Culture

International team including University of Warwick scientists identifies proteins that drive activation of our immune response

Adaptor proteins act as a 'clutch' to move clusters of proteins within cells

Could open opportunities to design immune cells to combat specific problems

Protein condensates are involved; have been found to play roles in many biological processes and diseases, including Huntington's disease, amyotrophic lateral sclerosis, and types of cancer

Two proteins that act as a 'clutch' in cells to put them in gear and drive our immune response have been identified for the first time.

A team of biochemists and cell biologists--gathered from the University of Warwick (UK), the University of Texas Southwestern (UTSW) Medical Center (USA), University of California, San Francisco (UCSF) (USA), and from the National Centre for Biological Sciences (NCBS-TIFR), Bangalore (India) -- working together at the Marine Biological Laboratory, Woods Hole in the United States thanks to funding by the Howard Hughes Medical Institute -- have uncovered a process within cells that shows how they move contents around inside them. It appears that they move in a manner similar to switching gears in a car.

The research, published in the journal eLife, could give insights into the mechanisms that activate immune cells and could eventually drive the development of new treatments.

The research focused on the composition of protein condensates - clusters of different types of proteins bound together that are found inside cells. These condensates have been found to play significant roles in many biological processes, and have also been implicated in diseases, including Huntington's disease, amyotrophic lateral sclerosis, and several types of cancer.

One system that protein condensates play an important role in is the activation of T cells, which are very important for producing antibodies and for communicating to the rest of the body that there is an infection present. T cells are constantly screening for small amounts of antigen presenting cells, which are vital for an effective adaptive immune response, so have to be easily but accurately triggered.

When a T cell binds to an antigen presenting cell, the T cell receptors are activated, and a cascade of processes are triggered. The T cell starts to rearrange its cortex and create a zone around these receptors called the immunological synapse.

A network of filaments within the cell made from actin guides a condensate carrying a protein called LAT from the cell periphery towards the centre of the cortex continuously to keep the T cell activated.

The researchers were able to demonstrate that two adaptor proteins, Nck and N-WASP/WASP, act like a 'clutch' in a car, allowing the condensate to slot into the correct gear position and speed up its progress to the centre of the cell.

The discovery sheds light on the control mechanisms for the activation of our immune response, and potentially could open opportunities to design T cells that are only active for particular problems.

Dr. Darius Köster, an Assistant Professor at the Centre for Mechanochemical Cell Biology - Warwick Medical School, explains: "Proteins condensates have distinct compositions and distinct preferential locations within cells, and they are associated with distinct biological functions, including DNA replication, RNA metabolism, signal transduction, synaptic transmission, and stress response.

"For this research, colleagues rebuilt these condensates in vitro to demonstrate that LAT can be the seed for forming these protein assemblies. We then combined this system with a rebuilt actin cortex system to get a better understanding of what happens to phase-separating protein bunches in the vicinity of an actively moving actin network.

"Depending on which modular molecules are used in the LAT clusters, their interaction with actin changes. It's a bit like a clutch in your car, some molecules interact weakly with the actin, but by adding another molecule they will interact much more strongly.

"Using this reconstituted system allowed us to make much more minute changes to the protein condensate composition that would not be so easy to do in the live cell."

Professor Satyajit Mayor (NCBS-TIFR) commented on the unique way in which scientists from different institutes and continents came together with their respective experience and expertise to collaborate on solving a central question that is emerging in the new area of phase separating membrane-less molecular assemblies.

He comments: "This effort was made possible by a unique collaboration. An idea supported by Howard Hughes Medical Institute (HHMI), produced the 'HHMI/MBL Summer Institute', (organized primarily by the HHMI investigators Mike Rosen (UTSW), Ron Vale (UCSF) and Jim Wilhelm (UC San Diego) to study the mechanisms that control the composition and consequent function of these exciting phases in living cells. While the lead author of this study, Jon, was reconstituting the phase separating T Cell receptor signalling complex (at UTSW) along with Xiaolei Su (at UCSF), Darius brought his in vitro actomyosin membrane cortex (developed at the NCBS) to the heady collaborative atmosphere of the Marine Biological Laboratory in Woods Hole, Massachusetts. The natural consequence was to mix one system with the other. The understanding gained from this active mixture provided crucial insights into the functioning of the molecular clutch that couples the T cell signalling complex with a centripetally moving acting cytoskeleton. This coupling in turn regulates the function of T cell receptors in aiding the immune system to recognize foreign antigens."

Dr. Michael Rosen echoes this sentiment, adding: "The Summer Institute brought together scientists from across the globe to participate in a unique collaborative environment at the MBL. By living and working together for eight weeks over several summers, we were able to make scientific discoveries that would have been impossible for any of our groups individually. The work described in our eLife paper, combining extremely complex biochemistry with cutting-edge imaging and image analysis, exemplifies the spirit and accomplishments of the Summer Institute."

Virtually every day, millions of children and adolescents are being bombarded by sexually explicit direct-to-consumer advertising, despite pharmaceutical CEOs' claims to the contrary.

Leading business ethicist Denis Arnold from the University of North Carolina at Charlotte co-authored the study, "Self-Regulation in the Pharmaceutical Industry: The Exposure of Children and Adolescents to Erectile Dysfunction Commercials," published in the just released Journal of Health Politics, Policy and Law. Jim Oakley, professor and chair of marketing at Lewis University, is the study co-author.

Arnold, the Surtman Distinguished Professor of Business Ethics in the Belk College of Business, and Oakley studied marketing campaigns for erectile dysfunction (ED) drugs during a six-year period. These products include sildenafil citrate, manufactured and marketed as Viagra in the United States by Pfizer; and tadalafil, manufactured and marketed as Cialis in the United States by Eli Lilly.

