Culture

Results from an international clinical trial found that men with advanced prostate cancer who have mutated BRCA1/BRCA2 genes can be treated successfully with a targeted therapy known as rucaparib, resulting in recent FDA approval.

Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. Metastatic, castrate-resistant prostate cancer (mCRPC) is an incurable form of prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels. Researchers are looking for new treatment options to use for mCRPC.

Rucaparib (trademarked as Rubraca®) is one of a new class of anticancer drugs called poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors, which work by targeting cancer cells that have a defect in how they repair damage to their DNA. PARP inhibitors are already successfully used to treat ovarian cancers and some inherited forms of breast and pancreatic cancer.

"There is a critical need for personalized medicines to effectively treat advanced prostate cancer," said Akash Patnaik, MD, PhD, national authority on prostate cancer research at the University of Chicago Medicine and one of the study authors, who presented the findings from this study at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology in San Francisco in February 2020. "Approximately 12% of advanced prostate cancer patients have tumors that harbor a BRCA1 or BRCA2 alteration. We have arrived at an exciting inflection point in the field, as we now have the first FDA approved targeted therapy that can effectively treat a genetically defined subset of mCRPC patients, with poor prognosis and worse clinical outcomes on conventional treatments."

The TRITON2 phase II study investigated whether or not rucaparib can safely and effectively treat men with mCRPC who are predisposed to prostate cancer because of their genetic profile. Men whose cancer had progressed after completing hormone therapy and chemotherapy were eligible to participate. The University of Chicago Medicine Comprehensive Cancer Center was the second lead site internationally to enroll patients to this practice-changing study.

Patnaik and colleagues from cancer centers in the U.S. and across the world enrolled 115 patients whose genetic screening revealed abnormalities in their BRCA genes. The patients then received 600 mg of rucaparib twice a day. The objective response rate was 41%. Over half of the patients (53.9%) had improvements in their prostate-specific antigen (PSA) levels.

The researchers noted that in addition to demonstrating a significant anti-cancer response in mCRPC patients that had progressed on two prior lines of therapy, the rucaparib treatment had a manageable safety profile consistent with that reported in other solid tumor types, with the most common side effect reported being anemia.

Based on the initial efficacy and safety results from TRITON2, the FDA granted accelerated approval for rucaparib in mCRPC patients with BRCA1/2 mutations on May 15, 2020. Results from TRITON2 have been previously presented to the medical community at the European Society for Medical Oncology (ESMO) Annual Congress (October 19-23, 2018, and September 27-October 1, 2019), the American Society of Clinical Oncology (ASCO) Annual Meeting (May 31-June 4, 2019), and the ASCO Genitourinary Cancers Symposium (February 13-15, 2020).

A publication summarizing the TRITON2 results was published today at the Journal of Clinical Oncology. "In a separate publication, we have demonstrated that additional non-BRCA1/2 mutations within the DNA repair pathway in mCRPC patients could confer sensitivity or resistance to PARP inhibitor rucaparib," Patnaik said. "We still have a lot more to learn about which patients with additional genetically defined alterations in the DNA repair pathway will benefit most from this therapy."

He continued, "Studies are underway within our laboratory and clinical trials to test combinations of PARP inhibitors with other conventional or experimental therapies to substantially increase the fraction of mCRPC patients that respond to PARP inhibitors. Based on these investigations, we are optimistic about the development of additional personalized treatment options for our mCRPC patients."

