Brain

A randomized clinical trial involving 97 medical centers in 20 countries, including Moores Cancer Center at UC San Diego Health, found that treating patients who have chemotherapy-resistant head and neck cancer with the immunotherapy drug pembrolizumab is more effective and less toxic than standard chemotherapy, reports an international team of researchers in the November 30 online issue of The Lancet.

Previous research had shown that pembrolizumab (Keytruda) was safe and effective for treating patients with recurrent or metastatic head and neck squamous cell carcinoma whose disease had progressed while on or after receiving standard chemotherapy. Data from this clinical trial called KEYNOTE-040, a phase III study sponsored by Merck & Co., the manufacturer of the drug, takes the research a step further by comparing the immunotherapy drug head-to-head to three go-to chemotherapy drugs currently used as standard treatment: methotrexate, docetaxel and cetuximab.

"We compared pembrolizumab against standard of care to see if it fulfilled the promise of early data for patients who are unlikely to do well on standard therapy," said Ezra Cohen, MD, professor of medicine at University of California San Diego School of Medicine and corresponding author on the study.

"In this trial, patients who received pembrolizumab alone had a higher response rate compared to those receiving standard chemotherapy while those responses lasted, on average, one-and-a-half years. Furthermore, the median survival at one year was markedly better. I feel it is safe to say that these types of therapies should be the new standard therapy for people with cancer that recurs and is resistant to therapy."

Pembrolizumab is an antibody that inhibits the abnormal interaction between the molecule PD-1 on immune cells and the molecule PD-L1 on tumor cells, allowing the immune cells to activate and attack tumors. Similar results were recently published for another anti-PD-1 drug, nivolumab (Opdivo). Both drugs should be considered by treating physicians for patients with this disease, said Cohen.

The study also pointed to potential biomarkers that can guide oncologists to determine which patients are most likely to respond to these anti-PD-1 drugs.

"It's fairly clear that patients whose tumors express PD-L1 are most likely to benefit from this type of immunotherapy drug," said Cohen, associate director for translational science at Moores Cancer Center and an internationally recognized physician-scientist who specializes in novel cancer therapies. "In this trial, overall survival was driven by PD-L1 expression. Only patients whose tumors expressed PD-L1 had a response to pembrolizumab and those responses tended to be durable."

Over a 17-month period, 247 patients were randomized to receive pembrolizumab and 248 patients were randomly selected by their physicians to receive one of the three standard therapies. The median overall survival for patients receiving immunotherapy was 8.4 months and 6.9 months for patients treated with standard care. Patients received treatment until their cancer progressed, they developed unacceptable toxicity, they withdrew or their physician removed them.

The median duration of response was 18.4 months in the pembrolizumab group, compared with five months in the standard therapy group.

Twelve months after initiating the trial, 37 percent of patients receiving pembrolizumab were alive compared to 26.5 percent of patients on standard therapy.

ANN ARBOR--By essentially turning down the pitch of sound waves, University of Michigan engineering researchers have devised a way to unlock greater amounts of data from acoustic fields than ever before.

That additional information could boost performance of passive sonar and echolocation systems for detecting and tracking adversaries in the ocean, medical imaging devices, seismic surveying systems for locating oil and mineral deposits, and possibly radar systems as well.

"Acoustic fields are unexpectedly richer in information than is typically thought," said David Dowling, a professor in U-M's Department of Mechanical Engineering.

He likens his approach to solving the problem of human sensory overload.

Sitting in a room with your eyes closed, you would have little trouble locating someone speaking to you at normal volume without looking. Speech frequencies are right in the comfort zone for human hearing.

Now, imagine yourself in the same room when a smoke alarm goes off. That annoying screech is generated by sound waves at higher frequencies, and in the midst of them, it would be difficult for you to locate the source of the screech without opening your eyes for additional sensory information. The higher frequency of the smoke alarm sound creates directional confusion for the human ear.

"The techniques my students and I have developed will allow just about any signal to be shifted to a frequency range where you're no longer confused," said Dowling, whose research is primarily funded by the U.S. Navy.

Navy sonar arrays on submarines and surface ships deal with a similar kind of confusion as they search for vessels on the ocean surface and below the waves. The ability to detect and locate enemy ships at sea is a crucial task for naval vessels.

Sonar arrays are typically designed to record sounds in specific frequency ranges. Sounds with frequencies higher than an array's intended range may confuse the system; it might be able to detect the presence of an important contact but still be unable to locate it.

Any time sound is recorded, a microphone takes the role of the human ear, sensing sound amplitude as it in varies in time. Through a mathematical calculation known as a Fourier transform, sound amplitude versus time can be converted to sound amplitude versus frequency.

With the recorded sound translated into frequencies, Dowling puts his technique to use. He mathematically combines any two frequencies within the signal's recorded frequency range, to reveal information outside that range at a new, third frequency that is the sum or difference of the two input frequencies.

"This information at the third frequency is something that we haven't traditionally had before," he said.

In the case of a Navy vessel's sonar array, that additional information could allow an adversary's ship or underwater asset to be reliably located from farther away or with recording equipment that was not designed to receive the recorded signal. In particular, tracking the distance and depth of an adversary from hundreds of miles away--far beyond the horizon--might be possible.

And what's good for the Navy may also be good for medical professionals investigating areas of the body that are hardest to reach, such as inside the skull. Similarly, remote seismic surveys that parse through the earth seeking oil or mineral deposits could also be improved.