"PhRMA Guiding Principles," for which both companies have certified their compliance, state that 90 percent of the audience viewing sexually explicit advertisements must be 18 or older. These principles, developed by the Pharmaceutical Research and Manufacturers of America trade organization (PhRMA), were first introduced in 2005, and under these guidelines, a company must commit to internal processes to ensure compliance with the principles, complete an annual certification of compliance and submit a document to PhRMA signed by the CEO and chief compliance officer attesting to compliance.

"Pfizer and Eli Lily have never met the standard, and public disclosure of this misconduct in 2013 did not alter their behavior," stated Arnold, past president of the Society for Business Ethics. "The most reasonable explanations for this misconduct are that a public commitment to the standard helps block additional regulation, while at the same time there are no penalties for routinely violating the standard.

"Firms continued to aggressively advertise ED drugs when they knew children and adolescents would be exposed to these sexually explicit ads billions of times," Arnold added.

In 2013, Arnold and Oakley published a research article also in the Journal of Health Politics, Policy and Law that found firms never met the industry standard during a different four-year period they analyzed. This study was widely publicized and acknowledged by the manufacturers of ED drugs and PhRMA. In this new study, Arnold and Oakley sought to answer this question, "Would public disclosure of non-compliance with industry standards improve firm behavior?" The answer, as determined by their recent study, is "no."
Eric Patashnik, editor-in-chief of the Journal of Health Politics, Policy and Law and the Julis-Rabinowitz Professor of Public Policy and Professor of Political Science at Brown University, stated,

"Broadly, they [Arnold and Oakley] found that public disclosure did not cause firms to alter their behavior, suggesting that the pharmaceutical industry is simply not willing to police itself."

Other findings from "Self-Regulation in the Pharmaceutical Industry: The Exposure of Children and Adolescents to Erectile Dysfunction Commercials" include:

Twenty years after its introduction in the U.S., spending on direct-to-consumer advertising rose to $6.083 billion or five times as much as 1996 in inflation-adjusted dollars. This is more than double what the U.S. film industry spent on marketing

On average, there were 35-40,000 ED advertising impressions on children and adolescents daily, totaling more than five billion impressions, between Jan. 1, 2010, and Dec. 31, 2015

Public disclosure of non-compliance with self-regulatory direct-to-consumer advertising standards did not bring advertising into compliance. Results demonstrate that firms failed to meet the industry standard during every quarter of this study's six-year period

Results support previous research that demonstrated that pharmaceutical self-regulation is a deceptive blocking strategy aimed at preventing further regulation rather than a means for the industry to police itself

BOSTON, MA - Patients over age 50 who underwent an all inside arthroscopic repair technique had lower rates of subsequent total knee surgery than a similar group that was only observed, according to research presented at the American Orthopedic Society of Sports Medicine Annual Meeting today.

Dr. Jason L. Dragoo from Stanford Medicine in Redwood City, Calif., and his team of researchers followed 48 patients over age 50 who were diagnosed with a meniscal root tear. The meniscus is the spongy cartilage that provides cushion in the knee.

Dragoo and his team set out to compare the clinical outcomes of patients undergoing an all-inside arthroscopic repair technique versus non-operative management for posterior meniscal root tears.

Meniscal root tears affect both young healthy athletes and older patients with early degenerative knees. Root tears lead to de-tensioning of the meniscus and have been associated with increased contact forces and cartilage damage. Management of older patients with root tears is controversial and the efficacy of different treatment options is unclear.

During the follow-up period, only 3.3 percent of patients who received arthroscopic repair required a total knee surgery while 33.3 percent of patients in the observation group needed knee surgery.

"Our study found a significant improvement in all clinical outcome scores in the surgery group at two-year follow-up," said Dr. Dragoo. "Surgical management showed higher functional outcomes and decreased TKA conversion rates as compared to observation and should be considered as a treatment option for the treatment of meniscal root tears in the older population," he said.

A team of paleontologists led by Prof. Jingmai O'Connor from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences, together with researchers from the Shandong Tianyu Museum of Nature, have discovered a new specimen of the volant dromaeosaurid Microraptor zhaoianus with the remains of a nearly complete lizard preserved in its stomach. Their findings were published in Current Biology.

The lizard is unlike any previously known from the Cretaceous and represents a new species, Indrasaurus wangi. The lizard was named after Prof. WANG Yuan from IVPP, who is also director of the Paleozoological Museum of China. Prof. WANG is an expert on the paleoherpetofauna of China and has been in charge of numerous exhibitions of Chinese fossils.

The name Indrasaurus was inspired by a Vedic legend in which the god Indra was swallowed by a dragon during a great battle (the dragon here referring to Microraptor).

Dr. DONG Liping, a former student of Prof. WANG's, ran the most extensive phylogenetic analysis of Cretaceous lizards ever conducted and showed that all known Cretaceous species were more closely related to each other than to any modern lineage. The new lizard had teeth unlike any other previously known from the Jehol Biota, thus expanding the diversity of this clade and possibly suggesting a unique diet for this new species.

This is the fourth documented occurrence of a Microraptor preserving stomach contents - this dinosaur is now known to have fed on mammals, birds, fish, and lizards, supporting the interpretation that it was an opportunistic predator.

The lizard is nearly complete and articulated, showing that it was swallowed whole and head first, meaning that Microraptor fed in a manner similar to living carnivorous birds and lizards.

Although the Jurassic troodontid Anchiornis has been recently demonstrated to have egested pellets similar to extant carnivorous birds (most famously documented in owls), this ability was apparently absent in Microraptor, further adding to the evidence that the evolutionary transition from dinosaur to bird was characterized by extreme homoplasy - that is, numerous traits evolved multiple times independently in closely related groups.