The synthetic drug ebselen can bind to both the catalytic region and a previously unknown distant site on the SARS-CoV-2 virus' main protease, according to a molecular simulation analysis of the drug's interactions with this enzyme. The results suggest that ebselen could be a potential treatment for COVID-19, if future work can confirm its ability to inhibit the activity of the viral protease, which is involved in viral gene expression and replication. While current virtual screening campaigns primarily focus on drugs that target the catalytic site of the SARS-CoV-2 main protease, the findings highlight another binding site that may provide an effective target for other drugs previously written off as ineffective. Since researchers typically require years to design and develop drugs for widespread use, repurposing previously approved pharmaceuticals is considered an essential strategy to quickly combat the current global pandemic. Recently, computational-experimental screenings identified several existing drugs, including ebselen, that may work to inhibit the virus' main protease. However, the molecular mechanisms by which this drug interacts with the main protease had yet to be understood. To investigate this interaction, Cintia Menendez and colleagues performed molecular simulations, identifying sites at which the drug and the main protease interact while evaluating the effect of different binding sites on molecular stiffness and strain. They found that ebselen appears to target both a binding site within the catalytic region and another between binding site domains II and III. Menendez et al. suggest that future experiments will be necessary to validate these findings, especially concerning the distant binding site.

Scientists have identified a small molecule that inhibits multiple different viruses, including SARS-CoV-2, in tissue culture and in mice by targeting the same signaling pathway. By identifying a host cell pathway that a wide variety of viruses rely on for successful infection, the findings suggest a possible target for broad-spectrum antiviral drugs. Novel viruses - including SARS-CoV-2, HIV, Zika virus, and avian influenza A - can present unique challenges for researchers, since interactions between viruses and their hosts often drive evolutionary changes that diversify both the viruses and hosts' responses. To keep ahead of this arms race, scientists have sought evolutionarily conserved mechanisms, common to many host-virus interactions, that can offer sweeping solutions. To investigate whether the TGF-β signaling pathway could serve as a target for antiviral therapies against numerous viruses, Shuofeng Yuan and colleagues performed screens of previously identified inhibitors of the pathway. They found that one such compound, the small molecule N-(p-Amylcinnamoyl)anthranilic acid (or ACA), successfully inhibited influenza A, MERS-CoV, SARS-CoV-2, HIV, adenovirus, and two picornaviruses, both in tissue culture and in mice. They also found that ACA achieved this by blocking the interaction of AP2M1, a subunit of the AP2 adaptor complex that is known to interact with the TGF-β pathway, with an amino acid sequence present in many viral proteins. Blocking this host-virus protein interaction interfered with proper subcellular localization of virus components, thereby inhibiting a productive infection. These findings point to a target and a possible broad-spectrum therapy to treat viral outbreaks, including the current COVID-19 pandemic.

Supercomputers around the world work around the clock on research problems. In principle, even novel materials can be simulated in computers in order to calculate their magnetic and thermal properties as well as their phase transitions. The gold standard for this kind of modelling is known as the quantum Monte Carlo method.

Wave-Particle Dualism

However, this method has an intrinsic problem: due to the physical wave-particle dualism of quantum systems, each particle in a solid-state compound not only possesses particle-like properties such as mass and momentum, but also wave-like properties such as phase. Interference causes the "waves" to be superposed on each other, so that they either amplify (add) or cancel (subtract) each other locally. This makes the calculations extremely complex. It is referred to the sign problem of the quantum Monte Carlo method.

Minimisation of the problem

"The calculation of quantum material characteristics costs about one million hours of CPU on mainframe computers every day", says Prof. Jens Eisert, who heads the joint research group at Freie Universität Berlin and the HZB. "This is a very considerable proportion of the total available computing time." Together with his team, the theoretical physicist has now developed a mathematical procedure by which the computational cost of the sign problem can be greatly reduced. "We show that solid-state systems can be viewed from very different perspectives. The sign problem plays a different role in these different perspectives. It is then a matter of dealing with the solid-state system in such a way that the sign problem is minimised", explains Dominik Hangleiter, first author of the study that has now been published in Science Advances.

From simple spin systems to more complex ones

For simple solid-state systems with spins, which form what are known as Heisenberg ladders, this approach has enabled the team to considerably reduce the computational time for the sign problem. However, the mathematical tool can also be applied to more complex spin systems and promises faster calculation of their properties.

