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It has previously been reported that human visual system has a temporal limitation in processing visual information when perceiving things that occur less than half a second apart. This temporal deficit is known as "attentional blink" and has been demonstrated in a large number of studies. These studies reported that adults could recognize two things when these two were temporally separated over 500 ms, but adults overlooked the second thing when the temporal interval was less than 500 ms. Recently, this attentional blink phenomenon has been observed in even preverbal infants less than one-year old.

In the study from Chuo University, Japan Women's University, and Hokkaido University, infants aged 7 and 8 months were required to identify two female faces among images of sceneries which were presented successively at a rate of 100 ms per image. In one set of images, the faces were placed 200 ms apart; in the other, they were placed 800 ms apart. Researchers found that infants could identify two faces when the temporal interval between these two faces was 800 ms. Furthermore, infants overlooked the second face when the separation was 200 ms, suggesting that they exhibited the attentional blink phenomenon. These results suggest that infants take less than a second to completely process visual information and have the same temporal limitation in processing visual information as seen in adults.

"This is the first study revealing the attentional blink in preverbal infants and provides opportunities to further investigate the visual awareness in infants focusing on the attentional blink phenomenon. This phenomenon is of especial interest as, it has recently been used as a consciousness marker," said Shuma Tsurumi from Chuo University.

Jun-ichiro Kawahara, a professor at Hokkaido University said, "Our study demonstrated what is happening at the first half-second when infants see multiple visual objects. This contrasts sharply against previous studies that mainly focused on visual learning at much longer periods, such as an order of 5 seconds." He continued, "Moreover, our study could provide a new way to test whether existing theories of the attentional blink phenomenon can hold for underdeveloped infants."

The work, carried out by Pilar Madrigal and Sandra Jurado, from the UMH-CSIC Neurosciences Institute in Alicante, a joint center of the Spanish National Research Council and Miguel Hernández University, has been published in Communications Biology, a Nature group´s journal.

"Our in-depth analysis of the oxytocin-vasopressin circuit in the mouse brain has revealed that these two molecules have distinct dynamics throughout embryonic development. It is likely that these adaptations modulate the functional properties of different brain regions according to their developmental stage, contributing to the refinement of the neural circuits that are at the basis of social behaviors," explains Dr. Sandra Jurado, director of the Synaptic Neuromodulation Laboratory and the Cell and Systems Neurobiology Unit of the Institute of Neurosciences.

Very similar in structure, oxytocin and vasopressin are two neuropeptides that are evolutionary conserved and are involved in the regulation of complex social behaviors such as maternal care and pair bonding.

Although it is not known how oxytocin and vasopressin modulate brain function, numerous studies in animals and humans suggest that alterations in these circuits may underlie mental disorders characterized by deficits in social interaction, such as autism, anxiety and social aggression or schizophrenia. "For us, it has been very important to identify how these circuits are formed during brain development, in order to detect potential alterations that could be related to social disorders," says Dr. Jurado, who has led the research.

To date, most of the studies to characterize the expression of oxytocin and vasopressin projections have used histological methods and in situ hybridization in brain sections that provide relevant information, but which are difficult to extrapolate to the formation of three-dimensional circuits in the brain.

In addition, most previous work has focused on the rat brain, although an increasing number of studies employ the mouse as an experimental model, highlighting the need for more accurate connectivity maps for this commonly-used species in the laboratory.

MODULATION OF SOCIAL BEHAVIOR

Produced in the hypothalamus, the brain region responsible for controlling essential behaviors for survival, oxytocin acts both as a hormone and as a neurotransmitter. This small, primitive molecule plays an important role in both basic functions such as osmotic balance in invertebrate species and complex behaviors like reproduction and maternal behaviors in humans.

Although oxytocin is best known for increasing muscle contraction during childbirth, it also plays an important role in reproductive and social behaviors. Thanks to this hormone, our brain is able to maintain affective relationships with our peers. And one of the most primitive and strongest in mammals is precisely the close relationship between a mother and her children. Oxytocin is popularly known as the "love hormone", as it promotes social contact, partner preferences and subsequent attachment. It also produces a sense of security and well-being and reduces stress.

Similarly, vasopressin promotes social contact, mate preference and attachment, modulates territorial behaviors towards potential same-sex rivals, increases attraction, as well as sexual and reproductive behaviors.

THE TRANSPARENT BRAIN

In this study, Madrigal and Jurado have implemented the iDISCO+ clarification technique, which allows the removal of a large part of the lipid (fat) content of the brain without damaging its structure, to make it transparent. This method, in combination with light sheet fluorescence microscopy, has allowed the researchers to generate 3D reconstructions with high cellular resolution of the oxytocinergic and vasopressinergic systems of the entire mouse brain, from early development to adulthood.

Thanks to this methodology they have been able to make a precise classification of the cells that synthesize oxytocin and vasopressin in deep brain nuclei, such as the hypothalamus. Interestingly, the Spanish researchers have observed that the various hypothalamic nuclei show marked differences in the expression of oxytocin and vasopressin during embryonic development.

In addition, they have seen a high presence of mixed (oxytocin and vasopressin) cells during early developmental stages, which declines in most hypothalamic nuclei as growth progresses. "It is likely that these dynamic adaptations allow modulation of oxytocin and vasopressin levels in different brain regions according to developmental stage. This change would make possible the refinement of neural circuits that underlie social behaviors," the researchers said.

These adaptations show differences between the mouse and rat brain, making this study a new benchmark for researchers studying social behavior based on murine models, whose neurodevelopment shares many characteristics with the human brain.

In spite of decades of research, cancer remains an enigma. Conventional wisdom holds that cancer is driven by random mutations that create aberrant cells that run amok in the body.