"The science that goes into biomedical ultrasound and the science that goes into Navy sonar are nearly identical," Dowling said. "The waves that I study are scalar, or longitudinal, waves. Electromagnetic waves are transverse, but those follow similar equations. Also, seismic waves can be both transverse and longitudinal, but again they follow similar equations.

"There's a lot of potential scientific common ground, and room to expand these ideas."

BINGHAMTON, N.Y. -- Can you deceive a deceiver? That's the question that computer scientists at Binghamton University, State University of New York have recently been exploring.

Assistant Professor of Computer Science Guanhua Yan and PhD student Zhan Shu are looking at how to make cyber deception a more effective tool against malicious hackers.

Their study was inspired by the 2013 Target data breach that affected 41 million consumers and cost Target $18.5 million, and the 2017 Equifax hack which exposed the personal information of 147.7 million Americans. Both of these were what can be classified as Advanced Persistent Threats (APTs).

Yan and Shu wanted to improve the ways in which hackers are countered when attempting APTs, so they focused on refining existing cyber deception tools.

Cyber deception is a responsive technique that puts malicious hackers into a fake environment once the system detects a hack in progress.

In the abstract of the study, the researchers wrote that "the main objective of our work is to ensure deception consistency: when the attackers are trapped, they can only make observations that are consistent with what they have seen already so that they cannot recognize the deceptive environment."

They found that this focus on only showing attackers what has been seen before increases the efficiency of the deception.

"The issue is that sometimes cyber deception uses what are called 'bad lies' that are easily recognizable by the attacker. Once the deception is realized, the attacker can adjust and work around this form of protection," said Yan.

The deception consistency method that Yan and Shu created was tested on college students who had recently completed a cybersecurity course. The students were asked to act like malicious hackers, with some ending up in the deceptive environment.

The researchers found that because the deceptive environment was consistent with what students had previously seen, most did not realize they had entered into the deception.

"It was clear that most students were simply guessing whether they had entered into the deceptive environment or not. They couldn't quite tell the difference when we used our consistent model," said Yan.

Although the deception consistency may make it more difficult for APT attackers to recognize the deception, the researchers were clear that their proposed method is not a cure-all for things like what happened to Target and Equifax.

"It may not hold up against more advanced attacks, but we will continue to improve the effectiveness of the deception-based methods against a variety of attack scenarios," said Yan.

Yan and Shu published "Ensuring Deception Consistency for FTP Services Hardened against Advanced Persistent Threats" as part of the recent Proceedings of the 5th ACM Workshop on Moving Target Defense.

Researchers have discovered evidence that endurance exercise, such as running, swimming, cross-country skiing and cycling, will help you age better than resistance exercise, which involves strength training with weights.

In a study published in the European Heart Journal [1] today (Wednesday), researchers in Germany looked at the effects of three types of exercise - endurance training, high intensity interval training and resistance training - on the way cells in the human body age, and they found that endurance and high intensity training both slowed or even reversed cellular aging, but that resistance training did not.

Our DNA is organised into chromosomes in all the cells in our bodies. At the end of each chromosome is a repetitive DNA sequence, called a telomere, that caps the chromosome and protects its ends from deteriorating. As we grow older, the telomeres shorten and this is an important molecular mechanism for cell aging, which eventually leads to cell death when the telomere are no longer able to protect the chromosomal DNA. The process of telomere shortening is regulated by several proteins. Among them is the enzyme telomerase that is able to counteract the shortening process and can even add length to the telomeres.

The researchers led by Professor Ulrich Laufs, of Leipzig University, Germany, enrolled 266 young, healthy but previously inactive volunteers and randomised them to six months of endurance training (continuous running), high intensity interval training (warm-up, followed by four bouts of high intensity running alternating with slower running, and then a final cool down of slower running), resistance training (circuit training on eight machines, including back extension, crunch, pulldown, seated rowing, seated leg curl and extension, seated chest press and lying leg press), or to an unchanged lifestyle (the control group).

The participants who were randomised to the three forms of exercise undertook three 45-minutes sessions a week, and a total of 124 completed the study. The researchers analysed telomere length and telomerase activity in white blood cells in blood taken from the volunteers at the start of the study, and two to seven days after the final bout of exercise six months later.

Prof Laufs said: "Our main finding is that, compared to the start of the study and the control group, in volunteers who did endurance and high intensity training, telomerase activity and telomere length increased, which are both important for cellular aging, regenerative capacity and thus, healthy aging. Interestingly, resistance training did not exert these effects."

Telomerase activity was increased two- to three-fold and telomere length was increased significantly in the endurance and high intensity training groups compared to the resistance and control groups.

"The study identifies a mechanism by which endurance training - but not resistance training - improves healthy aging. It may help to design future studies on this important topic by using telomere length as indicator of 'biological age' in future intervention studies," said Prof Laufs.

Co-author of the study, Dr Christian Werner, of Saarland University, Germany, said: "The study has several implications: Our data support the European Society of Cardiology's current guideline recommendations that resistance exercise should be complementary to endurance training rather than a substitute. The data identify telomerase activity and telomere length as sensitive ways to measure at cell level the effects of different forms of exercise. Using these measurements to guide training recommendations for individuals may improve both adherence to and efficacy of exercise training programmes in preventing cardiovascular disease."

Previous research has shown that longer telomeres and increased telomerase activity are associated with healthy aging. However, this is the first prospective, randomised controlled study of the effects of different forms of exercise on these two measurements of cellular aging.

Prof Laufs said: "Physical exercise is widely recommended. However, prospective randomised controlled training studies are very rare because they require a great effort and there are no funding sources from industry. The numbers of participants in our study may appear small compared to large drug trials, however, to the best of our knowledge, this is the largest randomised study comparing well defined training modalities with a control group and with a long duration of six months. We hope that our project will stimulate confirmation and further studies in this field."