Over the past 20 years, direct evidence of trophic interactions in the Jehol Biota has slowly accumulated. There are now 20 predator-prey relationships documented through direct evidence of stomach contents.

The authors used these relationships to reconstruct the first Jehol food web. Although certainly preliminary, this food web indicates that fish formed the most important food source for secondary and tertiary consumers. This food web can be used in the future to better understand the Jehol ecosystem.

They look like smears of pink bubblegum on the rocks off British Columbia's coast, indistinguishable from one another.

But a new DNA analysis of coralline algae led by UBC and Hakai Institute researchers has revealed a wealth of different species - a diversity that could hold the key to protecting critical underwater habitats like kelp forests.

"Corallines play really important roles in their ecosystem, from cementing coral reefs together to giving off scents that attract other species like sea urchins, abalone, corals, and kelps to the area," said Patrick T. Martone, a professor of botany at UBC who supervised the research. "Some coralline species are better at attracting organisms than others and respond to climate stressors like rising ocean temperatures in different ways. But they all look the same so it's hard to tell how changes to their environment are really impacting them."

Coralline algae appear to be among the only species to benefit from the loss of sea otters, an endangered species native to the North Pacific Ocean. When sea otters are lost, sea urchins bloom and mow down kelp forests, which provide important habitat for many marine organisms. The resulting "sea urchin barrens" are largely devoid of life, except for coralline algae which appear to thrive in the landscape.

"The fact that corallines do better in this environment would be an exception to our understanding of the impacts of losing 'keystone' species like sea otters, which typically result in an overall loss of biodiversity," said Martone.

In order to find out if corallines are really doing better in the absence of the furry creatures, the researchers surveyed the diversity of corallines in both sea urchin barrens and kelp forests. They counted how many individuals were present, took samples and sequenced the DNA back in the lab.

"What we found is that there are a lot of species down there," said Katharine Hind, lead author and former Hakai post-doctoral researcher. "And while some corallines do grow more abundantly in sea urchin barrens, we found more species and greater diversity in kelp forests."

The researchers also found that while coralline communities in the different kelp forest sites were similar to one another, they were different in the urchin barren sites, which were dominated by just a few species.

"So what we begin to see is actually a loss of coralline diversity, despite the apparent increase in abundance. This greater understanding changes our interpretation of the ecological pattern - a lesson that should be applied to cryptic species in other biological systems, like fungi, insects, or plants on land," said Hind. "It's possible we could be losing some kind of ecosystem function as a result of this loss of diversity."

The researchers hope to figure out what role each of the coralline species is playing next.

"We are seeing a decline in kelp forests along the coast as they are being replaced by these urchin-dominated barrens," said Martone. "We think corallines might hold the key to understanding the maintenance of urchin barrens- certain species that urchins prefer to settle on could result in a positive feedback to bring more urchins to the area. Conversely, corallines that kelp spores respond more positively to could help bring kelp forests back to stripped reefs."

PROVIDENCE R.I. [Brown University] -- Researchers have used ultra-high-speed x-ray pulses to make a high-resolution "movie" of a molecule undergoing structural motions. The research, published in Nature Chemistry, reveals the dynamics of the processes in unprecedented detail -- capturing the excitation of a single electron in the molecule.

The ability to see molecular motions in real time offers insights into chemical dynamics processes that were unthinkable just a few decades ago, the researchers say, and may ultimately help in optimizing reactions and designing new types of chemistry.

"For many years, chemists have learned about chemical reactions by essentially studying the molecules present before and after a reaction has occurred," said Brian Stankus, a recent Ph.D. graduate from Brown University and co-lead author on the paper. "It was impossible to actually watch chemistry as it happens because most molecular transformations happen very quickly. But ultrafast light sources like the one we used in this experiment have enabled us to measure molecular motions in real time, and this is the first time these sorts of subtle effects have been seen with such clarity in an organic molecule of this size."

The work is a collaboration between chemists from Brown, scientists at SLAC National Accelerator Laboratory and theoretical chemists from the University of Edinburgh in the U.K. The team was led by Peter Weber, professor of chemistry at Brown.

For the study, the researchers looked at the molecular motions that occur when the organic molecule N-methyl morpholine is excited by pulses of ultraviolet light. X-ray pulses from SLAC's Linac Coherent Light Source (LCLS) were used to take snapshots at different stages of the molecule's dynamic response.

"We basically hit the molecules with UV light, which initiates the response, and then fractions of a second later we take a "picture" -- actually we capture a scattering pattern -- with an x-ray pulse," Stankus said. "We repeat this over and over, with different intervals between the UV pulse and x-ray pulse to create a time-series."

The x-rays scatter in particular patterns depending on the structure of molecules. Those patterns are analyzed and used to reconstruct a shape of the molecule as the molecular motions unfold. That pattern analysis was led by Haiwang Yong, a graduate student at Brown and the study's co-lead author.

The experiment revealed an extremely subtle reaction in which only a single electron becomes excited, causing a distinct pattern of molecular vibrations. The researchers were able to image both the electron excitation and the atomic vibration in fine detail.

"This paper is a true milestone because for the first time, we were able to measure in great clarity the structure of a molecule in an excited state and with time resolution," said Weber, the study's corresponding author.

"Making these types of nearly noise free measurements in both energy and time is no small feat," said Mike Minitti, a senior staff scientist at SLAC and study co-author. "Over the past seven years, our collaboration has learned a great deal on how best to use the various LCLS diagnostics to precisely measure the small fluctuations in X-ray intensities, and to an even greater extent, track the femtosecond timescale changes the molecules evolve on. All of this has informed the development of custom data analysis routines that virtually eliminate pesky, unwanted signals to our data. These results demonstrate the fidelity we can achieve."