In a new paper published this week in the journal BioEssays, Arizona and Australian researchers challenge this model by proposing that cancer is a type of genetic throwback, that progresses via a series of reversions to ancestral forms of life. In contrast with the conventional model, the distinctive capabilities of cancer cells are not primarily generated by mutations, the researchers claim, but are pre-existent and latent in normal cells.

Regents' Professor Paul Davies, director of Arizona State University's Beyond Center for Fundamental Concepts in Science and Kimberly Bussey, cancer geneticist and bioinformatician from the Precision Medicine Program at Midwestern University, Glendale, Ariz., teamed up with Charles Lineweaver and Anneke Blackburn at the Australian National University (ANU) in Canberra to refine what they call the Serial Atavism Model (SAM) of cancer. This model suggests that cancer occurs through multiple steps that resurrect ancient cellular functions.

Such functions are retained by evolution for specific purposes such as embryo development and wound healing, and are usually turned off in the adult form of complex organisms. But they can be turned back on if something compromises the organism's regulatory controls. It is the resulting resurrection steps, or atavistic reversions, that are mostly responsible for the ability of cancer cells to survive, proliferate, resist therapy and metastasize, the researchers said.

Davies and Bussey are also members of ASU's Arizona Cancer Evolution Center (ACE) which seeks to understand cancer, not just in humans, but across all complex species, in the light of evolutionary processes.

"Cancer research has been transformed in recent years by comparing genetic sequences across thousands of species to determine gene ages," Davies said. Just as geologists can date rock strata, so geneticists can date genes, a technique known as phylostratigraphy.

"The atavistic model predicts that the genes needed for cancer's abilities are mostly ancient - in some cases little changed over billions of years," Davies added.

Lineweaver explained, "In biology, nothing makes sense except in the light of evolution, and in the case of cancer nothing makes sense except in the light of the deep evolutionary changes that occurred as we became multicellular organisms."

"The atavistic model of cancer has gained increasing traction around the world," added Bussey. "In part, this is because it makes many predictions that can be tested by phylostratigraphy, unlike the conventional somatic mutation theory."

Blackburn, a cancer biologist in ANU's John Curtin School of Medical Research, agreed.

"Appreciation of the importance of gene ages is growing among oncologists and cancer biologists," she said. "Now we need to use this insight to develop novel therapeutic strategies. A better understanding of cancer can lead to better therapeutic outcomes."

E-scooters as a new micro-mobility service: SMART researchers explore the potential of e-scooter sharing as a replacement for short-distance transit in Singapore

SMART researchers found that e-scooters are not only a last-mile solution to complement transit services, but also provide a mobility service for short-distance transit trips

- Through a stated preference survey and mixed logit models, SMART researchers found that fare, transit transfer, and transit walking distance are significant factors driving the use of e-scooters as an alternative means of transit. The uncertainty is higher in predicting e-scooter usage preferences of male, young and high-income groups.

- In analyzing the travel demands under different levels of transit inconvenience, researchers discovered that a higher level of transit indirectness, more transfers, and longer access-egress walking result in a higher average probability of using e-scooters.

- The study revealed several implications for more effective harnessing and regulation of e-scooters as a mode of transit, including where to deploy e-scooters to satisfy demand unmet by other modes of transit, and how best to strike a balance between private operators and public welfare.

Singapore, 20 May 2021 - A new study by scientists from Future Urban Mobility (FM), an Interdisciplinary Research Group (IRG) at the Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore, has found that e-scooters, while considered by some to be a hazard to pedestrians and others, provide an important alternative mode of transit, particularly in urban areas. This study sheds important light on the growing utility of e-scooters as a micro-mobility service in Singapore, and will also inform operators, planners, and policymakers on how best to harness and regulate this growing mode of mobility.

This new study is described in a paper titled, "E-scooter sharing to serve short-distance transit trips: A Singapore case", published recently in Transportation Research Part A: Policy and Practice. The paper was led by Zhejing Cao, PhD researcher at Tsinghua University when she was a visiting SMART FM student, and co-authored by SMART FM Lead Principal Investigator and Associate Professor at MIT Department of Urban Studies and Planning, Jinhua Zhao, and Xiaohu Zhang, an assistant professor at The University of Hong Kong, as well as Kelman Chua and Honghai Yu from Neuron, a Singapore e-scooter sharing operator.

Having first been introduced in Singapore around 2013, the e-scooter, also known in Singapore as a type of Personal Mobility Device (PMD), grew swiftly in popularity as an affordable and convenient mobility alternative to driving on Singapore's often congested roads during peak hours. The number of e-scooter users grew rapidly, swelling to around 100,000 registered e-scooters in Singapore by November 2019. Their popularity, however, came at a cost, with a number of fatal and non-fatal incidents involving e-scooters and their riders colliding with pedestrians, and ultimately led to a government-mandated ban on their use on footpaths across Singapore in November 2019.

Nonetheless, e-scooters are currently a legal mode of mobility on some 440km of cycling paths islandwide and remain in widespread use in Singapore today. An industry providing e-scooter sharing services has also become a new micro-mobility service in many cities worldwide, including Singapore, with the emergence of companies such as Telepod and Neuron. E-scooter sharing services provide a convenient micro-mobility service to the public, with rental locations situated across the island and with e-scooters that can be unlocked and paid for via a smartphone app. In addition, e-scooters are an environmentally-friendly alternative to other transportation options via reduced carbon emissions, engender improved life quality and health, and offer mobility aid to the elderly and the disabled.