A possible mechanism that might explain why endurance and high intensity training could increase telomere length and telomerase activity is that these types of exercise affect levels of nitric oxide in the blood vessels, contributing to the changes in the cells.

"From an evolutionary perspective, endurance and high intensity training may mimic the advantageous travelling and fight or flight behaviour of our ancestors better than strength training," said Dr Werner.

Limitations of the study include the fact that the number of participants is small, even though it represents the largest study to investigate this in a prospective and randomised controlled way; and the everyday activities of the participants outside the training sessions may have included elements of the other forms of exercise, but this would be likely in all the groups, including the control group.

In an accompanying editorial [2] by Professor Konstantinos Stellos and Professor Ioakim Spyridopoulos, from Newcastle University and Freeman Hospital, Newcastle Upon Tyne, UK, who were not involved in the research, write that so far there has been no evidence that the role played by telomerase to maintain telomere length is implicated in the onset of cardiovascular disease, except maybe for heart failure. Rather, it appears that an acceleration in telomere shortening may be a sign of increased oxidative stress and a higher turnover of cells, coinciding with diminished telomerase activity. However, telomerase leads to enhanced nitric oxide, decreased oxidative stress, reduced damage to cells' DNA and reduced cell death, which are all important for delaying the clogging up of arteries with fatty deposits. They conclude that the findings from the study by Dr Werner and Prof Laufs "clearly underline the advantage of aerobic endurance training compared to resistance training in cardiovascular ageing".

New research disputes a long-held view that our earliest tool-bearing ancestors contributed to the demise of large mammals in Africa over the last several million years. Instead, the researchers argue that long-term environmental change drove the extinctions, mainly in the form of grassland expansion likely caused by falling atmospheric carbon dioxide (CO2) levels.

Tyler Faith, curator of archaeology at the Natural History Museum of Utah and assistant professor in the Department of Anthropology at the University of Utah, led the study. The research team also includes John Rowan from the University of Massachusetts Amherst, Andrew Du from the University of Chicago, and Paul Koch from the University of California, Santa Cruz.

The study is published today in the journal Science.

"Despite decades of literature asserting that early hominins impacted ancient African faunas, there have been few attempts to actually test this scenario or to explore alternatives," Faith says. "We think our study is a major step towards understanding the depth of anthropogenic impacts on large mammal communities, and provides a convincing counter-argument to these long-held views about our early ancestors."

To test for ancient hominin impacts, the researchers compiled a seven-million-year record of herbivore extinctions in eastern Africa, focusing on the very largest species, the so-called 'megaherbivores' (species over 2,000 lbs.) Though only five megaherbivores exist in Africa today, there was a much greater diversity in the past. For example, three-million-year-old 'Lucy' (Australopithecus afarensis) shared her woodland landscape with three giraffes, two rhinos, a hippo, and four elephant-like species at Hadar, Ethiopia.

When and why these species disappeared has long been a mystery for archaeologists and paleontologists, despite the evolution of tool-using and meat-eating hominins getting most of the blame.

"Our analyses show that there is a steady, long-term decline of megaherbivore diversity beginning around 4.6 million years ago. This extinction process kicks in over a million years before the very earliest evidence for human ancestors making tools or butchering animal carcasses and well before the appearance of any hominin species realistically capable of hunting them, like Homo erectus," says Faith.

Taking a Closer Look

Faith and his team quantified long-term changes in eastern African megaherbivores using a dataset of more than 100 fossil assemblages spanning the last seven million years. The team also examined independent records of climatic and environmental trends and their effects, specifically global atmospheric CO2, stable carbon isotope records of vegetation structure, and stable carbon isotopes of eastern African fossil herbivore teeth, among others.

Their analysis reveals that over the last seven million years substantial megaherbivore extinctions occurred: 28 lineages became extinct, leading to the present-day communities lacking in large animals. These results highlight the great diversity of ancient megaherbivore communities, with many having far more megaherbivore species than exist today across Africa as a whole.

Further analysis showed that the onset of the megaherbivore decline began roughly 4.6 million years ago, and that the rate of diversity decline did not change following the appearance of Homo erectus, a human ancestor often blamed for the extinctions. Rather, Faith's team argues that climate is more likely culprit.

"The key factor in the Plio-Pleistocene megaherbivore decline seems to be the expansion of grasslands, which is likely related to a global drop in atmospheric CO2 over the last five million years," says John Rowan, a postdoctoral scientist from University of Massachusetts Amherst. "Low CO2 levels favor tropical grasses over trees, and as a consequence savannas became less woody and more open through time. We know that many of the extinct megaherbivores fed on woody vegetation, so they seem to disappear alongside their food source."

The loss of massive herbivores may also account for other extinctions that have also been attributed to ancient hominins. Some scientist suggest that competition with increasingly carnivorous species of Homo led to the demise of numerous carnivores over the last few million years. Faith and his team suggest an alternative.

"We know there are also major extinctions among African carnivores at this time and that some of them, like saber-tooth cats, may have specialized on very large prey, perhaps juvenile elephants" says Paul Koch. "It could be that some of these carnivores disappeared with their megaherbivore prey."

"Looking at all of the potential drivers of the megaherbivore decline, our analyses suggest that changing climate and environment played the key role in Africa's past extinctions," said Faith. "It follows that in the search for ancient hominin impacts on ancient African ecosystems, we must focus our attention on the one species known to be capable of causing them - us, Homo sapiens, over the last 300,000 years."

