Culture

MINNEAPOLIS, MN- November 14, 2019 - New research suggests that during decision-making, neurons in the brain are capable of much more complex processing than previously thought.

In a study published in eLIFE, researchers, including first author Aaron Kerlin, PhD, who is an assistant professor in the Department of Neuroscience and member of the Medical Discovery Team on Optical Imaging and Brain Science at the University of Minnesota Medical School, were the first to develop a microscope that rapidly images large stretches of the dendrite where neurons receive thousands of inputs from other neurons.

Dr. Kerlin conducted this research while at Janelia Research Campus and found that neighboring inputs to small sections of dendrite tended to represent similar information about upcoming actions.

The results show that during decision-making, there are a multitude of small sections of dendrite throughout each neuron that process information before it is sent to other neurons. This suggests that much more complex processing can occur in the brain through these many, tiny segments of dendrite.

Not only do these findings help researchers understand what the total computational power of the brain might be but they also may help to better understand some diseases. In many cognitive disorders, including autism, it is known that disruption of proteins related to the function of synapses--the connections between neurons--is likely to be involved. It is also likely that there are disruptions of these local computations, which have been difficult to investigate before.

"Now that we have these findings and approaches, we may gain a better understanding of what's happening in diseases that affect synaptic function and why they affect information processing in the way they do," Dr. Kerlin said.

Dr. Kerlin believes that future research may include investigating patterns of local processing in neurons within mouse models of autism to determine which dendritic computations are disrupted and over what scale the disruptions occur.

Dr. Kerlin also created a web browser that allows the entire dataset to be publicly available to other researchers, which is part of his dedication to advancing the Open Science movement. He hopes that this will encourage theorists and other researchers to make new discoveries with this rich dataset and embark on further research within this field.

November 14, 2019 -- A new study at Columbia University Mailman School of Public Health found a consistent association between the adoption of state Prescription Drug Monitoring programs (PDMP) and death rates from heroin poisoning. However, the research showed that rates vary by program type. States with Proactive Prescription Drug Monitoring programs, which are more likely to report outlying prescribing and dispensing and provide broader access to law enforcement, reported a 6 percent reduction in heroin poisoning mortality by the program's third year. Findings are published online in the International Journal of Drug Policy.

PDMPs are state-level databases of information collected on controlled prescription medications dispensed in a particular state. As of December 2017, all U.S. states except Missouri had an operational monitoring program. Heroin poisonings in the United States have increased nearly 5-fold from 2010 to 2017.

Researchers from Columbia, NYU Langone Health, and UC Davis studied these programs for the years 2002 to 2016 and classified them into latent classes (Cooperative, Proactive, and Weak) for each state and year, across three time intervals (1999-2004, 2005-2009, 2010-2016). The researchers then examined associations between the probability of PDMP latent class membership and the rate of county-level heroin poisoning death.

The data showed that states with Cooperative prescription drug monitoring reported 19 percent higher heroin poisoning rates compared to states with Weak PDMPs. Cooperative PDMPs share data with other states, include more drug schedules and require more frequent reporting.

"On the one hand, our findings raise questions about the potential for certain types of drug monitoring programs to support efforts to decrease heroin overdose risk, on the other hand, there are types of PDMPs associated with a decrease in heroin poisoning mortality," said Silvia Martins, MD, PhD, associate professor of epidemiology and director of PHIOS (Policies and Health Initiatives on Opioids and Other Substances) at Columbia Mailman School, and the study's lead author.

Another finding showed there is a consistent, positive association between state electronic PDMP adoption and heroin poisoning mortality. By the third year of implementation there was a 22 percent increase in heroin poisoning rates.

"It's pretty striking that this is the second study where we have found that PDMPs with robust features such as sending unsolicited alerts about outlying prescribing and dispensing patterns to PDMP users, and providing more open access to PDMP data, are associated with a small decline in opioid overdose deaths," noted Magdalena Cerdá, DrPH, associate professor and director of the Center for Opioid Epidemiology and Policy at NYU Langone Health, and the study's senior author. "In our prior study we found that these types of PDMPs were associated with a decline in prescription opioid overdose deaths, and this new study suggests Proactive PDMPs may also have a downstream protective effect on heroin overdose risk."

"While colleagues have studied PDMPs, none of the prior research examined specific characteristics of PDMP programs in the level of detail that we examined in our study, and most did not take into account variation across time and across states," noted Martins. "To the best of our knowledge, this study is the first to identify specific classes of PDMP characteristics that are most strongly associated with changes in rates of fatal heroin poisonings. We believe those authorized to access the data should be trained to protect individual privacy and confidentiality and ensure that it is used only to improve care for the patient."

Martins projects that monitoring programs which provide feedback about potentially problematic dispensing and prescribing practices may help change inappropriate prescribing and help to better identify patients in need of treatment for opioid use disorder, thus decreasing the potential probability of transition from prescription opioid into heroin use.

In a surprising finding using the standard animal model of Down syndrome (DS), scientists were able to correct the learning and memory deficits associated with the condition -- the leading genetic cause of cognitive disability and the most frequently diagnosed chromosomal disorder in the U.S. -- with drugs that target the body's response to cellular stresses.

In a study published Nov. 14, 2019 in the journal Science, a team led by researchers at UC San Francisco and Baylor College of Medicine show that some of the intellectual impairments associated with DS may be traced to altered protein production in a region of the brain called the hippocampus, which is central to learning and long-term memory formation.