A particularly interesting aspect of the reaction, the researchers say, is that it's coherent -- meaning when groups of these molecules interact with light, their atoms vibrate in concert with each other.

"If we can use experiments like this one to study how exactly light can be used to direct the collective motion of billions of molecules, we can design systems that can be coherently controlled," Stankus said. "Put simply: If we understand exactly how light directs molecular motions, we can design new systems and control them to do useful chemistry."

CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12 and targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain.

McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), described in the journal Science.

Zhang and his team, including first co-authors Omar Abudayyeh and Jonathan Gootenberg(both now McGovern fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine — thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang’s team that changes adenine bases into inosine in RNA.

RESCUE significantly expands the landscape that CRISPR tools can target to include modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.

“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” says Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT. Zhang has appointments in MIT’s departments of Brain and Cognitive Sciences and Biological Engineering.

Expanding the reach of RNA editing to new targets

The previously developed REPAIR platform used the RNA-targeting CRISPR/Cas13 to direct the active domain of an RNA editor, ADAR2, to specific RNA transcripts where it could convert the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine, or C to U.

RESCUE can be guided to any RNA of choice, then perform a C-to-U edit through the evolved ADAR2 component of the platform. The team took the new platform into human cells, showing that they could target natural RNAs in the cell, as well as 24 clinically relevant mutations in synthetic RNAs. They then further optimized RESCUE to reduce off-target editing, while minimally disrupting on-target editing.

New targets in sight

Expanded targeting by RESCUE means that sites regulating activity and function of many proteins through post-translational modifications, such as phosphorylation, glycosylation, and methylation, can now be more readily targeted for editing.

A major advantage of RNA editing is its reversibility, in contrast to changes made at the DNA level, which are permanent. Thus, RESCUE could be deployed transiently in situations where a modification may be desirable temporarily, but not permanently. To demonstrate this, the team showed that in human cells, RESCUE can target specific sites in the RNA encoding β-catenin, that are known to be phosphorylated on the protein product, leading to a temporary increase in β-catenin activation and cell growth. If such a change were made permanent, it could predispose cells to uncontrolled cell growth and cancer, but by using RESCUE, transient cell growth could potentially stimulate wound healing in response to acute injuries.

The researchers also targeted a pathogenic gene variant, APOE4. The APOE4 allele has consistently emerged as a genetic risk factor for the development of late-onset Alzheimer’s disease. Isoform APOE4 differs from APOE2, which is not a risk factor, by just two differences (both C in APOE4 versus U in APOE2). Zhang and colleagues introduced the risk-associated APOE4 RNA into cells and showed that RESCUE can convert its signature Cs to an APOE2 sequence, essentially converting a risk to a non-risk variant.

To facilitate additional work that will push RESCUE toward the clinic, as well as enable researchers to use RESCUE as a tool to better understand disease-causing mutations, the Zhang lab plans to share the RESCUE system broadly, as they have with previously developed CRISPR tools. The technology will be freely available for academic research through the nonprofit plasmid repository Addgene.

Additional information can be found on the Zhang lab’s webpage.

The researchers studied a group of 720 boys and 794 girls who studied in 13 schools in Reus. They were monitored during three developmental periods: 10 years old, 11 years old and 13 years old. At the beginning of the study, the students answered a series of psychological tests that were used to detect which of them presented emotional symptoms related to depression, anxiety and obsessive compulsive disorder (OCD). From their responses, two groups were created: one group at risk of emotional problems and a control group.

The disorders were diagnosed with standardised international criteria and the boys and girls were monitored to see how suicidal ideation developed throughout the research period.

The figures were quite stable. During the first period, 16% of the students stated that they had thought about suicide, of whom 33% stated the same one year later. In both the second and the third period, ideas of suicide were expressed by 18% of the students surveyed. The risk of suicide was determined in a personal interview and was present in 12.2% of the children with an average age of 11 years old. Although there were no differences between the sexes, the severity of the suicidal behaviour was greater in boys.

The researchers also observed what factors predicted suicidal ideation and they found here that there were differences between the sexes. "In boys it is previous depressive symptoms which determine subsequent suicidal ideation," says Núria Voltas, one of the researchers involved in the study. In girls, on the other hand, it is a combination of anxiety symptoms, OCD and the family's socioeconomic situation.

The results of this research, published in the scientific journal Archives of Suicide Studies reveal the factors that can trigger ideas of suicide in this age group. "Our results will enable us to have greater control over this particular aspect and take prevention measures in preadolescents, who are going through a period of considerable vulnerability," she concludes.

Damaged peripheral nerves can regenerate after an injury, for example, following a forearm fracture. Axons, the long projections of neurons that transmit stimuli or signals to other cells, are affected in the case of injury and need to regrow to recover their function. The research team led by Prof. Claire Jacob at Johannes Gutenberg University Mainz (JGU) and at the Swiss University of Fribourg investigated the details of this repair process and have demonstrated that the same mechanism could be activated in cells of the central nervous system - after a spinal cord injury, for instance. Their results have been published in the renowned journal Cell Reports.

"An injury in the peripheral nervous system quickly triggers the activation of a fascinating repair process that allows the injured nerve to regenerate and regain its function. There is no such repair process in the central nervous system, thus injuries often lead to permanent damage such as paraplegia," explains Claire Jacob, Head of Cellular Neurobiology at JGU. Strategies to improve axon regeneration in the central nervous system must therefore be developed to enable healing.