The prevalence of allergic diseases has increased significantly over the last decades, creating substantial financial and societal burdens. Due to this, researchers are trying to discover new approaches to the prevention and treatment of these diseases. A new PhD thesis from the University of Eastern Finland shows that there is a link between immune responses and diverse early life exposures, such as obstetric factors, farm dust and air pollution. Some changes in immune responses are visible up until adolescence.

There is strong evidence that different exposures early in life can alter the risk of allergic diseases. One of these exposures is farming. Exposure to the farm environment in childhood, and even prenatally, has been shown to decrease the risk of allergic diseases. On the other hand, being born by caesarean section is recognised as a risk factor. The roles of other obstetric factors are less studied. Another harmful exposure is air pollution, and especially exposure to particulate matter, which has been shown to increase asthma prevalence and exacerbations in children. However, the underlying mechanisms are unclear, causing a delay in the development of asthma-preventive strategies.

Earlier studies have shown that immunological development and maturation starts already during pregnancy and in early childhood. Therefore, exposure at this critical point of immune development may modify immune responses and cells, and thus influence the risk of allergies and other immune diseases.

The study explored how different exposures during pregnancy, birth or childhood modulate asthma-related immune responses in children. The study focused on three different exposures: one that is asthma-protective (farming) and two that predispose to asthma (caesarean section and air pollution).

"We studied whether circulating dendritic cells associate with farming, asthma or atopy, whether obstetric factors affect immune responses at teenage in children born by caesarean section, and whether farm dust and urban air particulate matter have immunomodulatory effects on children's circulating immune cells," says Early Stage Researcher Maria-Viola Martikainen, MSc, from the University of Eastern Finland.

To answer these questions, the researchers studied associations between exposures and immunological responses. Circulating dendritic cell subsets of farm and non-farm children were examined at the age of 6 to assess whether they mediated the protective effect of farm exposure. Cytokine secretion of unstimulated and stimulated peripheral blood mononuclear cells, PBMCs, at teenage were examined to identify whether obstetric factors alter immune responses later in life. PBMCs of 4-year-old children were stimulated with farm dust and size-segregated particulate matter to discover shared and distinct immune pathways between two different environmental exposures.

The studied environmental exposures were associated with asthma-related immune responses. Inverse association between farm exposure and one of the subsets studied, and the association between this subset and asthma in farm children, suggested that this subset plays a role in farm-related immunoregulation. On the other hand, the lack of natural birth processes during delivery and neonatal intensive care treatment seemed to lead to long-lasting alterations of immune responses. The observed stimulatory effects of farm dust and inhibitory effects of particulate matter on immune responses indicate that these exposures could modify responses towards respiratory pathogens and allergens, and partly explain differences in asthma prevalence between the studied environments.

The study demonstrated associations between diverse early life exposures and immune responses, both ex vivo and in vitro. Some changes in immune responses seemed to be observable up to teenage. The study revealed some of the potential immunological mechanisms behind different exposures and advanced knowledge of immune mechanisms that either protect from or predispose to asthma. Moreover, the developed methodological approach offered a new perspective, which could be used when studying environment-related immune diseases and their mechanisms. These studies suggest that acquiring comparable data from various exposure environments could lead to the discovery of new immunological pathways and provide novel tools for risk assessment and for the development of preventive strategies.

A first-in-class OGG1 inhibitor found to decrease lung inflammation in mice and could hold the key to treating life-threatening Acute Respiratory Distress Syndrome

Isolating an inhibitor which triggers our immune systems response is a major breakthrough and could lead to better treatments for diseases such as sepsis and potentially autoimmune diseases

Unlike other anti-inflammatory treatments the new research blocks the onset of inflammation that is associated with oxidative stress

Scientists from the University of Sheffield have discovered a new inhibitor which decreases lung inflammation and could hold the key to treating Acute Respiratory Distress Syndrome - a life-threatening disease which affects thousands of people in the UK.

In the pioneering research, an international team of scientists aimed to make an inhibitor to an enzyme involved in repairing oxidated DNA, OGG1.

The study revealed the OGG1 protein signals inflammation and that the newly created inhibitor could prevent the onset of inflammation. This is a new mechanism - different to other anti-inflammatory drugs currently available - and could also help to prevent our own immune system attacking itself in conditions such as sepsis, multiple sclerosis, crohn's disease and potentially other autoimmune disorders.

Inflammation is a process where the body's white blood cells protect us from infection, such as bacteria and viruses. However, in some conditions the immune system triggers an inflammatory response when there is no infection to fight off. This causes the body's normally protective immune system to cause damage to its own tissues.

Professor Thomas Helleday, from the University of Sheffield's Department of Oncology and Metabolism and lead author of the study, said: "When oxygen regulation in our cells goes wrong it can cause damage to our DNA and trigger our immune system to responding.

"Our immune system is our defence mechanism which normally fights off invasion from bacteria and viruses, however sometimes it can misfire and attack our own bodies.

"Isolating an inhibitor which can switch this response off is a major breakthrough and we are really excited about developing our research to see if we can not only decrease existing inflammation in other areas of the body, but prevent inflammation altogether.

"This would pave the way for new, effective treatments for life-threatening diseases like sepsis."

In 2013, renowned Boston Children's Hospital pain researcher Clifford Woolf, MB, BCh, PhD, and chemist Kai Johnsson, PhD, his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. Woolf had shown that tetrahydrobioptrin -- a protein also known as BH4 -- is a primary natural modulator of neuropathic and inflammatory pain sensitivity. Quartet was founded on the premise that inhibiting BH4 production could prevent the progression of acute pain to chronic pain in millions of patients, without threat of addiction or tolerance.