But in the so-called Ts65Dn mouse, engineered to capture genetic, behavioral, and cognitive features of human Down syndrome, these changes can be undone. When the researchers administered drugs that target one of the cell's key stress response pathways, they were able to bring protein levels back to normal, which caused the cognitive deficits typical of the Ts65Dn mouse to vanish.

Although the cognitive features of DS have generally been thought of as irreversible, the researchers say, these findings indicate that it may be possible to improve cognitive function in human DS using similar compounds.

A New Approach for Studying Down Syndrome

Because DS is caused by an extra copy of chromosome 21, scientists have generally studied the disease through the lens of genetics, focusing primarily on ways in which the superfluous chromosome disrupts normal gene activity. But in the new study, rather than restricting their efforts to genes and chromosomes, the scientists trained their sights on the largely unexplored role of "proteostasis" -- a technical term for the cell's protein manufacturing and quality control machinery -- in DS.

"The vast majority of the field has been focusing on individual genes on chromosome 21 to figure out which ones are causally related to Down syndrome and its pathologies. Our approach was different. We were trying to uncover a link between proteostasis defects and DS," said Peter Walter, PhD, professor of biochemistry and biophysics at UCSF and co-senior author of the new study.

Walter spearheaded the new study with collaborator Mauro Costa-Mattioli, PhD, a professor of neuroscience at Baylor College of Medicine who is currently a visiting professor in Walter's lab thanks to a UCSF Presidential Chair Award.

To identify proteostasis problems that might contribute to DS, the researchers turned to a common mouse model that captures most of the chromosomal, developmental and cognitive abnormalities that define the human version of the syndrome.

Using polysome profiling, a technique that allows scientists to take a detailed snapshot of the cell's protein factories in action, the researchers found that up to 39 percent less protein was being produced in the hippocampus of DS mice, prompting them to ask why extra copies of genes could lead to a decline in protein production.

Stress Response to Blame for Cognitive Impairments Seen in Down Syndrome

The researchers discovered that hippocampal cells in DS mice had activated what's known as the integrated stress response (ISR), a biological circuit that detects when something's awry -- the presence of an extra chromosome, for example, in the case of DS -- and engages a protective response that activates machinery to tamp down protein production.

"The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation," said Walter.

Backing up these results, the scientists also found that the ISR was also activated in postmortem samples of brain tissue from people with DS. And by a stroke of pure luck, the researchers were able to obtain a tissue sample from a person with DS in whom some cells carried the expected third copy of chromosome 21, while others were genetically normal -- the ISR, however, was only active in the cells with the extra chromosome.

Taken together, these findings strongly suggest that the ISR is involved in, and perhaps even responsible for, certain DS symptoms.

Though the ISR can be activated by four different enzymes, the scientists found that only one of them, named PKR, was involved in activating the ISR in hippocampal cells in DS. By blocking the activity of PKR they were able to prevent ISR activation and reverse the declines in protein production that had been observed in the brains of DS mice. But even more impressive, the researchers found that blocking the ISR significantly improved cognitive function in these mice as well.

Blocking the Stress Response Improves Memory and Learning

The researchers used three different approaches to dial down ISR activity -- deleting the PKR gene, using a drug that suppresses PKR activity, and finally, using a safe, well-studied drug called ISRIB that activates protein-manufacturing machinery that competes directly with the ISR's efforts to shut off protein production. All three approaches yielded a marked improvement in cognition, as demonstrated by two different memory and learning tests.

Importantly, these changes were physiological as well as behavioral. DS mice that were given ISR inhibitors showed improved function at synapses, sites between nerve cells where changes associated with learning take place. In fact, after ISR activity was blocked, the brains of DS mice were transmitting fewer of the inhibitory signals that can make it harder for the brain to learn and form new long-term memories.

Though the results of the study were extremely promising, Walter cautions that much more in this area remains to be studied. Still, the findings are an important first step towards finding therapies that could improve the lives and overall health of people living with DS, a condition that has generally been considered untreatable.

"We started with a situation that looked hopeless," Walter said. "Nobody thought anything could be done. But we may have struck gold."

Findings from a new study led by researchers at Dartmouth's Geisel School of Medicine and Harvard Medical School and published in the journal Circulation: Cardiovascular Quality and Outcomes, show that the way in which pharmaceutical companies are permitted to share information about their drugs can influence physician prescribing practices.

In an effort to ensure safety and efficacy of new medications, the Food and Drug Administration (FDA) has, historically, only allowed manufacturers to promote their drugs for approved uses. But a few recent court rulings at the federal level have created some exceptions to that rule.

In one case, the pharmaceutical company Amarin won a decision which allowed it to promote its prescription fish oil Vascepa? to physicians as an effective add-on therapy to a statin for certain heart patients, even though no clinical benefit had been demonstrated at that time (in reducing patients' cardiovascular risk).

"Using the Vascepa? case as a model, we conducted a national randomized survey with cardiologists, internists, and endocrinologists to assess how providing different forms of information about a drug would affect their beliefs about its efficacy," explains lead author Steven Woloshin, MD, MS, a general internist and a professor of medicine, community and family medicine, and of The Dartmouth Institute for Health Policy and Clinical Practice.

In the study, the researchers sent the physicians one of three information scenarios about a hypothetical prescription fish oil product (based on Vascepa?), asking them if they felt it would lower patients' cardiovascular risk and if they would prescribe it.

The first scenario described the drug as FDA-approved to reduce very high triglyceride levels. The second scenario included an off-label (non-FDA approved) claim about reducing heart attack risk for patients with high triglyceride levels, despite taking a statin, along with disclaimers stating that the drug was not approved by the FDA for this purpose and that relevant evidence was "supportive but not conclusive."