In the Singapore Central Area (SCA), despite the high accessibility of the Mass Rapid Transit (MRT) system islandwide, the level of MRT indirectness (ratio of MRT network distance to the shortest street path) can be up to 4.112 - much higher than the global average. Furthermore, 20.98% of MRT trips in SCA have at least one transfer, higher than the average transfer level in Singapore, and passengers may have to walk an average of nearly one kilometre to enter and exit MRT stations. As a result, even if the origin and destination of a trip are in close geographical proximity, the overall travelling journey may be suboptimal and could be made more efficient.

Hence, while public transit serves efficiently for most trips in high-density urban environments such as the SCA, it can be inconvenient to take certain short-distance transit trips due to excessive indirectness, transfer, and walking distance. E-scooters can provide a valuable alternative in this segment. As such, it is valuable to explore and investigate the practicality and potential of using e-scooter sharing to replace certain short-distance transit trips where alternative transit methods may not be convenient.

In this study, the researchers collaborated with Neuron to explore the potential of using e-scooter sharing to replace short-distance transit trips in the SCA. The researchers conducted a stated preference survey of e-scooter users in the SCA and estimated mixed logit models to examine factors influencing a user's choice of e-scooter and transit. Based on this, the number of transit trips that can be replaced by e-scooters was calculated, and the researchers then analysed decisions made by e-scooter companies in terms of the trade-offs between serving more e-scooter trips and generating more revenue under varying fares.

The researchers found that fare, transit transfer, and transit walking distance have significant negative impacts on mode utilisation, with seemingly random choices among respondents. The uncertainty is higher in predicting e-scooter usage preferences of male, young and high-income groups. In analyzing the travel demands under different levels of transit inconvenience, the researchers discovered that a higher level of transit indirectness, more transfers, and longer access-egress walking result in a higher average probability of using e-scooters as a mode of transit.

Through analysing the decision of e-scooter companies in terms of the trade-offs between serving more e-scooter trips and making more revenue under varying fares, the researchers also found that the revenue losses borne by e-scooter companies can be significant if e-scooter mode share is maximised with no regard for other considerations, and vice versa.

In order to achieve a better balance between these two competing goals, the researchers found the optimal trade-off places in between two maximisation extremes, thus finding the sweet spot where a small sacrifice in maximizing one goal can prevent great loss in the other.

Zhejing Cao, lead author of the study, said, "E-scooter sharing services have shown enormous potential to become an important component of transit systems in urban environments in Singapore and other cities worldwide. Our study has highlighted the shortcomings of public transport in serving short-distance journeys in the SCA. E-scooter sharing services are able to bridge this gap and provide a convenient micromobility service to the public."

Xiaohu Zhang, co-author of the study, said, "E-scooter sharing as a new form of micro-mobility will improve the overall efficiency of urban transportation systems through enhancing last-mile connectivity as well as serving short-distance travels. It also has huge potential in the future if powered by autonomous driving technology."

The findings of the SMART study can be used to inform operators, planners, and policy-makers on how to harness and regulate this new mobility service, as well as provide suggestions on deploying shared e-scooters to satisfy demand unmet by transit, especially where transit travel involves greater indirectness, transfer, and access-egress walking distance. E-scooter supply strategies at different locations can be varied according to various socio-demographic factors which influence e-scooter preference and mode choices.

When public authorities and private operators take conflicting positions on whether to serve more individual trips or generate greater revenue, the trade-off can be gauged to achieve balance. Such possible means of mitigating disparity between the two goals and achieving balance include administrative regulations (e.g. requiring operators to serve inconvenient short transit trips at certain designated locations) or economic interventions (e.g. subsidies to operators provided by public authorities).

SMART FM Lead Principal Investigator and Associate Professor at MIT Department of Urban Studies and Planning, Jinhua Zhao, added, "Evidently, e-scooters present unique advantages and challenges for regulators and policymakers. If managed and regulated effectively, e-scooter sharing services can play an important role in the public mobility circuit, filling a gap in the short distance transit segment that public transport is, as yet, often unable to fill."

The research is carried out by SMART and supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) programme.

Tsukuba, Japan - Warm, dry wind events blowing down from mountain slopes, called foehns, are a meteorological phenomenon typically associated with the European Alps or the Rocky Mountains of North America. However, in recent decades, foehn winds in Japan have caused record-breaking hazardous warm weather events, bringing renewed interest in the behavior of these winds in this part of the world.

In a new study published in the International Journal of Climatology, a research team led by the University of Tsukuba has presented the first comprehensive climatological study of Japan's south foehn, a windstorm that originates from the Backbone Mountain Range and is observed along the coast of the Sea of Japan, including in the Toyama Plain in northwestern Honshu. This study aimed to determine which mechanisms and meteorological conditions lead to foehn occurrence, as well as the temporal distribution and paths of these events.

The research team identified 198 foehn events that occurred in the study area between 2006 and 2015 and investigated local meteorological parameters as well as the corresponding larger-scale weather conditions surrounding Japan.

Professor Hiroyuki Kusaka and his teams revealed that the primary mechanism of Japan's south foehn warming was dynamic in nature (i.e., temperature increase due to adiabatic compression associated with downdraft). It was previously assumed that the primary mechanism was thermodynamic (i.e., diabatic heating effect due to precipitation over the windward slope).

"It has previously been claimed that Japan's south foehn only blows while a cyclone or typhoon is approaching," study lead author Professor Hiroyuki Kusaka explains. "Over two-thirds of the foehns we identified occurred as an extratropical cyclone passing over the Sea of Japan, and 1 in 20 occurred while a typhoon existed near Japan. However, about one-fifth of the foehns actually occurred while an anticyclone was present over Japan."

