“The current drug treatments block healthy cells from becoming infected by the virus,” said Yiyang Lu, a PhD student in the Dar lab at the University of Illinois Urbana-Champaign. “The latent reservoir poses a bigger problem because it can start producing the virus at any time. Consequently, patients have to remain on antiretroviral therapy all their lives to prevent a viral rebound.”

So far, there are two types of drug treatment strategies: shock-and-kill, where reactivated cells are killed due to HIV, and a second drug cocktail prevents other cells from being infected, or block-and-lock, which forces the virus into a deep latent state so that it does not reactivate again. The problem with the first approach is that there are always some leftover reservoirs that do not get activated. The problem with the second approach, which the researchers are trying to solve, is that there aren’t many drugs that have been discovered.

Since the transition from latency occurs randomly, measuring the fluctuations in gene expression can provide more coverage than the average gene expression. “Commercial drug screens usually look at mean gene expression. Instead, we used a drug screen that looks at fluctuations in gene expression. Our screen allowed us to therefore find more compounds that could have been overlooked,” Lu said.

“We implemented a time-series drug screening approach that are less commonly used in other labs,” said Roy Dar, an assistant professor of bioengineering at Illinois and faculty member of the Carl R. Woese Institute for Genomic Biology. The researchers used a T- cell population, which is a reservoir for HIV, that had been infected by the virus. They imaged the cells in 15-minute intervals for 48 hours and tested over 1800 compounds. They looked at noise maps to identify which drugs can modulate the gene expression.

Using the screen, they were able to find five new latency-promoting chemicals, raising the possibility that similar screens can be successfully adapted to study other systems that exhibit variability in gene expression, such as cancer. They are currently working on understanding how the five novel drugs suppress viral reactivation. “We want to test if these drugs have off-target effects in terms of how many other genes they affect in the host cells,” Dar said. “We also want to test these drugs in patient samples to see whether these drugs suppress HIV in them.”

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Materials provided by Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign. Original written by Ananya Sen. Note: Content may be edited for style and length.

Topological materials burst onto the scene in the physical sciences about fifteen years ago, decades after their existence had been theorized. Called ‘topological’ because their bulk electronic bands are “knotted” together, the surfaces of topological insulators “untie the knot” and become metallic. Researchers at the Ames Laboratory’s Center for the Advancement of Topological Semimetals (CATS) are seeking to discover, understand, and control the exceptional conduction properties of these materials.

Much of modern technology relies on crystalline materials, which are solids composed of a repeating (periodic) arrangement of atoms that forms a lattice. Due to the periodicity, the lattice looks the same after certain symmetry operations such as translation, specific rotations, mirror, and/or inversion. The existence or absence of these symmetries affect electronic band topology and surface electronic conduction. Magnetic ordering can modify the symmetries exhibited by the material, providing an additional means to control the topological state.

In collaboration with scientists at Oak Ridge National Laboratory’s Spallation Neutron Source, McGill University, and the University of Missouri Research Reactor Center, the CATS team discovered the existence of low-symmetry helical magnetic ordering in EuIn2As2 which supports a highly sought-after topological state called an axion insulator. This state shares similarities with the axion particle in quantum chromodynamics which is a candidate component of dark matter. In solid-state materials, it provides remarkable parallel coupling between magnetic and electrical properties.

In the presence of EuIn2As2’s complex helical magnetic ordering, the axion state leads to topological features in the surface electronic spectrum called Dirac cones. When a Dirac cone occurs on a surface of the material penetrated by a fundamental axis of the magnetic ordering, the cone has no energy gap and the surface exhibits resistanceless conduction tied to the orientation of the electronic spin. The other surfaces have gapped Dirac cones and support half-integer quantized electrical conduction. The researchers predict that application of a relatively moderate magnetic field switches which surfaces support which type of Dirac cone, allowing the surface conduction to be tuned.

The ability to switch between surface states by a magnetic field provides an experimental avenue to examine the unique properties of its topological states. This tunability is also promising for technologies such as high-precision sensors, resistanceless nanowires, magnetic storage media, and quantum computers. Future studies will look at bulk crystals while applying a magnetic field and will synthesize and study nanoscale-thin films in order to pave the way for technological applications.

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The international study, led by the University of Sheffield’s Neuroscience Institute, may have a significant impact on the future treatment of Parkinson’s patients who develop the illness due to PINK1 defect or similar gene defects.

The development of novel treatments and therapies to slow down disease progression, halt or reverse Parkinson’s may now focus on enhancing the generation of new dopamine-producing neurons, rather than just trying to protect these neurons from dying later.

