relies on animal carcasses to reproduce but has to compete for them with the more temperature-resistant blowfly.

The model predicts that when a low temperature-loving species such as the burying beetle is in an environment where it has to compete with a high temperature-loving, more flexible species such as the blowfly, the beetle's actual optimal temperature for activities such as breeding and moving falls below what would be predicted in a lab, in the absence of competitors. Similarly, if a species that thrives at high temperatures has to compete with one that thrives at low temperatures, the opposite is true: the best temperature for breeding and movement becomes higher than the one that seems optimal in a controlled lab experiment.

To test this in practice, the team studied the breeding and movement of burying beetles in a controlled lab experiment. They found that breeding was optimal at 15.6C and beetles needed less energy to start flying at 16C than at other temperatures. However, when blowflies were introduced to the experiment, the beetles' optimal breeding temperature dropped to 13.1C, meaning they adjusted their optimal temperature for breeding in order to outcompete the blowflies. Indeed, once the blowflies were removed, the beetles shifted their optimal temperature for breeding closer to the temperature observed in the lab experiment.

Since previous work by the team suggests that beetles will cooperate to bury carcasses in the presence of blowflies, they predicted that a group of beetles in a warm environment would have a better chance of adapting to higher temperatures than solitary pairs of breeding beetles. As predicted, they found that the beetles that could form cooperative groups had an optimal breeding temperature that was identical to the one under lab conditions (their fundamental TPC). By contrast, the optimal breeding temperature of the solitary pairs was lower at 14.1C, similar to that achieved in the presence of the blowflies.

"In other words, cooperation enables beetles to better match their predicted and actual thermal performance curves, ultimately leading to higher fitness in the face of competition with other species," says co-author Dustin Rubenstein, Associate Professor of Ecology, Evolution and Environmental Biology at Columbia University in the City of New York, US.

"We have demonstrated that a species' actual temperature-dependent fitness is likely to change in response to factors such as competition," concludes senior author Sheng-Feng Shen, Associate Research Fellow at the Institute of Ecology and Evolutionary Biology, Taiwan University, and the Biodiversity Research Center, Academia Sinica, Taiwan. "Our study suggests that a more mechanistic understanding of how both competition and cooperation affect the optimal temperature performance of a species will be critical for understanding how climate change and habitat destruction affects its vulnerability."

Credit: 
eLife

Species competition and cooperation influence vulnerability to climate change

Organisms need to work together to adapt to climate change, especially in the presence of competitors, suggests a new study published today in eLife.

The findings show that some species can maximise their fitness in suboptimal environments by working together, highlighting how the pressing issue of habitat destruction affects the vulnerability of social organisms to climate change.

Organisms have a 'fundamental niche' - the ideal physical conditions they need to feed and reproduce (such as temperature and rainfall) - and a 'realised niche' - the actual conditions they live in, which includes biological influences such as competitor species and predators. Moreover, every species has a 'thermal performance curve' (TPC) which shows how temperature affects their physiological function and behaviours, such as breeding and movement. By combining these concepts for the first time, this study demonstrates how gaining a mechanistic understanding of within- and between-species social interactions can provide critical insights into how organisms might respond to global change.

"To the best of our knowledge, no study has ever distinguished between the fundamental and realised thermal performance curves of an organism, or quantified how this changes in the presence of competitor species," explains lead author Hsiang-Yu Tsai, Research Assistant at the Institute of Ecology and Evolutionary Biology, Taiwan University, and the Biodiversity Research Center, Academia Sinica, Taiwan. "Some studies have shown that cooperation within a species can help social organisms expand the environmental conditions they can thrive in, but little is known about how this is actually achieved."

The researchers sought to address this question in two ways: they first developed a theoretical model that predicts the width of thermal performance curves and how these change in response to competition with other species for resources. They then conducted a series of experiments to test the prediction of their model, using a species of Asian burying beetle - a social organism that relies on animal carcasses to reproduce but has to compete for them with the more temperature-resistant blowfly.