Myelin-forming cells are key to the axon regeneration process. Many axons are ensheathed by myelin, which serves as a protective layer while also enabling fast and efficient signal transmission. "Myelin is extremely important for the function of the entire nervous system, however it also hinders the repair process in case of an injury," adds Claire Jacob. Myelin is produced by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system; this difference has a major impact on axon regeneration, because Schwann cells and oligodendrocytes respond very differently to axonal injury.

Schwann cells can do everything - they break down myelin and damaged axons

When axons of the peripheral nervous system are injured, Schwann cells rapidly induce the disintegration of the cut-out axonal segments into small fragments, which can then be digested by Schwann cells themselves or later by macrophages. This elimination of axonal debris is one of the first and critical steps of the repair process. "Schwann cells can do everything. We discovered that they not only digest myelin following injury, but they also induce the disintegration of the long axon segments that are separated from their cell bodies due to the injury," points out Claire Jacob. In order to do that, Schwann cells form small spheres made of a protein called actin; these actin spheres exert pressure on the isolated axon segments until their disintegration into small pieces. This targeted degradation of cell debris is essential to enable the healthy part of the axon that remained attached to the neuron cell body to grow back, connect to its former target and thereby regain full functionality.

Severed axons transmit signals to Schwann cells

Of particular interest, the Jacob team found that severed axonal segments send a signal to Schwann cells that prompts them to start the actin sphere formation and axon disintegration process, an impressive and precisely coordinated form of interaction between the two cell types. If this mechanism is disrupted, axonal disintegration is slowed down and axonal fragments impair the regeneration of the affected nerve.

Manipulated oligodendrocytes can also generate actin structures

Claire Jacob's team went on to study the central nervous system and the behavior of oligodendrocytes. "After an injury, oligodendrocytes either die or remain apparently unresponsive," says Claire Jacob. Oligodendrocytes are not (normally) able, like Schwann cells, to form actin spheres and thus break down axon segments. One reason for this is that, unlike Schwann cells, they do not express VEGFR1, the receptor that triggers the production of actin spheres in Schwann cells. In the next step, the research team induced the expression of VEGFR1 in oligodendrocytes. This allowed oligodendrocytes to produce actin structures and disintegrate severed axonal fragments; this is an essential step to promote the regeneration of neurons in the central nervous system.

The team is currently working at identifying the molecular processes that trigger the removal of myelin at the site of injury in the central nervous system. In addition to the disposal of axonal debris, myelin removal is a second prerequisite necessary for the complete regeneration of neurons. "We have discovered a pathway that accelerates myelin degradation in the peripheral nervous system and are now trying to determine whether this can also trigger myelin removal in the central nervous system," adds Claire Jacob, describing the results of on-going research in her lab.

Rising temperatures could mean no male loggerhead turtles hatch at a key breeding ground by the end of this century, new research suggests.

The University of Exeter study also warns that - by 2100 - more than 90% of loggerhead nests on the Cape Verde islands could incubate at "lethally high temperatures", killing turtles before they hatch.

The sex of turtle hatchlings is determined by incubation temperature, and this study combined current temperature and hatchling data with projections from the Intergovernmental Panel on Climate Change (IPCC).

Even under a scenario based on low future emissions and warming, by 2100 just 0.14% of hatchlings would be male.

Under mid and high-emissions scenarios, hatching of male loggerheads could cease entirely.

"Cape Verde hosts one of the largest nesting population of loggerhead turtles in the world - up to 15% of the global nesting total," said Dr Lucy Hawkes, of the University of Exeter.

"We estimate that 84% of current hatchlings are female, and warmer temperatures will increase this proportion.

"Under all three climate change scenarios in our study, by 2100 more than 99% of hatchlings would be female - and under mid and high-emissions scenarios there could be no males at all."

Lead author Claire Tanner, who worked on the study as part of a masters at the University of Exeter, said: "What surprised us was how even the low emissions scenario has detrimental effects for this population.

"What this shows is that now is the time to act on climate change - before it is too late to prevent the estimations seen in this paper."

The projections in the study are based on current nesting behaviour, and the researchers say loggerheads could adapt to some extent by nesting earlier in the year, when it is cooler.

Dr Hawkes said natural selection should favour turtles that do this, but the long lifespan of loggerheads and the speed of climate change will probably mean they cannot evolve fast enough.

About 85% of loggerhead nests in Cape Verde are currently laid on Boa Vista, where incubation temperatures are coolest - so most of the population cannot switch to cooler islands.

However, the study says they might benefit from "refugia" - places where specific features, such as shade from trees or the landscape, provide cooler conditions.

It is not clear how long it will take the population to decline if males stop being produced, as the reproductive lifespan of males is not known - so older males may continue breeding for many years after new males stop being hatched.

The study used data gathered by CSIC (Seville, Spain) and three IPCC predictions for surface air temperature increase by the end of this century: low (1.8°C), mid (2.8°C) and high (3.4°C).

Previous studies have been done on turtles breeding in Cape Verde, but this study was unusual because it examined all the areas where turtles breed (known as rookeries).

Three papers in this issue demonstrate new fiber-based designs within the world of artificial muscles, showing how these twisted and coiled designs can be controlled via heat, electricity and chemistry. The resulting artificial muscle material could find uses in miniaturized medical devices, microrobots, and "smart" textiles that respond to environmental changes, among other applications. Mehmet Kanik and colleagues developed a two-faced polymer fiber that can be created through a scalable iterative drawing technique, producing artificial muscles that are activated by heat and that can lift more than 650 times their own weight and withstand strains of more than 1,000%, while remaining resilient over thousands of use cycles. Jiuke Mu and colleagues describe a fiber type where power is provided by an electrothermally sensitive sheath surrounding tightly coiled inexpensive materials including commercial nylon and bamboo yarns. The contractile power of muscles built from these fibers is 40 times that of human muscle and nine times that of the highest power alternative electrochemical muscle. Jinkai Yuan and colleagues' contribution is a high-energy microengine composed of shape memory nanocomposite fibers that are twisted to store energy that can be released on demand after a small temperature change. In a related Perspective, Sameh Tawfick and Yichao Tang discuss how these innovations bring us closer to realizing pervasive automation across a variety of fields.