The findings, published today (23 March 2021) in Scientific Reports, used two model systems to measure how inactivation of the PINK1 gene affects dopamine-producing neurons in the adult brain.

Dopamine-producing neurons are the most severely affected brain cells in Parkinson’s disease. It is typically thought that Parkinson’s genes, such as PINK1, cause early death of these neurons, with symptoms developing when neuron numbers fall. However, here, researchers found that a deficiency in PINK1 resulted in fewer dopamine-producing neurons being made throughout life.

Professor Oliver Bandmann, Professor of Movement Disorders Neurology at the Sheffield Institute for Translational Neuroscience (SITraN), said: “Neurogenesis is the process by which new neurons are formed in the brain. Recent evidence suggests that this process is ongoing throughout life but the relevance of this is poorly understood in neurodegenerative disorders such as Parkinson’s disease.”

“We know that mutations in the PINK1 gene cause an early onset, inherited form of Parkinson’s disease. If we can further our understanding about the impact of this genetic mutation on the dopamine-producing neurons we can develop new therapeutic approaches that aim to mitigate those effects.”

In collaboration with the University of Luxembourg, researchers used two complementary model systems to examine how neurons are reproduced throughout our lifetime.

Professor Marysia Placzek, Professor of Developmental Neurobiology in the Department of Biomedical Science, said: “This study attests to the power of using simple model organisms for pre-clinical translational research. We used the zebrafish to demonstrate that dopamine-producing neurons are generated into adulthood at a rate that decreases with age and that PINK1-deficiency impairs neurogenesis of these neurons, significantly in early adult life. Our international collaborators then confirmed these results in a human organoid cell model.”

The observation of impaired adult dopaminergic neurogenesis in PINK1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in Parkinson’s disease. Future research will aim to identify the precise mechanisms that link Parkinson’s genes to neurogenesis. This will allow us to explore the development of gene therapy or small molecule approaches to enhance neurogenesis in the brain of patients with Parkinson’s. The development of new therapies for brain diseases like Parkinson’s is the main focus of the Sheffield Institute for Translational Neuroscience (SITraN).

The research was funded by the Medical Research Council (MRC), Parkinson’s UK and the Wellcome Trust.

Parkinson’s disease is the second most common neurodegenerative disease, with approximately 10 million people affected worldwide. Currently, only symptomatic treatment options are available to patients.

The University of Sheffield launched a sustained fundraising effort for Parkinson’s disease research at the end of 2019. Since then, Sheffield staff, students, alumni and the general public have come together to raise more than £350,000 so far. The ongoing efforts of this campaign are set to continue as Sheffield dedicates itself to backing the next breakthrough.

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In the study published in Nature Ecology and Evolution, the researchers examined the genomes of more than 400 modern humans to investigate the interbreeding events between ancient humans and modern human populations who arrived at Island Southeast Asia 50,000-60,000 years ago.

In particular, they focused on detecting signatures that suggest interbreeding from deeply divergent species known from the fossil record of the area.

The region contains one of the richest fossil records (from at least 1.6 million years) documenting human evolution in the world. Currently there are three distinct ancient humans recognised from the fossil record in the area: Homo erectus, Homo floresiensis (known as Flores Island hobbits) and Homo luzonensis.

These species are known to have survived until approximately 50,000-60,000 years ago in the cases of Homo floresiensis and Homo luzonensis, and approximately 108,000 years for Homo erectus, which means they may have overlapped with the arrival of modern human populations.

The results of the study showed no evidence of interbreeding. Nevertheless, the team were able to confirm previous results showing high levels of Denisovan ancestry in the region.

Lead author and ARC Research Associate from the University of Adelaide Dr João Teixeira, said: “In contrast to our other cousins the Neanderthals, which have an extensive fossil record in Europe, the Denisovans are known almost solely from the DNA record. The only physical evidence of Denisovan existence has been a finger bone and some other fragments found in a cave in Siberia and, more recently, a piece of jaw found in the Tibetan Plateau.”

“We know from our own genetic records that the Denisovans mixed with modern humans who came out of Africa 50,000-60,000 years ago both in Asia, and as the modern humans moved through Island Southeast Asia on their way to Australia.

“The levels of Denisovan DNA in contemporary populations indicates that significant interbreeding happened in Island Southeast Asia.

“The mystery then remains, why haven’t we found their fossils alongside the other ancient humans in the region? Do we need to re-examine the existing fossil record to consider other possibilities?”