The model predicts that when a low temperature-loving species such as the burying beetle is in an environment where it has to compete with a high temperature-loving, more flexible species such as the blowfly, the beetle's actual optimal temperature for activities such as breeding and moving falls below what would be predicted in a lab, in the absence of competitors. Similarly, if a species that thrives at high temperatures has to compete with one that thrives at low temperatures, the opposite is true: the best temperature for breeding and movement becomes higher than the one that seems optimal in a controlled lab experiment.

To test this in practice, the team studied the breeding and movement of burying beetles in a controlled lab experiment. They found that breeding was optimal at 15.6C and beetles needed less energy to start flying at 16C than at other temperatures. However, when blowflies were introduced to the experiment, the beetles' optimal breeding temperature dropped to 13.1C, meaning they adjusted their optimal temperature for breeding in order to outcompete the blowflies. Indeed, once the blowflies were removed, the beetles shifted their optimal temperature for breeding closer to the temperature observed in the lab experiment.

Since previous work by the team suggests that beetles will cooperate to bury carcasses in the presence of blowflies, they predicted that a group of beetles in a warm environment would have a better chance of adapting to higher temperatures than solitary pairs of breeding beetles. As predicted, they found that the beetles that could form cooperative groups had an optimal breeding temperature that was identical to the one under lab conditions (their fundamental TPC). By contrast, the optimal breeding temperature of the solitary pairs was lower at 14.1C, similar to that achieved in the presence of the blowflies.

"In other words, cooperation enables beetles to better match their predicted and actual thermal performance curves, ultimately leading to higher fitness in the face of competition with other species," says co-author Dustin Rubenstein, Associate Professor of Ecology, Evolution and Environmental Biology at Columbia University in the City of New York, US.

"We have demonstrated that a species' actual temperature-dependent fitness is likely to change in response to factors such as competition," concludes senior author Sheng-Feng Shen, Associate Research Fellow at the Institute of Ecology and Evolutionary Biology, Taiwan University, and the Biodiversity Research Center, Academia Sinica, Taiwan. "Our study suggests that a more mechanistic understanding of how both competition and cooperation affect the optimal temperature performance of a species will be critical for understanding how climate change and habitat destruction affects its vulnerability."

Credit: 
eLife

Persistence of ADHD into adulthood is an important predictor of car crash risk

Washington, DC, August 18, 2020 - A new study reports that the risk of being involved in car crashes increases for those diagnosed with attention-deficit/hyperactivity disorder (ADHD). The study in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), published by Elsevier, looked specifically at the rate of car crashes by adulthood, which was 1.45 times higher in those with a childhood history of ADHD compared to adults with no ADHD.

The authors also found that children whose ADHD symptoms have decreased by adulthood have no increased risk for car crashes.

Lead author Arunima Roy, MBBS, PhD, and research fellow at the Royal's Institute of Mental Health Research, University of Ottawa said: "ADHD is a common neurodevelopmental disorder. Between 5 percent and 75 percent of children with ADHD can continue to have the disorder into adulthood. Extant research shows that ADHD is associated with more traffic violations, speeding violations, license suspensions, and risky driving behaviors.

"The likelihood of risky driving behavior increases with persistence of childhood ADHD symptoms into adulthood. Prior research from our group as well as by others also shows that, aside from driving behaviors, a persistence of ADHD into adulthood can impair functioning in other domains. These domains can include occupational performance, educational attainment, emotional functioning, substance use, and justice involvement."

The findings, based on the Multimodal Treatment Study of ADHD, a multisite study with six centers in the United States and one in Canada. The MTA is one of the largest studies on treatment strategies for ADHD and include a follow-up arm spanning 16 years.

A cohort of 441 children with ADHD and 231 age- and sex-matched comparison children without ADHD from the same classrooms were studied between the ages of 7 and 25 years.

The researchers tracked data on ADHD symptoms, driving outcomes as well as a number of comorbid conditions, such as oppositional defiant disorder, conduct disorder, antisocial personality disorder, and substance use during childhood and into adulthood.