A new type of therapeutic food, specifically designed to repair the gut microbiomes of malnourished children, is superior to standard therapy in an initial clinical trial conducted in Bangladesh.

An interdisciplinary team of investigators from Washington University School of Medicine in St. Louis and the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, have undertaken a new approach for addressing the pressing global health problem of childhood malnutrition. Their approach focuses on selectively boosting key growth-promoting gut microbes using ingredients present in affordable, culturally acceptable foods.

Their work supports the notion that healthy growth of infants and children is inexorably linked to healthy development of their gut communities following birth. The results of their research are described in two reports published July 12 in the journal Science.

"We found that children who are malnourished have incompletely formed gut microbial communities compared with their healthy counterparts" said senior author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology at the School of Medicine. "Therefore, we set about to design therapeutic foods to repair this immaturity and to determine whether such repair would restore healthy growth."

The clinical trial, which was conducted by a team led by Tahmeed Ahmed, PhD, the International Centre for Diarrhoeal Disease Research's director of Nutrition and Clinical Services, included 63 Bangladeshi children, 12-18 months of age, diagnosed with moderate acute malnutrition, meaning the children were ill but not close to death. The children were randomly assigned to one of four treatment groups. Children in three of the groups each received one of the three newly designed therapeutic foods, while those in the fourth group received a standard therapeutic food that was not designed based on a consideration of its effects on the gut microbiome.

All foods for the trial were locally produced at the International Centre for Diarrhoeal Disease Research. Children were brought twice daily to a nutritional rehabilitation center, where the therapeutic foods were administered by their mothers under the supervision of health-care workers. A set of measuring tools, developed through advances in genomic medicine, provided a new, much more comprehensive definition of molecular features associated with malnutrition, its underlying mechanisms, and the effectiveness of treatment.

One of the therapeutic foods stood out from the rest, even in this relatively short one-month trial. Measuring 1,300 blood proteins, including those intimately involved in directing bone growth, development of the brain, immune function, and metabolism in various tissues, revealed that this food prototype had produced a pronounced shift toward a healthy state compared with what was observed in the other three groups of children.

At the end of the study, the researchers also found that, unlike in the three other treatment groups, the gut microbial communities residing in the intestines of children receiving this lead therapeutic food had undergone a reconfiguration and more closely resembled microbial communities found in age-matched healthy children living in the same locale. This formulation contained, among other components, a mixture of nutrients from chickpea, soy, bananas and peanuts.

Childhood malnutrition is a massive global health problem, affecting 150 million children under age 5 worldwide, according to the World Health Organization. Many studies have shown that malnutrition is the result of many factors, with reliable access to adequate amounts of affordable, nutritious food being one but not the only factor.

Existing therapeutic foods were developed to increase the amount of key nutrients children consume. Malnourished children who receive these foods are less likely to die, but other consequences of malnutrition have remained largely unresponsive to treatment, including stunted growth, impaired immunity and reduced cognitive function. Gordon noted that these foods were not designed based on a consideration of their effects on the development of the gut microbiome.

The new microbiome-directed therapeutic foods developed by the Washington University and International Centre for Diarrhoeal Disease Research team emanated from their earlier studies of gut microbial community development in healthy children living in Bangladesh. Several years ago, the team discovered that children with malnutrition had immature gut communities - ones that appeared younger than their age-matched healthy counterparts. Ahmed noted that several years ago they found that conventional therapeutic foods failed to repair this immaturity in the malnourished children they had treated.

Gordon's group went on to transplant immature communities from malnourished children, and normally maturing communities from healthy children, into mice that had been raised under sterile conditions. The results revealed that immature communities were associated with reduced weight gain, defective bone development plus abnormal metabolic and immune functions in the recipient animals. These findings provided early evidence that failure to form a normal microbial community may be a cause rather than simply an effect of malnutrition.

"There is uncertainty about what foods are best to administer during the period of complementary feeding -- when children transition from exclusive milk feeding to solid foods," Gordon said. "Our studies were inspired by the notion that these commonly used, affordable, culturally acceptable complementary foods could contain ingredients coveted by key microbes that are underrepresented and underperforming in the gut microbiomes of malnourished children. These microbes were our therapeutic targets."

This study provides the first evidence that a therapeutic food, developed specifically to support growth and expansion of gut microbes linked to healthy microbiome development, has beneficial effects outside the gut related to many aspects of healthy growth. These effects involve key mediators of metabolism, and of bone, brain and immune system development -- organ systems that have been very difficult to repair in malnourished children by supplementing their diet with traditional therapeutic foods.

In first of the two papers -- co-first authors Jeanette L. Gehrig, PhD, Siddarth Venkatesh, PhD, and Hao-Wei Chang, all members of the Gordon lab -- describe how they first used germ-free mice, and then germ-free piglets, colonized with gut microbial community members from Bangladeshi children to screen a series of diets comprised of complementary food ingredients used in Bangladesh. They formulated Microbiome-Directed Complementary Food prototypes that could repair immature microbial communities from malnourished Bangladeshi children in both these animal models and improve the health of the animals. These prototypes then were tested in the double-blind controlled feeding study described above.