According to Professor Kusaka, "Although all foehns are associated with significant increases in temperature compared with the opposite side of the mountains from which the foehns originate, all cases of hazardous high temperatures over 35°C were among the 1 in 20 cases where a typhoon was present near Japan." The findings of this comprehensive analysis of foehn events on the Toyama Plain may help to predict particularly dangerous foehns and mitigate harm to local people and agriculture.

Chemical reactions, such as those that occur when charging and discharging a battery, take place primarily on surfaces and at interfaces. While it is very easy to study the macroscopic products of a reaction, it has so far been difficult to gain a more accurate picture of the course of chemical reactions at the atomic level. This requires measurement methods that allow observations to be made on the extremely short time scales on which chemical reactions take place.

In principle, spectroscopic methods with very short laser pulses for temporal resolution are suitable for this. At the same time, the laser light must be of a very short wavelength, as physicist Tobias Helk of Friedrich Schiller University Jena explains: "To be able to specifically investigate individual elements using core electron resonance, laser light with a wavelength of a few nanometres is required - i.e., radiation in the extreme ultraviolet (XUV) or X-ray range of the spectrum."

To observe chemical processes, it is also important to be able to study the interfaces between media and material surfaces where chemical reactions take place, adds Helk. In addition to short wavelengths and short durations, the laser pulses must also have an extremely high intensity to be able to cause non-linear effects, as they are called, which allow the measurement signal to be traced back to the interface.

So far, however, there are very few methods for generating such intense laser radiation in the XUV and X-ray range. "Until now, this has only been possible at large-scale research facilities such as the FLASH free-electron laser at DESY," says Prof. Christian Spielmann of the Institute of Optics and Quantum Electronics at the University of Jena. However, he and his team, together with researchers from the USA and France, have now found a way to make such investigations possible in a standard laser laboratory.

Non-linear frequency doubling on a titanium surface

To this end, a soft X-ray laser from the Laboratoire d'Optique Appliquee in Palaisseau (France) was used as the light source. "In our experiment, we set up a special focusing geometry, consisting of a elliptically shaped mirror that enables us to concentrate the laser radiation onto a very small area," says doctoral candidate Helk, lead author of the study. The radiation with a wavelength of 32.8 nanometres was focused on an ultra-thin titanium foil and its non-linear interaction with the matter particles was analysed.

"As is already known from studies with radiation in the visible and infrared range, light with new properties can be generated through the interaction of light particles and matter particles," explains Helk. In a process known as non-linear frequency doubling (or second harmonic generation), for example, two photons of the irradiated light are absorbed by the material and a photon with twice the frequency (twice the energy) is emitted.

And it is precisely this effect that the researchers were able to demonstrate. With a spectrometer, they separated the radiation resulting from the interaction with the titanium foil and recorded it using a camera. By comparing simulations with the measurement results, they were also able to show that the resulting radiation originates on the surface of the titanium foil and not within the material.

"Being able to perform this form of surface spectroscopy in the XUV range on a laboratory scale opens up completely new perspectives. For example, chemical processes on surfaces or at hidden interfaces can now be studied from the perspective of a single atom in otherwise complex chemical environments," says Prof. Michael Zürch of the University of California, describing the significance of the result. Furthermore, the short duration of the pulses used enables the investigation of dynamic processes at interfaces, such as those that occur during the charging and discharging of batteries.

DALLAS - May 20, 2021 - An experimental drug that has shown promise in protecting healthy tissue from collateral damage caused by radiation therapy for cancer also appears to enhance radiation's capacity to kill tumors, a new study led by UT Southwestern scientists shows. The findings, published online in Science Translational Medicine, could provide a much-needed boost to the radiation treatments used against a variety of tumor types.

The drug, avasopasem manganese (AVA), has already shown promise in clinical trials to prevent a side effect known as acute mucositis. This condition commonly occurs in head and neck cancer patients when radiation therapy damages mucous membranes. However, for this drug to become part of clinical care, it should protect healthy cells from radiation but not cancer cells, explains study leader Michael Story, Ph.D., professor of radiation oncology at UTSW and a member of the Harold C. Simmons Comprehensive Cancer Center.

To determine whether AVA was accomplishing this goal, Story and colleagues at UTSW and the University of Iowa treated cancerous cell lines with this compound before exposing them to radiation. The cancerous cells that received the drug were not protected from radiation and, surprisingly, appeared in some cases to respond more to radiation compared with those that did not receive AVA, particularly at high radiation doses.

This phenomenon also occurred in cancerous cell lines that had been implanted in mice and allowed to grow into tumors. The tumors shrank significantly more when animals were treated with AVA just before receiving a single high dose of radiation, similar to a technique referred to as stereotactic ablative radiotherapy (SAbR), which is used for cancer therapy, compared with those that did not receive the drug. When the treated mice received the drug both before radiation and in the days after, in some cases their tumors disappeared completely.

These positive results in animals were found in several different tumor types, including lung, pancreatic, and head and neck. Further experiments showed that AVA appears to exert its enhanced tumor-killing effects by converting superoxide, which are damaging oxygen ions generated by high doses of radiation, to hydrogen peroxide at levels that overwhelm a tumor's ability to tolerate hydrogen peroxide. Furthermore, using an engineered cell line that overexpressed an enzyme that rids tumors of excess hydrogen peroxide, the anti-tumor effect was nearly eliminated.

Story, a member of the Simmons Cancer Center's Experimental Therapeutics Research Program, notes that AVA is currently being tested in phase 1 and phase 2 clinical trials to enhance therapy, including one clinical trial that combined SAbR with AVA that nearly doubled overall survival in pancreatic cancer patients. "With this drug," he says, "the radiation doses we deliver could be profoundly more effective, while at the same time contribute to protecting adjacent normal tissues."