The third scenario included the off-label claim and disclaimers, but also included more extensive context, explaining that three clinical trials testing the effect of adding other drugs to statins to reduce high triglyceride levels did not show additional cardiovascular benefit.

The investigators found that standard disclaimers hardly changed perceptions about the hypothetical fish oil product, but that presenting more extensive context improved physician knowledge about the drug while reducing their enthusiasm for prescribing it. The proportion of physicians who endorsed the unproven, off-label claim that the drug reduced cardiovascular risk was similar for those randomized to the first two scenarios (35 percent versus 37 percent), but significantly lower among those randomized to the third scenario (21 percent).

The researchers also found that physicians who had received company-sponsored information about the off-label use of Vascepa? were more likely to report prescribing it as an off-label medication than those who did not (38 percent versus 7 percent).

Despite major concerns from physicians and the FDA, more off-label drug promotion may continue to expand due to actions by courts or legislatures.

"If it does, our study highlights the need for FDA to develop guidelines for creating evidence context, and the importance of allowing it to exert authority over the language and format used to ensure that the statements are explicit, clear, and prominently displayed," says Woloshin. "Otherwise, the victory of commercial speech will come at the expense of public health."

PHILADELPHIA - When we exercise, our muscles can become fatigued, sore and even damaged with very strenuous activities, like running a marathon. Over time our muscles are able to repair themselves through a complex set of cellular processes within each muscle fiber. New research from the MitoCare Center at Thomas Jefferson University, in collaboration with the Center for Genetic Medicine Research at Children's National Health System in Washington D.C., has identified how MICU1, a protein in the mitochondria, the "powerhouses" of all cells, is critical in the maintenance of muscle size and function, and the repair of damaged muscle fibers. The findings point to a potential role of MICU1 in neuromuscular diseases. The study was published in Cell Reports on October 29th.

The contraction and relaxation of our muscles is dependent on the proper balance of calcium ions inside each muscle fiber. Some of this calcium is taken up by mitochondria, where it is used to boost metabolism and produce energy. The protein MICU1 acts as a master regulator of calcium uptake into the mitochondria.

"Control of calcium transport by MICU1 helps to coordinate muscle fibers and their mitochondria," says György Hajnóczky, MD, PhD. "Disruption of this link prevents the proper communication between mitochondria and the rest of the muscle, making the muscle easier to damage and unable to exert as much force."

In fact, 50-60 patients without MICU1 have been identified and exhibit neuromuscular symptoms, such as muscle fatigue and weakness. There is an array of neuromuscular and neurodegenerative conditions like muscular dystrophy where calcium dysregulation in mitochondria may be a key player. The underlying mechanisms are unknown.

To tackle this problem, a multicenter collaboration was set up among the groups of Erin Seifert and György Hajn?czky at the MitoCare Center, Jyoti Jaiswal in Washington D.C. and Rita Horvath from the Wellcome Centre for Mitochondrial Research at Newcastle University in Newcastle-Upon-Tyne, UK. First author Valentina Debattisti, a post-doctoral fellow at MitoCare, and her colleagues created a mouse model in which MICU1 is specifically missing in skeletal muscles. They also harvested muscle fibroblasts from patients born without MICU1. This is a novel combined approach that allowed for the study of specific effects of MICU1 deletion in the muscle.

The researchers found that in both the mouse model and patient fibroblasts, loss of MICU1 changes the threshold at which mitochondria takes up calcium, meaning the mitochondria cannot sense the correct level at which to take up calcium. This leads to an imbalance in surrounding levels of calcium in the muscle fiber, preventing its proper function. They found that the muscle fibers produced less contractile force when stimulated, and mice in which MICU1 is deleted show increased fatigue upon exercise and more muscle atrophy, mirroring the symptoms seen in humans without MICU1.

They decided to dig deeper into the possible causes of fatigue and atrophy and honed in on muscle repair. The researchers provoked muscle damage in mice by having them run on a downhill treadmill, which is more strenuous than a running wheel. They then injected a dye that is able to permeate the muscle membrane; the less repair there is, the more dye is present. The researchers found that MICU1-deficient mice had more dye in the muscle, indicating that their ability to undergo muscle membrane repair was compromised. The same was observed in patient fibroblasts, in which they induced damage using a laser. Importantly, when they added MICU1 back to the fibroblasts, the muscle fibers were able to repair themselves.

"This means that mitochondrial calcium uptake is important for normal repair of muscle, and this was not known before," says co-author Dr. Seifert, assistant professor in the department of pathology, anatomy & cell biology and also part of the MitoCare Center. "So boosting this control mechanism could potentially aid in muscle recovery after exercise, especially if the control mechanism is compromised."

The findings demonstrate a new role for MICU1 in muscle function and establish a direct link between MICU1 and impairments found in neuromuscular diseases, positioning MICU1 as a potential therapeutic target.

"There are so many patients who experience more than normal fatigue when they exercise, which can be debilitating," says Dr. Hajnóczky. "In many cases it can stem from a mitochondrial disease where calcium transport is disrupted. These patients, as well as those who have other neuromuscular diseases might benefit from a better understanding of MICU1."