Co-author Chris Stringer of the Natural History Museum in London added:

“While the known fossils of Homo erectus, Homo floresiensis and Homo luzonensis might seem to be in the right place and time to represent the mysterious ‘southern Denisovans’, their ancestors were likely to have been in Island Southeast Asia at least 700,000 years ago. Meaning their lineages are too ancient to represent the Denisovans who, from their DNA, were more closely related to the Neanderthals and modern humans.”

Co-author Prof Kris Helgen, Chief Scientist and Director of the Australian Museum Research Institute, said: “These analyses provide an important window into human evolution in a fascinating region, and demonstrate the need for more archaeological research in the region between mainland Asia and Australia.”

Helgen added: “This research also illuminates a pattern of ‘megafaunal’ survival which coincides with known areas of pre-modern human occupation in this part of the world. Large animals that survive today in the region include the Komodo Dragon, the Babirusa (a pig with remarkable upturned tusks), and the Tamaraw and Anoas (small wild buffalos).

“This hints that long-term exposure to hunting pressure by ancient humans might have facilitated the survival of the megafaunal species in subsequent contacts with modern humans. Areas without documented pre-modern human occurrence, like Australia and New Guinea, saw complete extinction of land animals larger than humans over the past 50,000 years.”

Dr Teixeira said: “The research corroborates previous studies that the Denisovans were in Island Southeast Asia, and that modern humans did not interbreed with more divergent human groups in the region. This opens two equally exciting possibilities: either a major discovery is on the way, or we need to re-evaluate the current fossil record of Island Southeast Asia.”

“Whichever way you choose to look at it, exciting times lie ahead in palaeoanthropology.”

Analysis by researchers led by the University of Warwick has revealed that these substorms manifest as global-scale electrical current systems associated with the spectacular aurora, reaching across over a third of the globe at high latitudes.

New research which involves the University of Warwick, John Hopkins University — Applied Physics Laboratory, University of Bergen and Cranfield University, and published today (23 March) in the journal Nature Communications processes data on disturbances in the Earth’s magnetic field from over a hundred magnetometers in the Northern hemisphere using a new technique that enables them to find ‘like-minded friends’.

Magnetometers register changes in the Earth’s magnetic field. When charged particles from our Sun bombard the Earth’s magnetic field, it stores up energy like a battery. Eventually, this energy is released leading to large-scale electrical currents in the ionosphere which generate disturbances of magnetic fields on the ground. At extremes, this can disrupt power lines, electronic and communications systems and technologies such as GPS.

Using historical data from the SuperMAG collaboration of magnetometers, the researchers applied algorithms from network science to find correlations between magnetometer signals during 41 known substorms that occurred between 1997-2001. These use the same principles that allow a social networking site to recommend new friends, or to push relevant advertisements to you as you browse the internet.

Magnetometers detecting coherent signals were linked into communities, regardless of where they were located on the globe. As time progressed, they saw each substorm develop from many smaller communities into a single large correlated system or community at its peak. This led the authors to conclude that substorms are one coherent current system which extends over most of the nightside high latitude globe, rather than a number of individual small and disjointed current systems.

Dr Lauren Orr, who led the research as part of her PhD at the University of Warwick Department of Physics and is now based at Lancaster University, said: “We used a well-established method within network science called community detection and applied it to a space weather problem. The idea is that if you have lots of little subgroups within a big group, it can pick out the subgroups.

“We applied this to space weather to pick out groups within magnetometer stations on the Earth. From that, we were trying to find out whether there was one large current system or lots of separate individual current systems.

“This is a good way of letting the data tell us what’s going on, instead of trying to fit observations to what we think is occurring.”

Some recent work has suggested that auroral substorms are composed of a number of smaller electrical current systems and remain so throughout their lifecycle. This new research demonstrates that while the substorm begins as lots of smaller disturbances, it quite rapidly becomes a large system over the course of around ten minutes. The lack of correlation in its early stages may also suggest that there is no single mechanism at play in how these substorms evolve.

The results have implications for models designed to predict space weather. Space weather was included in the UK National Risk Register in 2012 and updated in 2017 with a recommendation for more investment in forecasting.

Co-author Professor Sandra Chapman adds: “Our research introduces a whole new methodology for looking at this data. We’ve gone from a data poor to a data rich era in space plasma physics and space weather, so we need new tools. It’s a first to show that you can take one of these tools to our field and get a really important result out of it. We’ve had to learn a lot to be able to do that, but in doing so it opens up a new window into the data.”

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