The researchers found that rates of licensure and ages at licensure were comparable between adults with and without a history of ADHD. However, the two groups differed in rates of car crash involvement by adulthood. Importantly, adults with continuing ADHD symptoms had the highest rate of car crash involvement compared to adults with no history of ADHD (1.81 times higher). Finally, rates of car crashes did not differ between adults whose ADHD symptoms remitted and adults who never had any ADHD.

"Clinicians must keep in mind the long-term effects of childhood ADHD on quality of life while attending to patients and take a holistic approach to treatment and management," Dr. Roy concluded.

Credit: 
Elsevier

Horse skeletons provide clues to preventing racehorse injuries

image: Johns Hopkins Medicine researchers recently compared the third metacarpal, or cannon bone, from three different breeds of horses (Thoroughbred, American Quarter Horse and feral Assateague Island ponies) to better understand how it responds to mechanical stresses, like those experienced during racing.

Image: 
Graphic by M.E. Newman, Johns Hopkins Medicine, using public domain images for the horse leg and bone, and a racehorse photo courtesy of M.J. Boswell

In an anatomical comparison of the third metacarpal, or cannon bone, among Thoroughbred racehorses, American Quarter Horses and feral Assateague Island ponies, Johns Hopkins Medicine researchers have found that fostering adaptations in these bones through training might help horses better endure the extreme conditions of racing and prevent serious, often life-ending injuries on the track.

Racehorses operate at a biomechanical extreme. The 1,000-pound or so animals can move up to 40 miles per hour on long, thin limbs genetically evolved to move them across long distances.

When pushed to race at high speeds, a horse's legs can fracture beneath them in an event called a breakdown. Seventy percent of these injuries occur in the third metacarpal bone between the horse's knee and pastern (the area just above the top of the hoof). Because of the fragile nature of their limbs, breaks such as these can cause irreparable tissue damage, resulting most often in the animal having to be euthanized.

"With so many Thoroughbreds breaking their legs this way, we thought there must be a way to predict and prevent it," says Deanna Goldstein, a doctoral candidate in the Center for Functional Anatomy and Evolution at the Johns Hopkins University School of Medicine and lead author on the paper, posted online August 17, 2020, in the journal The Anatomical Record.

To understand why racehorses break down, Goldstein compared the sizes, densities and abilities to bend without breaking of the three types of canon bones studied to examine the effect on them from each breed's lifestyle and training.

Thoroughbreds, for example, are trained to run long distances around turns for races like the Kentucky Derby. American Quarter Horses are trained to sprint short distances in mostly straight lines, and are named for their superior ability to run a quarter mile faster than any other breed. Assateague Island ponies are shorter, stockier animals that live wild, and therefore, offered an untrained population against which to compare Quarter Horses and Thoroughbreds.

"Comparisons between these breeds present an interesting opportunity to look at the relationship between the mechanical stresses on the bone and the bone's structural response in an animal that is pushed to its physiological limits," says Goldstein.

In the study, bones were collected only from horses who died or were euthanized for reasons unrelated to a broken or injured third metacarpal bone.

Although the size of the third metacarpal bone varied among the three horse breeds, Goldstein was surprised to find that the bone's strength and structure relative to body size were remarkably similar across the three types of horses.

"If Thoroughbreds are racing and training around turns, you would expect certain areas of their bones to be a lot stronger to reflect that," says Goldstein. "However, since the Thoroughbred third metacarpals are not more dense or stronger than the other two breeds, it indicates that the Thoroughbreds' bones are just not prepared for those forces."

What should be seen, says Goldstein, is evidence of bone remodeling -- the process by which new bone growth helps the skeleton respond to mechanical stress. Similar to how weightlifting strengthens human bones, exposure to the stresses of racing around turns should create anatomical differences between Thoroughbred horses and other breeds. These adaptations would prepare their bones to resist fracturing.

Goldstein suggests that adding training around tighter turns at higher speeds could give Thoroughbred horses' bones time to adapt to the extreme forces and be more resistant to breaks on the track.

Thoroughbred horseracing has been mired in controversy as numerous accounts, such as one in a June 22, 2019, article in the New York Times, reveal a growing number of fatalities in the sport, with many attributable to leg fractures. While some of these cases have been linked to animals being given performance-enhancing drugs, Goldstein and her colleagues believe that scientifically backed interventions in how racehorses are managed and trained could better protect them from stress-related breakdowns on the track.