As an alternative to the depletion of fossil resources, the reduction of CO2 emitted from fossil fuel combustion into valuable chemicals and fuel has drawn increasing attention. Due to the highly thermodynamic stability of CO2, it is still very challenging to find a sustainable and cost-efficient route to selectively convert inert CO2 at a high conversion rate under mild conditions.
The water could also be a significant factor governing the reaction mechanism. On the one hand, water is one product accompanied with CH3OH. H2O might trigger the autocatalysis to accelerate CO2 activation and methanol production. On the other hand, Cu is also a highly active catalyst for water-gas shift (WGS) reaction and its reverse reaction (RWGS). The water is also possible to launch or to suppress the side reaction, which could influence the selectivity.

Very recently, Dr. Cao and Prof. P. Hu's group at East China University of Technology systematically analyzed the effect of surface water on each elementary step to disclose its role in CO2 hydrogenation over the stepped Cu(211) surface. The influence of water on CO2 hydrogenation was respectively discussed at the levels of the electronic structure, energy and kinetics. The mechanisms between in the absence and presence of water were quantitatively compared based on microkinetic simulation upon density functional theory (DFT) calculations.

It has been found that the autocatalysis of water could be in favor of the formation of COOH intermediate through the proton transfer. This accelerates the CO generation while does not improve the methanol synthesis, giving rise to the higher CO2 conversion and the selectivity towards CO. In addition, the microkinetic analysis also sheds light on the fact that the too high initial partial pressure of water will thermodynamically inhibit the CO2 conversion due to the too high coverage of OH*. Hence, it is the first time to disclose how to modulate the activity and selectivity of CO2 hydrogenation through changing the H2O pressure.

Electrochromic films that display reversible spectral and color changes in response to electric or electrochemical stimulus are highly useful in a wide range of applications, such as smart windows, electronic displays, dynamic camouflage, and information storage. For practical applications, electrochromism with low operation voltage, high contrast ratio (in general no less than 30%), short response time (a few seconds or less), and excellent cyclic stability (at least over 1000 cycles) is required.

Compared to common materials and films showing electrochromism in the visible region, one challenging topic in this field is the realization of high-performance electrochromism in the near-infrared (NIR) region.

In recent years, Professor Yu-Wu Zhong's group at the Institute of Chemistry, Chinese Academy of Sciences, have prepared thin films of organometallic ruthenium complexes by electropolymerization or self-assembly (1-3). These films displayed NIR electrochromism with moderate contrast ratios at different NIR wavelength. In addition, the film preparation and cyclic stability of these films need to be further improved.

Currently (4), stimulated by the dye adsorption method commonly used in the fabrication of dye-sensitized solar cells, they prepared multilayer films of bridged diruthenium complexes by layer-by-layer (LBL) coordination assembly on metal oxide substrate and realized high-performance NIR electrochromism at 1150 nm (Figure 1).
A cyclometalated diruthenium complex with carboxylic acid groups on both terminal ligands has been prepared. The multilayer films of complex were prepared by the LBL coordinative deposition with Zr(IV)

ions on TiO2 or SnO2 substrates. The dye adsorption method is rather simple and high dye loading could be easily achieved by one-pot adsorption on metal oxides with high surface area, which is important for the efficient modulation of the contrast ratio of electrochromism.

These films display two reversible redox waves and electrochromism in the NIR region. In particular, the double-layered film on SnO2:Sb shows appealing electrochromic performance with a contrast ratio of 56% at 1150 nm, response time of a few seconds, and good cyclic stability being achieved. The higher electron conductivity and lower conduction band of SnO2:Sb with respect to TiO2 is believed beneficial to improve the electrochromic performance of the LBL films.

This work also demonstrates the capability of LBL films in realizing high-performance electrochromism and that the electrochromic performance could be regulated by the deposition cycles and the coordination LBL films on suitable substrates.

Two pathways diverged in a chemical synthesis, and one molecule took them both. Chemists at the University of Tokyo have studied how molecular building blocks can either form a spherical cage or an ultrathin sheet that shows some of the basic properties of a "smart" material that can respond to its environment.

"This molecule is interesting because it builds different structures depending on the conditions when it reaches the bifurcation point of its synthesis," said Professor Shuichi Hiraoka from the Department of Basic Science. Hiraoka's research interests are about how molecules put themselves together, including DNA in living cells or micelles, found in both nature and the cosmetics industry.

The bifurcation point is a "fork in the road" of the chemical synthesis pathway where the same precursor molecules can connect in two different ways to eventually form different final structures. In the present reaction, the precursors take different paths depending on the presence or absence of a third molecule.

The precursor molecules are palladium metal atoms and an organic molecule -- 1,4-bis(3-pyridyloxy)benzene -- made from three rings that can easily swing between an S-shape and C-shape orientation.

The third molecule whose presence or absence influences which path the precursors take is a negatively charged anion molecule (either nitrate or triflate).

In the presence of the anion, the organic molecule takes the C-shape and one at a time, four of those C's link together into two O-rings, locking the anion in a spherical cage. Two palladium atoms latch the four C's together at the top and bottom of the cage.

If the anion is absent, the organic molecule swings into the S-shape and connects together with other S-shaped molecules using the palladium atoms as links. Eventually, they form flat sheets about 4 nanometers thick and up to 5 micrometers in diameter.

However, when researchers add the anion to the completed sheet, the molecules will slowly rearrange themselves into the cage formation.

"The sheet is demonstrating some very primitive qualities of a so-called smart material -- one that can sense and respond to its environment. This shift from the micrometer-sized sheets to the nanometer-sized cages is a very dramatic structural change," said Hiraoka.

The research team hopes that their work to understand the fundamental chemical properties of these molecules will lead to the possibility of designing molecules that can self-assemble and independently reorganize depending on environmental conditions.