Elephants and lions are iconic species that help raise substantial funds for conservation. However, they also pose significant threats to people, crops, and livestock, and are themselves threatened with extinction.

Areas at severe risk are identified

In a new article published in the journal Nature Communications, scientists have identified the areas that are most at risk for conflicts between humans and elephants and lions in Africa. They also estimated the associated return on investment of building and maintaining high-quality fences, which are used to reduce conflict between humans and wildlife.

Associate Professor Enrico Di Minin, who is the lead author of this article and leads the Helsinki Lab of Interdisciplinary Conservation Science at the University of Helsinki, highlights that human pressure on elephants and lions is extremely high.

"We found that 82% of sites containing lions and elephants in Africa are adjacent to areas with considerable human pressure", says Di Minin.

"Areas at severe risk of conflict (defined as areas with high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species' ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations", he continues.

African forest and savanna elephants have recently been classified as Critically Endangered and Endangered in the IUCN Red List of species, while African lions are classified as Vulnerable. Human activities pose the greatest threats to these species, particularly retaliatory killings of lions in response to livestock losses and of elephants in response to crop damage. Elephants and lions also kill dozens to hundreds of people each year.

"We found that elephants and lions are now most abundant at localities where human population density is lowest. At a national scale, lion populations are higher in countries where funding for conservation is higher and elephant numbers are higher in countries with higher gross domestic product per capita", states Professor Rob Slotow from the University of KwaZulu-Natal in South Africa

"We also found that areas at high risk of conflict are especially found in East and West Africa", he continuous.

Benefits of mitigation fences

Although a variety of conflict mitigation strategies could be deployed to address human-wildlife conflict, the team has assessed the return on investment of deploying high-quality mitigation fences, which have been found to be effective in reducing human-wildlife but are very expensive to build and maintain.

"Our results show how mitigation fences would provide considerable return on investment via reduced cattle loss and crop damage, especially in Tanzania, Ethiopia, and Kenya", says Professor Craig Packer from the University of Minnesota in the US.

"Our analysis reveals the location of about 10,000 kms of protected-area boundaries immediately adjacent to landscapes with such high densities of people, farmland and cattle pastures that wildlife movements have already been largely blocked. Mitigation fencing would merely reflect the reality of conserving large, dangerous, wildlife species in the Anthropocene. More and more African countries are starting to rely on mitigation fencing to better protect their citizens from the most dangerous wildlife species.", he continues.

The authors highlight how attention should be paid to prevent further habitat fragmentation for any migratory species that still manage to traverse the worst affected areas and to carefully consider the values, preferences, and motivations of local people before building mitigation fences.

"However, areas of intensive human pressure already produce hard boundaries around remaining areas of natural habitat and bold strategies to conserve these species are immediately needed, especially as human pressure will increase in the future with Africa experiencing very high human population growth by the end of the century", concludes Associate Professor Enrico Di Minin.

Two experimental drug approaches that target vulnerabilities in cancer cell metabolism may extend survival and enhance the effectiveness of standard chemotherapies for a highly aggressive type of pediatric brain cancer.

The findings were reported by Johns Hopkins Kimmel Cancer Center researchers in two published studies.

Medulloblastoma is the most common malignant pediatric brain tumor. A subset of patients with tumors known as Group 3 MYC-amplified medulloblastoma have an overall survival rate of less than 25%. In these patients, the cancer-promoting MYC oncogene drives cancer cell growth by altering cancer cell metabolism. Cancer cells use energy in ways that are different from normal cells, so they are potentially vulnerable to therapies that target the abnormal metabolic pathways downstream of MYC. 

In the first study, published March 22 in the Journal of Neuropathology and Experimental Neurology, pediatric oncologist and senior author Eric Raabe, M.D., Ph.D., associate professor of oncology at the Johns Hopkins University School of Medicine, focused on the metabolism altering drug DON (6-diazo-5-oxo-L-norleucine). DON is a naturally occurring compound studied in adult and pediatric cancer clinical trials since the 1980s, but it was never systematically tested against MYC-driven brain tumors.

Although DON was safe in children in early cancer clinical trials, it is not currently clinically available.

The research team, led by Barbara Slusher, Ph.D., M.A.S., director of Johns Hopkins Drug Discovery and professor of neurology at the Johns Hopkins University School of Medicine, modified DON to increase its ability to cross the blood-brain barrier, creating a DON prodrug, JHU395. In a prodrug, the chemistry is changed so that the drug is activated only in cancer cells.

"The promise of DON prodrugs is to develop a treatment that wouldn't hurt normal cells but could be released preferentially in brain cancer cells," says Raabe.

In one set of experiments, investigators treated human high-MYC medulloblastoma cell lines with JHU395 and with DON. They found the prodrug effectively suppressed growth and killed the cancer cells at lower concentrations compared to DON alone.

Next, mice bearing implanted human medulloblastoma tumors were treated with JHU395. The researchers found the treatment led to selective killing of the MYC-driven cancer cells, while normal brain cells were spared. Furthermore, JHU395 treatment significantly extended survival. Treated mice lived nearly twice as long as mice given placebo.

"JHU395 is equally effective as DON at a lower dose because it has better penetration of the brain cancer cells," Raabe says. "Coming up with a new therapy with potentially reduced side effects means we can combine drugs for better patient survival, which is what this is all about."

In a second study, published online Feb. 8 in Cancer Letters, Raabe and colleagues at three other cancer research institutions targeted the mammalian rapamycin complexes involved in cell metabolism. The protein mTOR signals cancer cells to grow, invade healthy tissue and resist therapy. 