Credit: 
Johns Hopkins Medicine

This 'Cold Tube' can beat the summer heat without relying on air conditioning

image: Exterior of Cold Tube demonstration pavilion.

Image: 
Lea Ruefenacht

Many people beat the summer heat by cranking the air conditioning. However, air conditioners guzzle power and spew out millions of tons of carbon dioxide daily. They're also not always good for your health--constant exposure to central A/C can increase risks of recirculating germs and causing breathing problems.

There's a better alternative, say a team of researchers from the University of British Columbia, Princeton University, the University of California, Berkeley and the Singapore-ETH Centre.

They call it the Cold Tube, and they have shown it works.

"Air conditioners work by cooling down and dehumidifying the air around us--an expensive and not particularly environmentally friendly proposition," explains project co-lead Adam Rysanek, assistant professor of environmental systems at UBC's school of architecture and landscape architecture, whose work focuses on future energy systems and green buildings. "The Cold Tube works by absorbing the heat directly emitted by radiation from a person without having to cool the air passing over their skin. This achieves a significant amount of energy savings."

The Cold Tube is a system of rectangular wall or ceiling panels that are kept cold by chilled water circulating within them. Since heat naturally moves by radiation from a hotter surface to a colder surface, when a person stands beside or under the panel, their body heat radiates towards the colder panel. This creates a sensation of cooling like cold air flowing over the body even if the air temperature is quite high.

Although these types of cooling panels have been used in the building industry for several decades, what makes the Cold Tube unique is that it does not need to be combined with a dehumidification system. Just as a cold glass of lemonade would condense water on a hot summer day, cooling down walls and ceilings in buildings would also condense water without first drying out the air around the panels. The researchers behind the Cold Tube conceived of an airtight, humidity-repelling membrane to encase the chilled panels to prevent condensation from forming while still allowing radiation to travel through.

Cooling down the outdoors

The team built an outdoor demonstration unit last year in Singapore, inviting 55 members of the public to visit and provide feedback. When the system was running, most participants reported feeling "cool" or "comfortable," despite an average air temperature of 30 degrees Celsius (86 degrees Fahrenheit). The panels also stayed dry, thanks to the special membrane.

"Because the Cold Tube can make people feel cool without dehumidifying the air around them, we can look towards shaving off up to 50 per cent of typical air conditioning energy consumption in applicable spaces," said Eric Teitelbaum, a senior engineer at AIL Research who oversaw the demonstration project while working at the Singapore-ETH Centre.

"This design is ready. It can obviously be used in many outdoor spaces--think open-air summer fairs, concerts, bus stops and public markets. But the mission is to adapt the design for indoor spaces that would typically use central air conditioning," he added.

Beyond the energy savings, technologies like the Cold Tube have a great future, says project co-lead Forrest Meggers, an assistant professor at Princeton's school of architecture and the Andlinger Center for Energy and the Environment.

"Because the Cold Tube works independently of indoor air temperature and humidity, keeping windows open in our increasingly hot summers while still feeling comfortable becomes possible," said Meggers. "The Cold Tube can offer relief in different regions, from North American homes and offices that currently rely on standard HVAC systems to developing economies that foresee significant need for cooling in the coming half-century."

Keeping indoor air healthy during the pandemic

There's another aspect of the Cold Tube that is particularly relevant in 2020, says Adam Rysanek.

"The COVID-19 pandemic has brought to the public's awareness how sensitive our health is to the quality of the air we breathe indoors. Specifically, we know that some of the safest spaces in this 'new normal' are outdoor spaces," said Rysanek. "As the climate changes and air conditioning becomes more of a global necessity than a luxury, we need to be prepared with alternatives that are not only better for the environment, but also our health. The idea of staying cool with the windows open feels a lot more valuable today than it did six months ago."

The team is currently using the data collected in Singapore to update their projections of the Cold Tube's effectiveness in indoor spaces globally. They plan to demonstrate a commercially viable version of the technology by 2022.

Credit: 
University of British Columbia