Paths depend on thermodynamics and kinetics

The sheet and cage formations are more chemically stable in different ways. The cage formation is more thermodynamically stable, meaning it would require energy to move out of that formation. The sheet is more kinetically stable than the cage, meaning the molecules are slow to change position. Researchers are excited to have developed an artificial system that contains the complexities of these different stabilities.

"Complicated natural self-assembly reactions in living systems often have kinetic control," explains Hiraoka.

Proteins in living organisms are usually kinetically trapped to stay in their healthy formations even though it would be more thermodynamically stable to aggregate into useless clumps.

In the artificial system that Hiraoka's research team studied, when the precursor molecules form cages, the molecules stay in that final position because it is the lowest thermodynamic energy arrangement.

"The reaction in the early stage to form the cage is very fast, which tells us that the anion is acting as a kinetic template for the precursors to form the cage," said Hiraoka.

However, the reaction to form the sheet proceeds more slowly and researchers say that the molecules become kinetically trapped in the sheet formation without the presence of the anion to provide a template that pulls them into the cage formation.

Researchers plan to continue studying how the self-assembly pathway is controlled and how to manipulate the influence of the kinetic effect and thermodynamic stability.

The direction in which a galaxy spins depends on its mass, researchers have found.

A team of astrophysicists analysed 1418 galaxies and found that small ones are likely to spin on a different axis to large ones. The rotation was measured in relation to each galaxy's closest "cosmic filament" - the largest structures in the universe.

Filaments are massive thread-like formations, comprising huge amounts of matter - including galaxies, gas and, modelling implies, dark matter. They can be 500 million light years long but just 20 million light years wide. At their largest scale, the filaments divide the universe into a vast gravitationally linked lattice interspersed with enormous dark matter voids.

"It's worth noticing that the spine of cosmic filaments is pretty much the highway of galactic migration, with many galaxies encountering and merging along the way," says lead researcher Charlotte Welker, an ASTRO 3D researcher working initially at the International Centre for Radio Astronomy Research (ICRAR) and now at McMaster University in Canada.

ASTRO 3D is the ARC Centre of Excellence in All Sky Astrophysics, based in Australia.

The filaments are why the universe looks a little like a honeycomb, or a cosmic Aero chocolate bar.

Using data gathered by an instrument called the Sydney-AAO Multi-object Integral-field spectrograph (SAMI) at Australia's Anglo-Australian Telescope (AAT), Dr Welker, second author and ASTRO 3D principal investigator Professor Joss Bland-Hawthorn from the University of Sydney, and colleagues from Australia, the US, France and Korea studied each of the target galaxies and measured its spin in relation to its nearest filament.

They found that smaller ones tended to rotate in direct alignment to the filaments, while larger ones turned at right angles. The alignment changes from the first to the second as galaxies, drawn by gravity towards the spine of a filament, collide and merge with others, thus gaining mass.

It is a phenomenon that Dr Welker likens to roller-skating in the company of a friend.

"The flip can be sudden," she says. "Merging with another galaxy can be all it takes.

"Imagine you are skating after a friend and catching up. If you grab your friend's hand while you are still moving faster, you will both start rotating on a vertical axis - a spin perpendicular to your horizontal path.

"However, if a small cat - a much lighter bit of matter - runs after your friend and jumps on her she probably won't start spinning. It would take a lot of cats leaping on her at once to change her rotation."

Co-author Scott Croom from the University of Sydney, also an ASTRO 3D principal investigator, says the result offers insight into the deep structure of the Universe.

"Virtually all galaxies rotate, and this rotation is fundamental to how galaxies form," he says.

"For example, most galaxies are in flat rotating disks, like our Milky Way. Our result is helping us to understand how that galactic rotation builds up across cosmic time."

He adds that a new instrument, called Hector, set to be installed at the Anglo Australian Telescope next year, will enable a significant expansion of research in the field.

"Hector will be able to carry out surveys five times larger than SAMI," he says. "With this we will be able to dig into the details of this spin alignment to better understand the physics behind it."

The Milky Way, by the way, has a spin well aligned with its nearest cosmic filament, but belongs to a class of intermediate size galaxies that, over all, show no clear tendency towards parallel or perpendicular spins.

"It's like saying that there is no preference for tea or coffee among a group of people," says Dr Welker. "Individuals may still prefer either tea or coffee, but overall there is no general tendency towards coffee in the group."

Fossil animal droppings, charcoal from ancient fires and bone fragments litter the ground of one of the world's most important human evolution sites, new research reveals.

The latest evidence from southern Siberia shows that large cave-dwelling carnivores once dominated the landscape, competing for more than 300,000 years with ancient tribes for prime space in cave shelters.

A team of Russian and Australian scientists have used modern geoarchaeological techniques to unearth new details of day-to-day life in the famous Denisova Cave complex in Siberia's Altai Mountains.

Large carnivores such hyena, wolves and even bears and at least three early nomadic human groups (hominins) - Denisovans, Neanderthals, and early Homo sapiens - used this famous archaeological site, the researchers say in a new Scientific Reports study examining the dirt deposited in the cave complex over thousands of years.

"These hominin groups and large carnivores such as hyenas and wolves left a wealth of microscopic traces that illuminate the use of the cave over the last three glacial-interglacial cycles," says lead author, Flinders University ARC Future Fellow Dr Mike Morley.

"Our results complement previous work by some of our colleagues at the site that has identified ancient DNA in the same dirt, belonging to Neanderthals and a previously unknown human group, the Denisovans, as well as a wide range of other animals".

But it now seems that it was the animals that mostly ruled the cave space back then.