With solid human genetic data and chemical biology, plus $17 million in series A funding, Quartet looked primed for success. But in the summer of 2017, toxicology studies of the company's lead candidate revealed neurologic side effects. Hope for the promising pain drug cratered, taking Quartet with it.

Now, however, a surprising discovery about BH4 will likely rekindle interest in the once-promising pathway and could have profound implications for treating autoimmunity and cancer. In today's Nature, Woolf and his team at Boston Children's Hospital, together with immunologists from the Institute of Molecular Biotechnology (IMBA) in Vienna report that BH4 also functions as a kind of immunological thermostat in the body, raising and lowering the activity levels of T cells.

In animal models of autoimmune disease and human cell lines, the researchers were able to inhibit T cell proliferation by blockading the BH4 pathway pharmacologically. In models of cancer, they were able to enhance T cell responses by elevating BH4 levels.

"By targeting BH4, we are able to suppress T cell activity in inflammatory conditions and increase their activity in the case of cancer," says Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children's, who co-led the study. "The ability to target the same pathway in opposite directions is significant and represents a whole new therapeutic approach."

An immunological thermostat

Specifically, the researchers found that BH4 regulates the balance of available iron for mitochondria. To transition to an activated state, T cells need higher levels of mitochondrial energy; to produce it, mitochondria need higher levels of iron. When T cells are under pressure, the body produces more BH4, increasing the supply of available iron, allowing the cells to divide and activate. When BH4 levels are low, mitochondria can't get the iron they need and T cell activity is suppressed. In the case of cancer, the study revealed that a metabolite produced by tumors works to block BH4, inhibiting T cell activation and cancer surveillance. It also showed that this response could be countered by augmenting BH4.

"The beauty of it is that the effect is upstream of specific types of T cell function," says Woolf. "Most drugs being developed now to treat autoimmune conditions are targeting specific kinds of T cells. This covers them all."

The team found that the BH4 pathway is only active in cases of infection or when proliferation needs to occur -- and is not required for the normal formation of T cells.

Finally, the paper reports the development of a highly potent small molecule, QM385, that inhibits the BH4 pathway, blocking T cell proliferation and autoimmunity.

Hiding in plain sight

Shane Cronin, a post-doc researcher from Ireland, arrived in the Woolf lab in 2006. He had trained in Vienna with noted immunologist Josef Penninger, MD, PhD at IMBA, and now planned to shift his focus to the neurobiology of pain.

"I wanted to leave immunology behind," says Cronin, lead author of the study. "Fat chance."

Woolf's team had just had its first major BH4 publication, which characterized the pathway as a key modulator of pain. To identify compounds that inhibit the expression of BH4, Woolf devised a drug screen using GFP fluorescent mice and asked Cronin to oversee the project.

The screen yielded plenty of hits -- and for Cronin, an odd sense of déjà vu. The results pointed to the same compounds Cronin had used in his previous immunology lab to regulate T cell function.

"First I thought, okay, this is a bit of a quip, but it became very specific very quickly and I knew what I was seeing," says Cronin. But just to be sure, he reviewed existing literature on BH4, and used reagents and technology from a neighboring immunology lab to confirm his initial finding. Woolf was intrigued and encouraged Cronin to keep exploring. But Cronin had a problem: at the time, Woolf's lab lacked the tools and equipment for studying T cells.

When an opportunity to move back to Vienna presented itself, Cronin saw his chance. Penninger agreed to accept Cronin back into his lab at IMBA and threw his full support and knowledge behind the project. Cronin now had access to the resources and experience of one of Europe's leading immunology labs.

"And like that, it just worked out," says Cronin.

'Binary' therapeutic potential

Together, Penninger, Woolf, Cronin and the other members of the BH4 group, spent the next eight years extending their finding into models of immune-related diseases -- contact dermatitis, multiple sclerosis, colitis -- and finally cancer.

"There was no magic moment -- just eight years of collaborative effort, putting together a puzzle, taking it apart, starting again," says Cronin. "But I guess that's the beauty of science--starting with a 'that's odd' moment and finding something incredible."

Working with Penninger, who co-led the study with Woolf, Cronin probed the binary therapeutic potential of BH4. If T cells proliferated in immune-related diseases, he wondered, what about cancer, where the same cells are often suppressed? Penninger and Cronin were able to boost BH4 levels in several mouse models of cancer, and the effect was immediate. Tumors shrank and the metastatic spread all but ceased.

"As a trained immunologist who was involved in defining some of the paradigmatic T cell activation pathways, I had this idea that I basically knew it all and what was left to discover would only be details," says Penninger, who now leads the Life Sciences Institute of the University of British Columbia, Vancouver. "It was like opening an entirely new door in T cell biology - a door we can now rationally close to treat autoimmunity or keep open for T cells to kill cancer."

Which brings us back to Quartet.

Building on a 'successful failure'

In August of 2017, as the company neared completion of its initial IND, leadership received some troubling news. A preclinical study revealed that although the BH4-inhibiting pain drug was "on target," it was also crossing the blood brain barrier at higher than expected levels. Because BH4 also plays an essential role in the production of key neurotransmitters, the team worried that that BH4 inhibition would reduce or prevent certain nerve signals. Ultimately, the decision was made to bring Quartet to a close.

In a blog post, Quartet chairman and founding investor Bruce Booth eulogized the company, hailing it as a "successful failure." The company's three-year investment had characterized the BH4 pathway in vivo in various pain models, developed and tested more than 1,500 potential BH4 inhibitors and produced a vast amount of data.