In the second paper, first author Arjun S. Raman, MD, PhD, from the Gordon lab, describes development of new computational methods, based on methods originally developed by the field of econophysics to analyze how fluctuations in the economy affect features of complex, dynamic financial markets. The approach provided new, generally applicable ways of characterizing the organization of human gut communities -- their normal development, how they are perturbed in disease states such as malnutrition, and how they respond to therapeutic interventions designed to repair them.

"The goal of human microbiome research is not simply to describe the component parts of a microbial community but rather to characterize how the components interact with one another to shape community functions," Gordon said. "Complicating matters, the number of possible interactions between the components in a gut community is literally astronomical."

According to Raman, the researchers wanted to be able to focus their attention, finding ways to reduce the number of components or features of the microbiome to a minimum number that could portray in an informative way the organizational properties of healthy and diseased gut communities.

Studying the microbiomes of healthy Bangladeshi children sampled monthly from birth through five years, and using the new computational method, they identified a network of 15 gut bacterial community members that consistently interacted with one another. They named this network an ecogroup. The components of the ecogroup provided an accurate way of describing normal gut development of infants and children living in Bangladesh as well as several other low-income countries. It further served as a sensitive and accurate way of determining how severely disrupted microbial communities are in children with moderate and severe malnutrition, and the degree to which they are repaired with various treatments.

"A longer and larger clinical trial is currently underway at two sites in Bangladesh to see if the new Microbiome-Directed Complementary Food has sustained benefits," Ahmed said. "This trial includes children with moderate malnutrition as well as children with severe malnutrition treated with conventional therapy but left with incompletely repaired microbiomes, stunting and various other growth impairments."

Added Michael J. Barratt, PhD, an assistant professor of pathology and immunology and executive director of the Center for Gut Microbiome and Nutrition Research at Washington University: "It is possible that some children may have gut microbial communities so damaged that a food-based intervention alone won't be sufficient. So our Washington University and International Centre for Diarrhoeal Disease Research team is interested in studying the possibility of giving the specific beneficial organisms -- or even the beneficial products those microbes make, as we become more knowledgeable about what those are -- in combination with a Microbiome-Directed Complementary Food. That could be a second line of defense. Our studies also present the possibility of monitoring development of gut microbial communities and catching deviations from normal development earlier in life, giving us opportunities for prevention."

Gordon emphasized that their efforts designed to repair the perturbed microbial communities of malnourished children hold the promise of revealing more informed guidelines for feeding children in the first several years of life so that they can develop healthy microbiomes.

"We need to be effective stewards of the precious microbial resources of our children," he said. "If we are, the effects may be long-lived and herald a new dimension to preventive medicine -- one that starts with their developing microbiomes."

Scientists at the University of Cambridge have uncovered striking similarities in how two distantly related plants defend themselves against pathogens despite splitting from their common ancestor more than 400 million years ago.

Researchers from the Sainsbury Laboratory at the University of Cambridge compared how two distantly related plants - a common liverwort (Marchantia polymorpha) and a flowering plant, wild tobacco (Nicotiana benthamiana) - defend themselves against an aggressive pathogen (Phytophthora palmivora). This is the first time such a comparison has been undertaken. By studying how these distantly related plants - which split from their common ancestor roughly 400 million years ago - respond to pathogen infections, the research team discovered a suite of microbe-responsive gene families that date back to early land plant evolution.

Our current understanding of how plants successfully defend against disease-causing pathogens mainly originates from studying economically important crop plants and a small number of closely-related flowering plant model systems. Very distantly-related plants, such as non-flowering liverworts that are believed to resemble some of the first land plants, are often overlooked. As a result, not much was known about how these plants defend themselves from pathogens or how plant defence strategies have evolved.

Published in Current Biology today, the identification of these evolutionarily conserved genes is shedding new light on the strategies that were likely critical for the expansion of plants onto land.

"We have shown that molecular responses to pathogen infection typical of modern flowering plants are common to very distantly-related land plants and may therefore be more ancient than we previously thought," says Dr Sebastian Schornack, who led the research team that undertook the study. "Despite fluctuating environmental pressures over a broad evolutionary timescale, these conserved genes have retained their capacity to confer pathogen protection in plants, including in important agricultural crops."

Bioinformatics expert, Dr Anna Gogleva, identified a subset of one-to-one corresponding genes (single-copy orthologs) in the liverwort and wild tobacco and analysed their level of activity during the infection. A number of different genes were activated in both plants, but a set of metabolic genes involved in phenylpropanoid (flavonoid) biosynthesis were highly activated in response to infection.

These gene families are often associated with the stress-response in flowering plants, providing increased protection against biotic or abiotic stresses caused by chewing insects, pathogens and nutrient or light stress. However, this was the first time that these genes had been functionally linked to pathogen defence strategies in liverworts.

"Pathogen zoospores germinate on the surface of liverworts and eventually colonise the liverwort tissues, but in some areas we saw an accumulation of a purple/red pigment in the liverwort tissues where the pathogen was rarely detected," says Dr Philip Carella, lead author of the study.

"We produced liverwort plants with mosaic pigment patterns - resembling military camouflage fatigues - that allowed us to compare pathogen resistance in pigmented and non-pigmented areas of the same plant and found the pigment provided some resistance to pathogen infection."

The enormous diversity of traits and species that we see in modern plants today speaks to the millions of years of evolution that enabled plants to survive in dynamic and contrasting environments across the globe.

"The conflict between organisms can be a very powerful selective pressure that guides their evolutionary trajectory," says Dr Schornack. "Genes involved in fighting specific pathogens can evolve rapidly - both in plants and animals. But we have also now found these broadly-conserved genes responding to pathogen infection in very distantly-related plants, which suggests that land plants have retained a likely ancient pathogen deterrence strategy that is much too useful to lose.