Microscopic studies of 3-4 metres of sediment left in the cave network includes fossil droppings left by predatory animals such as cave hyenas, wolves and possibly bears, many of their kind made immortal in ancient rock art before going extinct across much of Eurasia.

From their 'micromorphology' examination of the dirt found in Denisova Cave, the team discovered clues about the use of the cave, including fire-use by ancient humans and the presence of other animals.

The study of intact sediment blocks collected from the cave has yielded information not evident to the naked eye or gleaned from previous studies of ancient DNA, stone tools or animal and plant remains.

Co-author of the new research, University of Wollongong Distinguished Professor Richard (Bert) Roberts, says the study is very significant because it shows how much can be achieved by sifting through sedimentary material using advanced microscopy and other archaeological science methods to find critical new evidence about human and non-human life on Earth.

"Using microscopic analyses, our latest study shows sporadic hominin visits, illustrated by traces of the use of fire such as miniscule fragments, but with continuous use of the site by cave-dwelling carnivores such as hyenas and wolves," says Professor Roberts.

"Fossil droppings (coprolites) indicate the persistent presence of non-human cave dwellers, which are very unlikely to have co-habited with humans using the cave for shelter."

This implies that ancient groups probably came and went for short-lived episodes, and at all other times the cave was occupied by these large predators.

The Siberian site came to prominence more than a decade ago with the discovery of the fossil remains of a previously unknown human group, dubbed the Denisovans after the local name for the cave.

In a surprising twist, the recent discovery of a bone fragment in the cave sediments showed that a teenage girl was born of a Neanderthal mother and Denisovan father more than 90,000 years ago.

Denisovans and Neanderthals inhabited parts of Eurasia until perhaps 50,000 to 40,000 years ago, when they were replaced by modern humans (Homo sapiens).

Study Highlights:

A simple test of walking speed may be a reliable tool to evaluate whether young stroke survivors are ready to return to work.

Walking faster than 3 feet per second predicted a stroke survivor's likelihood of returning to work.

DALLAS, Sept. 26, 2019 -- A simple walking speed test may help predict whether young adult stroke survivors are ready to return to work, according to new research published in Stroke, a journal of the American Stroke Association, a division of the American Heart Association.

Today, one of every four people who have a stroke is under the age of 65, and up to 44% of those may not be able to return to work, mostly due to challenges they experience with walking.

"Stroke affects motor control and motor function. To return to work, you must be able to walk to your car, bus, office and meeting rooms. If you can't walk or you get tired easily, your ability to do your job is going to be seriously impacted," said Hannah Jarvis, Ph.D., lead study author and research associate at Manchester Metropolitan University in Manchester, United Kingdom.

Researchers analyzed the relationship between walking speed and readiness to return to work after stroke. They compared mobility in 46 stroke survivors from Wales, U.K. - between the ages of 18 and 65 - to 15 people who had not had a stroke. Using a walking test, researchers measured how fast and far participants walked in three minutes. A benchmark measure was calculated that predicted readiness to return to work. They found:

A walking speed of more than 3 feet per second was a critical threshold. Stroke survivors walking slower than this were significantly less likely to return to work.

Of the 23% who returned to work, 90% walked faster than the critical threshold. Those who returned to work walked almost 6 feet per second, compared to those who didn't go back to work and only covered about two and a half feet per second.

Young stroke survivors were less efficient at walking (known as metabolic cost of walking) than their healthy counterparts. This means that walking at a similar pace requires more effort and results in becoming tired more easily.

"There was a huge range in outcomes in our stroke population, highlighting the fact that some people recover quickly and can return to work, while others are so severely affected that they cannot go back to work," Jarvis said.

"Walking speed is a really useful tool for clinicians to use to predict return to work. It's simple, low cost and effective. In addition, clinicians can use this measure to guide their patients during rehabilitation. For example, they can focus on increasing walking speed and maintaining quality of walking in order to give their patients a chance of going back to work," Jarvis added.

According to the American Stroke Association, someone in the U.S. has a stroke every 40 seconds on average, and 5.2 million first strokes (31%) are in those younger than 65.

Scientists have confirmed for the first time that bacteria can change form to avoid being detected by antibiotics in the human body.

Studying samples from elderly patients with recurring urinary tract infections, the Newcastle University team used state-of-the art techniques to identify that a bacteria can lose its cell wall - the common target of many groups of antibiotics.

The research by the Errington lab which turns on its head current thinking about the bacteria's ability to survive without a cell wall, known as "L-form switching", is published today in Nature Communications.

The World Health Organisation has identified antibiotic resistance as one of the biggest threats to global health, food security, and development today.

Lead author, Dr Katarzyna Mickiewicz researcher at Newcastle University said: "Imagine that the wall is like the bacteria wearing a high-vis jacket. This gives them a regular shape (for example a rod or a sphere), making them strong and protecting them but also makes them highly visible - particularly to human immune system and antibiotics like penicillin.

"What we have seen is that in the presence of antibiotics, the bacteria are able to change from a highly regular walled form to a completely random, cell wall-deficient L-form state- in effect, shedding the yellow jacket and hiding it inside themselves.

"In this form the body can't easily recognise the bacteria so doesn't attack them - and neither do antibiotics."

L-form - flimsy but survives

The research which used samples obtained through a collaboration with clinicians at the Newcastle Freeman Hospital part of Newcastle upon Tyne Hospitals Foundation Trust organised by Dr Phillip Aldridge and Dr Judith Hall shows that when antibiotics are present - such as in a patient with a UTI receiving penicillin or other cell wall-targeting antibiotic - then the bacteria has the ability to change form, losing the cell wall which is often the target of the antibiotic.