Those data can now be used to advance the new discovery toward the clinic. Woolf believes that clinical testing for immune-related diseases could begin in as early as 18 months.

"It's unusual to start out with lots of chemistry, lots of knowledge. Normally, you've just got interesting biology and you have to build a startup from there," Woolf says. "Because of the fruits of Quartet's chemistry and data, we're nearly ready to go."

Keeping an open mind

Initial targets of interest for this BH4 inhibitor could include atopic dermatitis, psoriasis, systemic lupus erythematosus, polyarthritis and inflammatory bowel disease. On the oncology side, the team is starting more or less from scratch.

"We're seeing great biological effect in terms of tumor suppression, but we still need to identify an effective pharmacological way to achieve this and address the full safety issues," says Woolf.

The team is exploring compounds to augment BH4 in cancer patients, with the hope they could one day be used either alone or in combination with other therapies, such as immune checkpoint inhibitors. Although it's still early, Woolf and Penninger are excited about the potential applicability of the technique, and a bit in awe of how it all came together.

"It's just strange," says Woolf. "I'm a neurobiologist -- I never expected to be working in immunology. But these days, I guess we all try to avoid locking ourselves into silos."

"There are many interesting discoveries to be made at the intersections and borders of fields if one keeps an open mind and is willing to follow what nature tells us," says Penninger.

LA JOLLA, CA - November 15, 2018 - Scientists at Scripps Research have discovered that a mysterious family of cellular proteins called OSCAs and TMEM63s are a novel class of mechanosensitive ion channels.

Mechanosensitive ion channels convert biologically relevant physical forces into biochemical signals. For example, a plant's response to environmental cues like wind, water currents, or physical barriers depend on mechanosensation. In mammals, sense of touch, pain sensation and blood pressure regulation are performed by mechanosensitive ion channels. Despite their importance, very little is known about the molecules that perform these functions in plants and animals.

The scientists also deciphered the atomic structure of one member of the OSCA protein family, an advance that will allow them to study how these ion channels do their jobs, information that could be critical to identifying how dysfunctions in mechanosensing play a role in disease.

The original work to discover the role of OSCA proteins was led by Swetha Murthy, PhD, professional scientific collaborator in the lab of Ardem Patapoutian, PhD, professor at Scripps Research and investigator with the Howard Hughes Medical Institute. In her new eLife study, Murthy and her colleagues show that OSCA channels are not only pressure-sensitive ion channels, but they appear to have held onto their "mechanosensitive" properties as life evolved.

"We wanted to see if the mechanosensitivity properties were conserved across the 15 different members of the OSCA family, and across different species," says Murthy.

The new findings suggest the pressure-sensing abilities of these ion channels are indeed "conserved" among the types of OSCA channels. Furthermore, while OSCA channels are present in plants, their related proteins in animals, TMEM63s, are also mechanosensitive.

"This finding will facilitate the study of these channels in model organisms such as flies and mice and will help identify their role in human biological processes and other disease states linked to mechanosensation," says Murthy.

A follow-up study was led by Sebastian Jojoa Cruz, graduate student, and Kei Saotome, PhD, at Scripps Research, and published simultaneously in eLife. Working with Professor Andrew Ward, PhD, the researchers used an imaging technique called cryo-electron microscopy to study the structural details of a member of the OSCA family, called OSCA1.2.

This first look at OSCA's structure suggests that part of the protein may sit close enough to the cell membrane to sense membrane tension and translate that tension to the rest of the ion channel. The researchers are looking forward to investigating exactly how this pressure sensing process works.

"By revealing the first structural snapshot of an OSCA channel, we have provided a valuable starting point to unravel the details of a force sensation mechanism that is widespread throughout biology," says Saotome.

"Force is a difficult phenomenon to study at the molecular level, so future studies will require innovative and multidisciplinary approaches," adds Ward. For example, molecular dynamics simulations of OSCA1.2, conducted by co-authors Alex Tsui and Mark Sansom, DPhil, at Oxford University, offer tantalizing clues about the role of lipids in channel function.

Saotome and Jojoa Cruz say it was "striking" to see how similar the OSCA structure was to the structure of an unrelated family of proteins called TMEM16, especially in the transmembrane domain. TMEM16s have diverse roles in membrane biology, including as ion channels and manipulators of the cell membrane. Therefore, the structural similarity could suggest this protein architecture is responsible for more biological functions than previously believed.

"The next step will be to determine the physiological role of these proteins in plants and animals," says Murthy.

It is known that certain areas of the brain are responsible for certain functions of the body. The cerebellum, a structure found in the back of the skull, is known to be important for the control of movement, while the frontal cortex is responsible for cognitive functions such as short-term memory and decision making. However, as researchers continue to unlock the mystery of how billions of neurons in the brain interact, it is becoming more apparent that it is not that black and white.

Dr. Nuo Li, assistant professor of neuroscience and a McNair Scholar at Baylor College of Medicine, and his colleagues have found the first direct evidence that the cerebellum does more than just control muscle activity. It also plays a role in cognitive functions.

"We knew that the frontal cortex and the cerebellum are anatomically connected with each other," Li said. "We also knew that in humans, cerebellar damage has been known to cause memory or planning problems, so the two might be connected."

Li and his colleagues examined activity in the cerebellum during time periods when animals are not moving, but instead are thinking. To do this, the researchers trained mice in a task that required them to make decisions based on short-term memory. Mice were shown a single object in a specific location. After a delay, the animal had to remember where the object was and indicate its location by licking in a left or right direction. The delay represented a moment when the mice had to use short-term memory to recall where the object was before acting out the correct movement.