"Fossil evidence shows that plants have engaged in close-interactions with microbial life forms throughout their evolutionary history. Our research has uncovered a common set of pathogen-responsive genes shared in early-divergent land plants and more evolutionarily young flowering plants, which are all likely to have been critical for the expansion of plants onto land. Further comparative studies focusing on other distantly related land plants and their aquatic algal predecessors should reveal even more information about the evolution and role of these vital gene families."

Botanist Dr. Clement Coiffard of the Museum für Naturkunde Berlin discovered the oldest, completely preserved lily in the research collection: Cratolirion bognerianum was found in calcareous sediments of a former freshwater lake in Crato in northeastern Brazil. With an age of about 115 million years, Cratolirion is one of the oldest known monocotyledonous plants. These include orchids, sweet grasses, lilies and lilies of the valley.

Cratolirion is extraordinarily well preserved, with all roots, the flower and even the individual cells are fossilised. With a length of almost 40 centimetres, the specimen is not only extremely huge, but also shows almost all the typical characteristics of monocotyledonous plants, including parallel-veined, narrow leaves with a leaf sheath, a fibrous root system and triple flowers.

However, it was not trivial to examine the fossilised object, as it consisted of iron oxides associated with the stone. In order to see details here, Coiffard collaborated with the HZB physicist Dr. Nikolay Kardjilov, who is an expert in 3D analysis with X-rays and neutrons. At the HZB he also built up a 3D computed x-ray tomography and refined the data analysis in such a way that hardly any disturbing artefacts arise during the investigation of large, flat objects. This made it possible to analyse the details of the inflorescence hidden in the stone. A colour coding in the CT scan makes these details visible: the main axis is marked in turquoise, the supporting leaves in dark green, the pistils in light green and the remains of the actual petals can still be seen in orange.

Many early dicotyledonous flowering plants have already been described from the same sediments of the former freshwater lake in Crato. These include water lilies, aron rods, drought-resistant magnolias and relatives of pepper and laurel. In contrast to other flowering plants of the same age from the USA, Portugal, China and Argentina, the flowering plants of the Crato-Flora are unusually diverse. This could be due to the fact that Lake Crato was in the lower latitudes, but all other fossils of early flowering plants come from the middle latitudes.

From this newly described plant Cratolirion bognerianum and the species of Crato flora mentioned above, it can be deduced that the tropical flowering plants were already very diverse. "It is probable that flowering plants originated in the tropics, but only very few fossils have been described to date," explains Coiffard. This study thus provides new insights into the role of the tropics in the development of early flowering plants and their rise to global supremacy.

Sequencing a genome is getting cheaper, but making sense of the resulting data remains hard. Researchers have now found a new way to extract useful information out of sequenced DNA.

By cataloging subtle evolutionary signatures shared between pairs of genes in bacteria, the team was able to discover hundreds of previously unknown protein interactions. This method is now being applied to the human genome, and could produce new insights into how human proteins interact.

The project is a collaboration between scientists at the University of Washington School of Medicine and Harvard University. Their report appears in the July 11 issue of Science.

"Protein-protein interactions are fundamental to biological function. It's remarkable that they can now be predicted en masse using the large amounts of genomic sequence data that have been generated in recent years," said senior author David Baker, professor of biochemistry at the University of Washington School of Medicine.

Cells are packed with proteins, many of which must physically interact in order to function. This can mean coming together to copy DNA or to form long fibers like those found in muscle. In many cases, however, scientists still do not know which proteins interact. Discovering new pairings can be slow, laborious, and costly.

Looking for a better way, a team of four computational biologists studied a phenomenon called co-evolution, wherein changes in one gene are associated with changes in another. This can indicate that two genes are linked in some important way.

For example, if one gene mutates to produce a protein with an altered shape, a second may evolve to produce a protein with a shape complementary to the first, thereby preserving the ability of the two proteins to interact.

In recent years, researchers have found evidence for some of these subtle molecular interactions in an organism's DNA.

"Co-evolution has been useful for understanding how specific proteins interact, but we can now use it as a tool for discovery," said lead author Qian Cong, a postdoctoral fellow at the UW School of Medicine.

The research team compared more than 4,000 genes from E. coli to DNA sequences from more than 40,000 other bacterial genomes. This large stockpile of genetic information allowed the researchers to use a bespoke statistical model to assess co-evolution between each E. coli gene.

After several rounds of analysis, 1,618 pairs were found to have the strongest evidence of co-evolution. By comparing their results to a small set of already characterized protein-protein interactions, the researchers achieved considerably higher accuracy than previous experimental screening methods.

Among the newly discovered interactions were a few that hint at new biological insights. One of these, an interaction between a protein toxin and its antitoxin, may help explain, the researchers speculate, why some E. coli dominate their microbial niche. Another newfound pairing suggests that a protein called PstB, which was known to play a role in metabolism, may also help coordinate protein synthesis and mineral transport.

"It is rare in biology for a software tool to make predictions that are promising enough to test, but that is exactly what's happening here," said Cong. There are literally hundreds of follow-up experiments that could be performed in labs around the world."

The team also scoured the genome of Mycobacterium tuberculosis, a disease bacterium distantly related to E. coli. They identified 911 protein-protein interactions with high confidence. 95 percent of these had never been previously described. Seventy involve proteins that may contribute to the virulence of M. tuberculosis, the researchers report. These findings may open new routes to develop drugs against the deadly pathogen.

"We are going to apply this tool to more pathogens, and the human genome," says Cong. "Our success will depend on how much work other scientists put into annotating which parts of the genome are genes and which parts are something else."