"This provides us with a new method for accelerated development of materials with special spin properties", says Eisert. These types of materials could find application in future IT technologies for which data must be processed and stored with considerably less expenditure of energy.

Children with autism born to mothers who had immune conditions during their pregnancy are more likely to have behavioral and emotional problems, a UC Davis Health study has found. The study examined maternal immune history as a predictor of symptoms in children with autism.

"We tested the ability of maternal immune history to predict ASD symptoms and the possible role that the sex of the offspring plays," said Paul Ashwood, professor of microbiology and immunology and faculty member at the UC Davis MIND Institute.

Published Aug. 14 in Translational Psychiatry, the study found that offspring sex may interact with maternal immune conditions to influence outcomes, particularly in terms of a child's cognition.

Maternal immunity conditions and autism

Maternal immune conditions are caused by a dysfunction of the mother's immune system. They include allergies, asthma, autoimmune diseases, autoinflammatory syndromes and immunological deficiency syndromes. Previous studies have shown that maternal immune conditions are more prevalent in mothers of children with autism spectrum disorder (ASD).

The researchers enrolled 363 mothers and their children (252 males and 111 females) from the Autism Phenome Project (APP) and Girls with Autism Imaging of Neurodevelopment (GAIN) study at the UC Davis MIND Institute. The median age of the children was three years.

The researchers measured the children's autism severity and assessed a set of behavioral and emotional problems such as aggression and anxiety. They also measured the children's development and cognitive functioning.

The study found that around 27% of the mothers had immune conditions during their pregnancy. Of these mothers, 64% reported a history of asthma, the most common immune condition. Other frequent conditions included Hashimoto's thyroiditis (hypothyroidism), Raynaud's disease (blood circulation disease), alopecia (hair loss), psoriasis (skin disease) and rheumatoid arthritis (joint tissue inflammation).

The study also found that maternal immune conditions are associated with increased behavioral and emotional problems but not reduced cognitive functioning in children with autism.

Does the sex of the offspring interact with the influence of maternal immune conditions on autism symptoms?

According to the Centers for Disease Control and Prevention (CDC), ASD is four times more common among boys than among girls.

"Our study explored whether offspring sex interacts with the presence of maternal immune conditions to influence behavioral outcomes in children," said Ashwood. "Maternal immune conditions may be one environmental factor which contributes to the higher male prevalence seen in ASD."

The study found that a history of maternal immune conditions was more common in male children with ASD (31%) compared to female (18%). Specifically, asthma was twice as common in mothers of male children with ASD than in mothers of female children with ASD.

The study also showed that in cases of ASD where maternal immune conditions are present, female offspring are less likely to be susceptible to adverse cognitive outcomes in response to maternal inflammation than male offspring.

"This critical finding links offspring sex and maternal immune conditions to autism," said Ashwood. "It provides more evidence that male offspring are at higher risk of adverse outcomes due to maternal immunity activation compared to female offspring."

Future studies would include identifying the type, severity and gestational timing of immune conditions, and then examining offspring outcomes over time.

Oak Ridge National Laboratory researchers have developed artificial intelligence software for powder bed 3D printers that assesses the quality of parts in real time, without the need for expensive characterization equipment.

The software, named Peregrine, supports the advanced manufacturing "digital thread" being developed at ORNL that collects and analyzes data through every step of the manufacturing process, from design to feedstock selection to the print build to material testing.

"Capturing that information creates a digital 'clone' for each part, providing a trove of data from the raw material to the operational component," said Vincent Paquit, who leads advanced manufacturing data analytics research as part of ORNL's Imaging, Signals and Machine Learning group. "We then use that data to qualify the part and to inform future builds across multiple part geometries and with multiple materials, achieving new levels of automation and manufacturing quality assurance."