Making moves and memories

In previous work, researchers have found memory activity in the frontal cortex during the delay period that predicted what future movement the mice will make. Li and colleagues found that memory activity during the delay period was seen in both the frontal cortex and the cerebellum. Researchers silenced areas of the cerebellum during the delay period, which led to incorrect responses but did not interfere with the movement. At the same time, the memory activity in frontal cortex also was disrupted. This showed that memory activity in frontal cortex was dependent on the cerebellum. They then silenced areas in the frontal cortex, which stopped memory activity in the cerebellum.

"We found that the output of the cerebellum targets the frontal cortex and vice versa. When we disrupt the communication between the two areas of the brain, memory activity is disrupted. Our results show that activity orchestrating a single behavior is coordinated by multiple regions of the brain," Li said.

The cerebellum is known to guide our movement by learning from errors. Li explains that when we learn to shoot a basketball, we initially have lots of missed shots. However, the brain can adjust our shots by adjusting our movements based on errors from the missed shots and eventually produce accurate shots. It is known that the cerebellum is responsible for this motor learning. It combines errors from the missed movements and the movement that was made to produce a more accurate movement.

Li's team currently is pursuing experiments testing this hypothesis that the cerebellum may perform a similar function on brain activity related to thoughts, such as when playing a game of chess.

Each year 5-10 per cent of all the children born in the world are born prematurely. At this stage, their organs and immune system are not mature, and the children are therefore highly susceptible to serious infections. One of the problems facing a lot of children born prematurely is the immaturity of the gastrointestinal tract, which among other things causes them to be hypersensitive to bacteria. Now a study conducted by researchers of biomedicine at the University of Copenhagen offers new hope.

In the study the researchers, using pigs born prematurely, have tested faeces transplantation - a new type of treatment used on those born prematurely - and shown a drop in the incidence of the fatal bowel disease necrotizing enterocolitis (NEC) following transplantation.

'We are able to protect the bowels of pigs born prematurely by transferring faeces from healthy donor pigs via the rectal opening. The composition of intestinal bacteria in these animals changes significantly, and we see 75 per cent fewer cases of NEC. And this is important, because a lot of children die from this disease. If the results can be transferred to children born prematurely, this form of treatment can save lives and possibly reduce the amount of antibiotics given to these patients', says co-author of the study, Professor Per Torp Sangild from the Department of Veterinary and Animal Sciences at the University of Copenhagen.

Fighting for Intestinal Balance

In the study the researchers examined 130 pigs born prematurely. They chose the pig as their test animal, because the gastrointestinal tract of pigs resembles that of humans and because pigs develop a severe intestinal infection that can be compared to NEC.

Scientists do not know exactly why children born prematurely develop this serious intestinal infection, which in up to 40 per cent of the cases is fatal, but they do know that intestinal bacteria play a vital role.

'The bowel is like a battlefront where the new-born and its bacteria must communicate with each other to establish peaceful coexistence. However, the immature bowel is probably not ready to take control and therefore needs good bacteria that contribute to the balance of the system. And the right composition of bacteria appears to be of vital significance. From previous studies among pigs we know that neither probiotics nor faeces from the mother are as effective as faeces transplantation. A comparison of seemingly uniform donors has even shown a clear difference in the ability to prevent NEC. We would like to know why this is so', says first author of the study, PhD Student Anders Brunse from the Department of Veterinary and Animal Sciences.

The Importance of Normal Flora

In the study the researchers have measured how the intestinal bacteria composition changes in pigs born prematurely following faeces transplantation. This has shown an increase in the wealth of bacteria and the introduction of bacteria that form part of the bowel's normal flora.

'Through faeces transplantation immediately after birth we can probably achieve stability in the intestinal bacteria composition faster. This can help them become resistant to bowel infection', says co-author of the study, Professor with Special Responsibilities Thomas Thymann from the Department of Veterinary and Animal Sciences.

Since the early days of CRISPR-Cas9, researchers have known that this gene editing technology is excellent for breaking things. With precision, these scissor-like tools can be sent to any location in the genome to make a snip and break a gene. But exactly where and how CRISPR-Cas9 will disrupt the gene was anyone's guess. Until now. Investigators at Brigham and Women's Hospital, in collaboration with colleagues at the Broad Institute and MIT, have discovered that template-free Cas9 editing is predictable, and they have developed a machine learning model that can predict insertions and deletions with high accuracy. The team, led by co-corresponding authors Richard Sherwood, PhD, David Liu, PhD, and David Gifford, PhD, has demonstrated that this approach can be used to edit and repair mutations related to three diseases in human cell lines -- Hermansky-Pudlak syndrome, Menkes disease and familial hypercholesterolemia - with a predictable repair outcome in more than half of instances. These advancements have implications for both research and clinical applications. The team's findings are published this week in Nature.

"Like many projects, this one came out of a puzzling result: We wanted to use CRISPR-Cas9 to cause a random set of mutations at a particular spot in the genome, but we were finding that the mutations we were getting were far from random," said Sherwood, a principal investigator in the Brigham's Division of Genetics. "It turns out that the underlying sequence to which you are directing CRISPR-Cas9 allows you to predict, with a high degree of accuracy, which mutations you are most likely to get."

Many genetic diseases arise from insertions and deletions that disrupt a gene's function so being able to replicate these or fix them with accuracy would be a major coup. Conventional wisdom among CRISPR-Cas9 researchers has held that the tool randomly generates insertions and deletions in a gene unless researchers include a so-called repair template. But Sherwood's team has found that even without a template, one can predict which insertions and deletions are most likely to occur. At certain genomic sites, one particular mutation dominates - the team used the term "precise-50" to indicate when a single such mutation comprised more than 50 percent of all major editing products.