In a previous publication, which appeared in Cell in 2018 (10.1016/j.cell.2018.01.021), the Errington team demonstrated that our immune system can also to some extend induce L-form switching but treatment with antibiotics have a much more profound effect. Current study showed that L-forms of various bacterial species typically associated with UTIs including E. coli, Enterococcus, Enterobacter and Staphylococcus were detectable in 29 out of 30 patients involved in the study.

In this L-form the bacteria are flimsy and weaker but some survive, hiding inside the body.

The research also captured on video for the first time, L-form bacteria isolated from a patient with UTI re-forming a cell wall after the antibiotic had gone - taking just 5 hours. The team was also able to show by a direct microscopy in transparent zebrafish model, that the L-form switching is possible in the context of whole living organism and not only in artificial conditions in the lab.

Dr Mickiewicz explained: "In a healthy patient this would probably mean that the L-form bacteria left would be destroyed by their hosts' immune system. But in a weakened or elderly patient, like in our samples, the L-form bacteria can survive. They can then re-form their cell wall and the patient is yet again faced with another infection. And this may well be one of the main reasons why we see people with recurring UTIs.

"For doctors this may mean considering a combination treatment - so an antibiotic that attacks the cell wall then a different type for any hidden L-form bacteria, so one that targets the RNA or DNA inside or even the surrounding membrane."

Diagnosis

The research also found that L-form bacteria is difficult to identify by traditional methods used in hospital as the gel used in effect "pops" the bacteria as they are put into it.

A special osmoprotective detection method was needed to support the weaker L-form bacteria, enabling them to be identified in the lab.

The team will be furthering the research with trials in patients who have had treatment.

CAMBRIDGE, MA -- Our brains contain millions of synapses -- the connections that transmit messages from neuron to neuron. Within these synapses are hundreds of different proteins, and dysfunction of these proteins can lead to conditions such as schizophrenia and autism.

Researchers at MIT and the Broad Institute of Harvard and MIT have now devised a new way to rapidly image these synaptic proteins at high resolution. Using fluorescent nucleic acid probes, they can label and image an unlimited number of different proteins. They demonstrated the technique in a new study in which they imaged 12 proteins in cellular samples containing thousands of synapses.

"Multiplexed imaging is important because there's so much variability between synapses and cells, even within the same brain," says Mark Bathe, an MIT associate professor of biological engineering. "You really need to look simultaneously at proteins in the sample to understand what subpopulations of different synapses look like, discover new types of synapses, and understand how genetic variations impact them."

The researchers plan to use this technique next to study what happens to synapses when they block the expression of genes associated with specific diseases, in hopes of developing new treatments that could reverse those effects.

Bathe and Jeff Cottrell, director of translational research at the Stanley Center for Psychiatric Research at the Broad Institute, are the senior authors of the study, which appears today in Nature Communications. The lead authors of the paper are former postdocs Syuan-Ming Guo and Remi Veneziano, former graduate student Simon Gordonov, and former research scientist Li Li.

Imaging with DNA

Synaptic proteins have a variety of functions. Many of them help to form synaptic scaffolds, which are involved in secreting neurotransmitters and processing incoming signals. While synapses contain hundreds of these proteins, conventional fluorescence microscopy is limited to imaging at most four proteins at a time.

To boost that number, the MIT team developed a new technique based on an existing method called DNA PAINT. Using this method, originally devised by Ralf Jungmann of the Max Planck Institute of Biochemistry, researchers label proteins or other molecules of interest with a DNA-antibody probe. Then, they image each protein by delivering a fluorescent DNA "oligo" that binds to the DNA-antibody probes.

The DNA strands have an inherently low affinity for each other, so they bind and unbind periodically, creating a blinking fluorescence can be imaged using super-resolution microscopy. However, imaging each protein takes about half an hour, making it impractical for imaging many proteins in a large sample.

Bathe and his colleagues set out to create a faster method that would allow them to analyze a huge number of samples in a short period of time. To achieve that, they altered the DNA-dye imaging probe so that it would bind more tightly to the DNA-antibody, using what are called locked nucleic acids. This gives a much brighter signal, so the imaging can be done more quickly, but at slightly lower resolution.

"When we do 12 or 15 colors on a single well of neurons, the whole experiment takes an hour, compared with overnight for the super-resolution equivalent," Bathe says.

The researchers used this technique to label 12 different proteins found in the synapse, including scaffolding proteins, proteins associated with the cytoskeleton, and proteins that are known to mark excitatory or inhibitory synapses. One of the proteins they looked at is shank3, a scaffold protein that has been linked to both autism and schizophrenia.

By analyzing protein levels in thousands of neurons, the researchers were able to determine groups of proteins that tend to associate with each other more often than others, and to learn how different synapses vary in the proteins they contain. That kind of information could be used to help classify synapses into subtypes that might help to reveal their functions.

"Inhibitory and excitatory are the canonical synapse types, but it is speculated that there are numerous different subtypes of synapses, without any real consensus around what those are," Bathe says.

Understanding disease

The researchers also showed that they could measure changes in synaptic protein levels that occur after neurons are treated with a compound called tetrodotoxin (TTX), which strengthens synaptic connections.

"Using conventional immunofluorescence, you can typically extract information from three or four targets within the same sample, but with our technique, we were able to expand that number to 12 different targets within the same sample. We applied this method to examine synaptic remodeling that occurs following treatment with TTX, and our finding corroborated previous work that revealed a coordinated upregulation of synaptic proteins following TTX treatment," says Eric Danielson, an MIT senior postdoc who is an author of the study.