Previous research showed that, in addition to high MYC expression, aggressive pediatric medulloblastoma tumors have high-level mTOR expression, pointing investigators toward mTOR inhibitors as having possible therapeutic value. A bioinformatics drug screen identified TAK228 (also known as sapanisertib), a brain-penetrating mTORC1/2 kinase inhibitor as a potentially effective agent for children, Raabe says.

Researchers found that TAK228 inhibited mTORC1/2, suppressed tumor cell growth up to 75% and effectively killed MYC-driven human medulloblastoma cancer cells.

Next, investigators focused on measuring the abnormal metabolism of MYC-driven medulloblastoma. In cancer, elevated glutathione is one means by which tumor cells become resistant to chemotherapy. Glutathione specifically allows cells to block the effect of chemotherapy drugs containing platinum, such as cisplatin and carboplatin. These platinum-containing drugs are some of the major components of medulloblastoma therapy. In human medulloblastoma tumors grown in mice, Raabe and colleagues found that the tumor cells have more glutathione than normal brain cells. Using the excess glutathione may be one way these cancer cells resist chemotherapy.

The researchers found that the TAK228 mTOR inhibitor disrupted and decreased glutathione synthesis in cancer cells. When they treated mice that had high-MYC medulloblastoma brain tumors with a combination of TAK228 and carboplatin, the combination effectively killed tumor cells and extended survival more than either drug used alone. Mice treated with combination therapy lived nearly twice as long as control mice. Of the combination-treated mice, 20% were considered very long survivors, living nearly 80 days after the start of the experiment, while all control mice died from their tumor within 25 days.

"By targeting the mTOR pathway, TAK228 overcame a key resistance mechanism that cancer cells have to traditional chemotherapy," Raabe says. "These MYC-driven cancers make a lot of glutathione -- they're growing so fast they need a lot of it. TAK228 reduces the amount they can make, and that makes them vulnerable to the chemotherapy."

"This is valuable pre-clinical data for future trials in children of combination mTOR inhibitor with traditional chemotherapy, which could ultimately change outcomes for children who will be diagnosed with MYC-driven medulloblastoma," he adds.

Study lead, Research Associate of the Neurobiology Lab Marat Minlebaev explains, "Our brain is a complex mechanism, and it's important to understand how it works. If we understand how our brain functions, we can put forth new treatment methodologies or prevent pathologies, both congenital and acquired."

A number of techniques were used to undertake the research, so, apart from biologists, other scientists were also invited to partake.

"Fourth year students Viktoria Shumkova and Violetta Sitdikova conducted experiments and analyzed their results," says Minlebaev. "To implement the idea, new software was needed. Here, we were helped by PhD student of the Institute of IT and Intelligent Systems Aleksey Leukhin. Senior year student of the Institute of Physics Ildar Reshapov created the necessary device. The merging of knowledge and competence of representatives of different branches of science helps conduct research on an entirely new level."

The paper proved that urethane, a previously widely used anesthetic, dose-dependently changes the cortical rhythms of brain activity and, due to this, is very suitable for experimenting. Another popular anesthetic, isoflurane, doesn't show such properties at the same scale. To conduct experiments, neonatal rats were used, because their developing brain is functionally similar to a human embryo brain during the latter half of intrauterine development. Thanks to a noninvasive technique (also developed by the team) brain activity can be monitored without skull penetration. Optical intrinsic signal imaging helped to register sensory evoked response and local changes in blood flow in the rats' cerebral cortex.

The practical significance of the results is that the data shows how different anesthetics influence brain functioning.

Researchers from Russia and Germany have created a genome-wide atlas of developmental alternative splicing changes of seven organs in six mammal species and chicken.

The research was published in the journal Nature Genetics.

As the protein encoding RNA matures in eukaryotes, it gets spliced, with some parts cut out and the remaining fragments stitched together. Alternative splicing means that the same RNA fragment can either be cut out from or kept within the mature RNA. In this case, one gene can encode several RNAs and, therefore, several proteins. Although alternative splicing is known to be essential for many tissues to develop and function properly and its various disorders may cause health problems, its function and regulation on genome-wide level are still very poorly understood. Comparative research on alternative splicing in different species has been performed mostly on adult organisms, but scientists believe that alternative splicing plays a very important role in an organism's development.

Professor Philipp Khaitovich and research scientist Pavel Mazin of the Skoltech Center for Neurobiology and Brain Restoration (CNBR) and their colleagues from the University of Heidelberg (Germany) decided to fill this gap. They used the RNA sequencing technology to create an alternative splicing atlas for seven different organs of six species of mammals and one bird species at different stages of their development, from the beginning of organogenesis to puberty. The team demonstrated the fundamental importance of alternative splicing in the formation of organs such as the brain, heart, and testes, whereas for the liver, kidneys, and ovaries alternative splicing revealed much weaker changes which, in addition, turned out to be very similar for all the studied species and were detected primarily in the genes expressed at the later stages of development and in several tissues simultaneously. This suggests that alternative splicing is needed mainly for creating tissue-specific protein isoforms that work in various tissues.

"Alternative splicing is difficult to handle due to high biological and experimental noise. Another challenge in this project was an enormous amount of data: we had to process about 2,000 samples totaling several terabytes. Yet, it was all the more exciting to see patterns and new insights emerge from this chaos," lead author Pavel Mazin says.