To conduct their project, Sherwood and colleagues, including Christopher Cassa, PhD, a principal investigator in the Brigham's Division of Genetics, constructed a library of 2,000 Cas9 guide RNAs (gRNAs) paired with DNA target sites. They used this library to train inDelphi, a machine learning model. They found that inDelphi could predict deletions of varying lengths and single base pair insertions with high accuracy (r = 0.87) in five human and mouse cell lines, and that it predicted up to 11 percent of the gRNAs were "precise-50."

To confirm these findings, the team used select gRNAs to correct mutations in cells collected from patients with genetic diseases that result from microduplications - a chromosomal change in which a small amount of genetic material gets duplicated. Hermansky-Pudlak syndrome, especially common in Puerto Ricans, causes blood clotting deficiency and albinism. Menkes disease results in copper deficiency. The team also generated cells with microduplications found in patients to result in familial hypercholesterolemia a disease in which LDL cholesterol levels are abnormally high. For all three diseases, delivering the appropriate Cas9 and guide RNA corrected the mutation with high efficiency.

The authors note that this work is still a proof-of-concept - while promising in cellular models in the lab, it requires further testing and additional steps to bring it into the clinic. In addition, only between 5 and 11 percent of Cas9 guide RNAs met the "precise-50" standard. Sherwood and the team will now work toward optimizing the efficiency of the guide RNAs by understanding why certain insertions or deletions are so much more common than others. They hope that others will leverage the tools they have developed to set regulatory standards for precision in existing therapeutic applications and expand what applications may be possible.

"Currently, most companies that are thinking about therapeutic applications for CRISPR-Cas9 are thinking about what genes you need to break to treat a disease. Our findings indicate that it's possible to predict where we may be able to repair mutations instead," said Sherwood. "We don't want to settle for 50 percent mutation correction - we want to continue to improve. Now that we know that CRISPR-Cas9 editing is predictable, we have a parameter to measure how to fix disease mutations even more precisely."

Statins have been linked with muscle pain and other musculoskeletal adverse events (MAEs) in some patients. A new Pharmacology Research & Perspectives study has examined the timing of MAEs that develop during statin therapy and determined whether concomitant drugs used concurrently with statin therapy shifts the timing of MAEs.

For the study, cases in which statins (atorvastatin, rosuvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, and pravastatin) were prescribed were extracted from the US Food and Drug Administration Adverse Event Reporting System Data Files.

The onset timing of statin-induced musculoskeletal adverse events (MAEs) differed with each statin. For example, the onset of MAEs was significantly faster with high-intensity statins including atorvastatin and rosuvastatin than with simvastatin. Concomitant use of drugs--even those that may increase the risk of MAEs--did not cause changes in the onset timing of MAEs associated with statins.

"Passive surveillance of adverse events has played a major role in securing drug safety as a system to detect unknown adverse events. Data mining using Food and Drug Administration Adverse Event Reporting System, which is a large-scale database, will be an aid to enhance drug safety," said senior author Dr. Daiuke Kobayashi, of Josai University, in Japan.

Griffith University researchers have demonstrated a procedure for making precise measurements of speed, acceleration, material properties and even gravity waves possible, approaching the ultimate sensitivity allowed by laws of quantum physics.

Published in Nature Communications, the work saw the Griffith team, led by Professor Geoff Pryde, working with photons (single particles of light) and using them to measure the extra distance travelled by the light beam, compared to its partner reference beam, as it went through the sample being measured - a thin crystal.

The researchers combined three techniques - entanglement?(a kind of quantum connection that can exist between the photons), passing the beams back and forth along the measurement path, and a specially-designed detection technique.

"Every time a photon passes through the sample, it makes a kind of mini-measurement. The total measurement is the combination of all of these mini-measurements," said Griffith's Dr Sergei Slussarenko, who oversaw the experiment. "The more times the photons pass through, the more precise the measurement becomes.

"Our scheme will serve as a blueprint for tools that can measure physical parameters with precision that is literally impossible to achieve with the common measurement devices.

Lead author of the paper Dr Shakib Daryanoosh said this method can be used to investigate and measure other quantum systems.

"These can be very fragile, and every probe photon we send it would disturb it. In this case, using few photons but in the most efficient way possible is critical and our scheme shows how do exactly that," he said.

While one strategy is to just use as many photons as possible, that's not enough to reach the ultimate performance. For that, it is necessary to also extract the maximum amount of measurement information per photon pass, and that is what the Griffith experiment has achieved, coming far closer?to the so-called Heisenberg limit of precision than any comparable experiment.

The remaining error is due experimental imperfection, as the scheme designed by Dr Daryanoosh and Professor Howard Wiseman, is capable of achieving the exact Heisenberg limit, in theory.

"The really nice thing about this technique is that it works even when you don't have a good starting guess for the measurement," Prof. Wiseman said. "Previous work has mostly focused a lot on the case where it's possible to make a very good starting approximation, but that's not always possible."

A few extra steps are required before this proof-of-principle demonstration can be harnessed outside the lab.

Producing entangled photons is not simple with current technology, and this means it is still much easier to use many photons inefficiently, rather than each set of entangled photons in the best way possible.

However, according to the team, the ideas behind this approach can find immediate applications in quantum computing algorithms and research in fundamental science.

The scheme can ultimately be extended to a larger number of entangled photons, where the difference of the Heisenberg limit over the usually achievable limit is more significant.