The researchers are now using this technique, called PRISM, to study how the structure and composition of synapses are affected by knocking out genes associated with various disorders. Sequencing the genomes of people with disorders such as autism and schizophrenia has revealed hundreds of disease-linked genetic variants, and for most of those variants, scientists have no idea how they contribute to disease.

"Understanding how genetic variation impacts neurons' development in the brain, and their synaptic structure and function, is a huge challenge in neuroscience and in understanding how these diseases arise," Bathe says.

Scientists have discovered that soil microbes can make plants more resistant to an aggressive disease - opening new possibilities for sustainable food production.

Bacterial wilt disease caused by Ralstonia solanacearum infects several plants including tomatoes and potatoes. It causes huge economic losses around the world especially in China, Indonesia and Africa.

Researchers from the University of York working with colleagues from China and the Netherlands, investigated the effect of the soil microbiome on the plant-pathogen interaction. Infections are often 'patchy' in the field not affecting the whole crop and the cause for this is unknown.

Dr Ville Friman from the Department of Biology said: "Even though we have discovered that the pathogen is present everywhere in tomato fields, it is not capable of infecting all the plants. We wanted to understand if this spatial variation could be explained by differences in soil bacterial communities."

To study the effect of soil microbiome for disease development, the scientists used a newly developed experimental system that allowed repeated sampling of individual plants in a non-destructive manner. This allowed scientists to go back in time and compare healthy and diseased plant microbiomes long before visible disease symptoms.

The sampling method allowed them to compare the micro-organisms that were present in the soils of those plants that remained healthy or became infected. Their analysis showed that the microbiomes of surviving plants were associated with certain rare taxa and pathogen-suppressing Pseudomonas and Bacillus bacteria.

Dr Friman added: "We found that improved disease resistance could be transferred to the next plant generation along with the soil transplants analogous to faecal transplants used in medicine.

"Our results show that it is important to focus not only the pathogen but also the naturally-occurring beneficial micro-organisms present in the rhizosphere. While the beneficial role of microbes for humans and plants have been acknowledged for a long time, it has been difficult to disentangle the cause and effect and important bacterial taxa based on comparative data."

The team are currently developing and testing different microbial inoculants for crop production. The research has opened up the possibility in the future that bacteria could be used as 'soil probiotics' to protect plants from pathogens.

Idiopathic pulmonary fibrosis (IPF) is a type of lung disease that results in scarring of the lungs, also known as fibrosis. Over time, the fibrosis gets increasingly worse so that it becomes hard for those with the condition to simply take in a deep breath to get the oxygen they need. However, it is not clear what the cause of this condition is, and while there are two treatments that can help slow the rate at which IPF progresses, there is currently no treatment that can stop or reverse the scarring of the lung. However, recent research may be paving the way towards a new approach for the treatment for IPF.

Research published in the journal Science Translational Medicine on 25 September by members of the Cardiovascular Disease Mechanisms group at the MRC LMS in collaboration with Duke-NUS Medical School, National Heart Centre Singapore & National Heart and Lung Institute, Imperial College London, showed that blocking a protein called interleukin-11 (IL-11) using therapeutic antibodies can reverse the fibrosis in the lung.

Hidden in plain sight

In 2013, Toby Maher; one of the authors on this paper, working with his colleague Elizabeth Renzoni, independently found that the expression of IL-11 was highly upregulated in this condition. In fact, it was the most highly expressed of all genes in lung fibroblasts, a specific type of structural cell which is capable of producing scar tissue, obtained from the lungs of patients with IPF. However, back then, the function of IL-11 was unclear, and there was no mention of IL-11 in relation to this disease previously. It wasn't until 2017 that the true biology of IL-11 was discovered. Only then did it become clear how important upregulation of IL-11 might be in IPF, as IL-11 causes lung fibroblasts to become highly active and to destroy the lung causing it to scar and not function.

In this study, the teams investigated whether drugs called therapeutic antibodies could reverse the process of lung fibrosis, as IL-11 was found to be crucial to the progression of IPF. Using mice designed to mimic patients suffering from the lung disease, antibodies designed to bind to IL-11 and neutralise its activity were administered. This treatment not only diminished the damage of the lungs in these mice, but reversed the fibrosis too, highlighting the potential of IL-11 as a possible target for the treatment of IPF. This is in addition to its potential in the liver, which was reported by the same group earlier this year to cause liver scaring, which could also be reversed with antibody therapy [insert link].

Stuart Cook, Head of the Cardiovascular Disease Mechanism group at the MRC LMS and senior author of this study discussed the exciting next steps for this research:

"We found that blocking the IL-11 protein with antibodies could reverse fibrosis in a mouse model of human lung disease. This is a remarkable finding as reversing fibrosis is tough to do. We believe this holds promise for treating fibrotic lung diseases, like IPF, in patients. We are aiming to test our antibodies in human safety trials by the end of 2020, and then start clinical trials with patients in 2021."

Toby Maher, Professor of Interstitial Lung disease and British Lung Foundation Chair in Respiratory Research at NHLI explained the importance of this research for patients:

"Idiopathic respiratory failure is a terrible disease with an untreated life expectancy of 3 years. Although we have treatments to slow disease progression, we desperately need new therapies to genuinely transform outcomes for people with IPF.

"This exciting research highlights the importance of IL-11 in driving the development of fibrosis and gives hope for a new treatment approach to halt and maybe even reverse the devastating lung scarring of IPF"