It is ingrained in parents to curtail the hours their children spend in front of the television. Anecdotal evidence suggests that prolonged viewing of television and use of smart gadgets during early years can adversely affect a child's eyesight and behavioral development. However, there is little scientific evidence to support such observations on the effects of excessive television exposure on children's visual acuity. Now, Professor MATSUO Toshihiko (M.D., Ph.D.) and Professor YORIFUJI Takashi (M.D., Ph.D.) from Okayama University describe how such exposure can indeed have detrimental effects on children's eyesight during later years.

The researchers used a national database of the Japan Government, based on the annual survey of all children born in the certain period of the year 2001. In 47,015 eligible children from the database over time, watching television or videos as a primary form of "play" and also daily duration of television-watching were assessed in the earlier years of life. The same children at elementary school were assessed yearly from the ages of 7 to 12 years to measure any concerns about visual acuity raised by their parents.

The Okayama University team first observed that if children had high television exposure at the ages of 1.5 years or 2.5 years, parents showed significant concerns around their children's eyesight in the second half of the study. This observation was consistent for children of both sexes and did not change based on parameters such as residential area or parents' education. Deeper analysis showed parents of children aged 2.5 years who watched television for greater than or equal to 2 hours/day had much greater concern for their children's visual acuity compared to those of children who watched television for up to 1 hour daily. However, as a child's age increased, their parent's concern during later years decreased.

To ensure uniformity of the results, the researchers re-analyzed the responses of a smaller pool of participants--those who participated in all surveys conducted when the children were between 7 to 12 years of age. Not only did the responses from this group reiterate their primary findings, but it was also found that the proportion of concerned parents increased as the children aged from 7 to 12 years. Visual acuity seems likely to deteriorate with age.

"This nationwide population-based longitudinal study is the first to demonstrate that television-watching only in the earlier years of life, but not in the later years, leads to the later consequence of visual acuity problems at elementary school age," conclude Professor MATSUO Toshihiko and Professor YORIFUJI Takashi.

Hence, carefully monitoring a child's television exposure up to the age of three could be a critical factor in healthy eyesight development. The research suggests that younger children should be encouraged to try more traditional ways of playing.

Oncotarget published "Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®" which reported that the authors developed and analytically validated a comprehensive genomic profiling assay, GEM ExTra, for patients with advanced solid tumors that uses Next Generation Sequencing to characterize whole exomes employing a paired tumor-normal subtraction methodology.

The assay detects single nucleotide variants, indels, focal copy number alterations, TERT promoter region, as well as tumor mutation burden and microsatellite instability status.

Additionally, the assay incorporates whole transcriptome sequencing of the tumor sample that allows for the detection of gene fusions and select special transcripts, including AR-V7, EGFR vIII, EGFRvIV, and MET exon 14 skipping events.

The assay has a mean target coverage of 180X for the normal and 400X for tumor DNA including enhanced probe design to facilitate the sequencing of difficult regions.

Proprietary bioinformatics, paired with comprehensive clinical curation results in reporting that defines clinically actionable, FDA-approved, and clinical trial drug options for the management of the patient's cancer.

Proprietary bioinformatics, paired with comprehensive clinical curation results in reporting that defines clinically actionable, FDA-approved, and clinical trial drug options for the management of the patient's cancer.

Dr. Thomas Royce from Ashion Analytics, LLC said, "Cancer has a high clinical burden and oncology therapies are expensive."

There are a few predominant laboratories that perform CGP tumor tests with the intended use of providing clinical decision support for therapy selection for cancer.

GEM ExTra uses Whole Exome Sequencing for tumor DNA profiling, testing for all protein-coding genes in a sample, indicating that the test will be comprehensive now and in the future.

GEM ExTra provides somatic variant calling based on tumor and matched germline sequencing allowing for improved discrimination of somatic variants from rare, benign germline variants when compared to tumor-only analysis used by other CGP tests.

GEM ExTra also identifies clinically actionable transcript variants and fusion genes through transcriptome sequencing. These are typically undetectable through conventional CGP tests, which only employ DNA analysis.

The test is designed to provide healthcare professionals with clinically actionable information to guide patient management decisions based on the genomic profile of a cancer patient's tumor.

The Royce Research Team concluded in their Oncotarget Research Output that the analytic performance characteristics of the assay were validated by comparison of patient samples to reference assays, and actionable variants were identified in tumors to guide oncology patient management decisions.

The test was utilized in over 1400 patient samples during a period of April 2018 and December 2019 across cancer centers to detect multiple actionable alterations in a variety of cancer types.

Reports of these actionable mutations were utilized to inform patient care, including matching patients to available targeted therapies or clinical trials.

The data from the clinical laboratory testing is generally concordant with data in the literature and emphasizes the value of the use of this pan-cancer comprehensive genomic test for the clinical management of patients with advanced cancer.

As of December 2019, Ashion was added to the list of commercial laboratories that are designated to identify and refer eligible patients to the NCI-MATCH trial.

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DOI - https://doi.org/10.18632/oncotarget.27945

Full text - https://www.oncotarget.com/article/27945/text/

Correspondence to - Thomas Royce - TRoyce@ashion.com

Keywords -
comprehensive genomic profiling,
whole exome sequencing,
RNA sequencing,
precision medicine,
pan-cancer

About Oncotarget

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Journal

Oncotarget

DOI

10.18632/oncotarget.27945

Scientists have made a major breakthrough in the study of embryonic development and how it can be impacted by external factors such as climate change.

Researchers at the University of Plymouth have developed a cutting edge technique which enables them to instantly examine the biological traits and behaviours of developing embryos as an energy signature, rather than focusing on individual characteristics.

The method, outlined in a study published in BMC Bioinformatics, is built around timelapse video captured by the researchers of aquatic animals - specifically, the embryos of a freshwater pond snail Radix balthica - during their earliest and most dynamic life stages.

With each video being composed of a series of individual pixels, whose brightness fluctuates from one frame to the next, the team developed a means of using these fluctuations to track detailed changes in energy usage.

The resulting energy proxy traits mean that rather than choosing individual aspects to measure, scientists can capture all of the traits visible in a video as a spectrum of energy values capturing a greater breadth of biological response.

Energy proxy traits respond markedly differently to traditional measurements of the phenotype (an organism's observable characteristics) such as heart rate or movement, and importantly they are highly specific to different temperatures throughout development.

The team also used the technique to demonstrate that the overall amount of energy expressed during the development of an embryo could be used to predict its growth rate, suggesting it may reflect the actual usage of energy by the embryo itself.

Dr Oli Tills, Research Fellow in the School of Biological and Marine Sciences and the new study's lead author, said: "Choosing what to measure can often be a tough choice for biologists, but it can drive the outcome of experiments. This choice can be likened to throwing darts while blindfolded, with the hope that you hit the bullseye by choosing biological traits of relevance that respond in informative ways during experiments.

"Biodiversity makes this task a significant challenge when studying the phenotype by presenting a huge range of form and function to choose from. This study has important implications for how we approach such studies in future. It presents a method that is transferrable to different species, experimental approaches and which moves away from the limitations of our previous pot luck approach."

The new research builds on existing work by the same Plymouth team applying bioimaging, robotics and computer vision to produce automated measurements of the size, shape, movement and function - including heart rate - of aquatic organisms.

Scientists of Tomsk Polytechnic University have developed a nanosensor-based hardware and software complex for measurement of cardiac micropotential energies without filtering and averaging-out cardiac cycles in real time. The device allows registering early abnormalities in the function of cardiac muscle cells, which otherwise can be recorded only during open-heart surgery or by inserting an electrode in a cardiac cavity through a vein. Such changes can lead to sudden cardiac death (SCD). Nowadays, there are no alternatives to the Tomsk device for a number of key characteristics in Russia and the world. The research findings of four-year measurement of cardiac micropotential energies using this device and the participation of a volunteer are published in Measurement academic journal (IF: 3,364; Q1).

The heart permanently generates electrical signals. These electrical signals cause cardiac muscle contraction and help the heart to function as a pump. Based on the form and duration of these pulses, it is possible to assess the condition of the heart. The main method of detection of electrical pulses, that is used everywhere, is electrocardiography (ECG). Nevertheless, ECG modern devices detect already critical changes in the function of the myocardium, cardiac muscle.

"Therefore, there is much concern about the creation of devices for early detection of these disorders, when it is still possible to restore cell function using medication and without surgical intervention. To implement this, it is required to record cardiac micropotential energies, electrical pulses emitted by separate cells. Here, there is a question of how to implement it noninvasive. Our research team have worked on this task for a long time, as a consequence, we jointly with the participation of our colleagues, doctors, have developed a hardware and software complex.

The core principles of its operation are similar to ECG, however, we changed sensors: we made nanosensors instead of conventional sensors and managed to measure signals of nanovoltage and microvoltage layers without filtering and averaging-out in broadband. The use of nanosensors led to the necessity to apply original circuit solutions, write individual software.

Ultimately, we gained a tremendous difference in sensitivity," Diana Avdeeva, Head of the TPU Laboratory for Medical Engineering, a research supervisor of the project, says.

The complex consists of a set of sensors, a tiny key device for recording incoming signals from sensors and software for data processing. The sensors are fixed on a human's chest using a conventional conducting gel. The monitoring procedure takes about 20 minutes.

Conventional ECG machines operate on frequencies from 0,05 Hz to 150 Hz, while the device of the Tomsk scientists operates on frequencies to 10,000 Hz.

Silver chloride electrodes are usually used for recording ECG of high quality. Our sensors are also silver chloride electrodes, however, we used silver nanoparticles. There are up to 16 thin plates from porous ceramics in every our sensor, silver nanoparticles are placed in these pores. There are millions of particles in one sensor, where every particle is a silver chloride electrode capable to enhance an electric field of the heart. Silver and gold nanoparticles are capable to enhance an electromagnetic field: visible light by 10,000 folds and infrared radiation by 20 folds. We also refused to use filters for rejection network interference and noises, which are usually used in conventional ECG and significantly distort micropotentials," Diana Avdeeva says.

The published article represents the monitoring data of one volunteer's heart function. He took part in research for four years and was monitored every 7-10 days.

"At the beginning of our research, we recorded clear violations of activity of cardiac muscle cells. His attending physician recommended surgery, he gained an inserted stent at the Cardiology Research Institute. Then, he continued to take part in the research and the device recorded the further gradual restoration of cardiac function," the scientist notes.

Previously, the project received sponsorship of the Technology Platform "Medicine of the Future" and the federal targeted program. The complex was created in partnership with experts of the Cardiology Research Institute of the Tomsk National Research Medical Center of the Russian Academy of Sciences. The industrial partner was the Scientific Production Association Ekran, a Moscow enterprise.

"A task to create a sensitive, tiny and affordable complex was set up, in order in a long run, outpatient clinics and patients at home could use it. Moreover, the developed methods and devices can be used not only in cardiology.

The fields of any electrophysiological research, such as electroencephalography, electromyography and so on are promising. Of course, before applying it to cardiology, we have to pass some essential stages. These are the collection of the required array of statistics, certification of the complex for medical use. All these stages require sponsorship, we are engaged in searching for partners and supporting programs," Mikhail Yuzhakov, Engineer of the TPU Laboratory for Medical Engineering, a participant of the research team, says.