The digital thread supports the factory of the future in which custom parts are conceived using computer-aided design, or CAD, and then produced by self-correcting 3D printers via an advanced communications network, with less cost, time, energy and materials compared with conventional production. The concept requires a process control method to ensure that every part rolling off printers is ready to install in essential applications like cars, airplanes, and energy facilities.

To devise a control method for surface-visible defects that would work on multiple printer models, ORNL researchers created a novel convolutional neural network -- a computer vision technique that mimics the human brain in quickly analyzing images captured from cameras installed on the printers. The Peregrine software uses a custom algorithm that processes pixel values of images, taking into account the composition of edges, lines, corners and textures. If Peregrine detects an anomaly that may affect the quality of the part, it automatically alerts operators so adjustments can be made.

The software is well suited to powder bed printers. These printers distribute a fine layer of powder over a build plate, with the material then melted and fused using a laser or electron beam. Binder jetting systems rely on a liquid binding agent rather than heat to fuse powdered materials.

The systems print layer by layer, guided by the CAD blueprint, and are popular for the production of metal parts.
However, during the printing process, problems such as uneven distribution of the powder or binding agent, spatters, insufficient heat, and some porosities can result in defects at the surface of each layer. Some of those issues may happen in such a very short timeframe that they may go undetected by conventional techniques.

"One of the fundamental challenges for additive manufacturing is that you're caring about things that occur on length-scales of tens of microns and happening in microseconds, and caring about that for days or even weeks of build time," said ORNL's Luke Scime, principal investigator for Peregrine. "Because a flaw can form at any one of those points at any one of those times, it becomes a challenge to understand the process and to qualify a part."

Peregrine is being tested on multiple printers at ORNL, including as part of the Transformational Challenge Reactor (TCR) Demonstration Program that is pursuing the world's first additively manufactured nuclear reactor. TCR is leveraging ORNL's rich history in nuclear science and engineering, materials science and advanced manufacturing to develop a microreactor with newer materials in less time at a lower cost, ensuring the future of this important carbon-free energy source.

"For TCR in particular, you could have a scenario in which the regulator will want detailed data on how a part was manufactured, and we can provide specs with the database built using Peregrine," Scime said.

"Establishing correlations between these signatures collected during manufacturing and performance during operation will be the most data-rich and informed process for qualifying critical nuclear reactor components," said Kurt Terrani, TCR program director. "The fact that it may be accomplished during manufacturing to eliminate the long and costly conventional qualification process is the other obvious benefit."

ORNL researchers stress that by making the Peregrine software machine-agnostic -- able to be installed on any powder bed system -- printer manufacturers can save development time while offering an improved product to industry. Peregrine produces a common image database that can be transferred to each new machine to train new neural networks quickly, and it runs on a single high-powered laptop or desktop. Standard cameras were used in the research, ranging in most cases from 4 to 20 megapixels and installed so they produce images of the print bed at each layer. The software has been tested successfully on seven powder bed printers at ORNL so far, including electron beam melting, laser powder bed, and binder jetting, as detailed in the journal Additive Manufacturing.

"Anything we can do to help operators and designers know what works and what doesn't helps with the confidence that the part will be okay for use," Scime said. "When you have a 3D map of every pixel where the network thinks there is an anomaly and what it thinks the problem is, it opens up a whole world of understanding of the build process."

As the monitoring system has evolved, Scime said researchers are able to combine the image data with data from other sources such as the printer's log files, the laser systems and operator notes, allowing parts to be uniquely identified and statistics from all parts tracked and evaluated.

The AI software was developed at the Manufacturing Demonstration Facility at ORNL, a U.S. Department of Energy user facility that works closely with industry to develop, test and refine nearly every type of modern advanced manufacturing technology.

"There's no place else like the MDF where this machine-agnostic algorithm could have been developed, simply because we have so many machines and so many builds going on all the time in the course of our research," Scime said. "Access to data is key. Here, we have the ability to place sensors easily and the technicians to make sure everything works and that we're getting our data. With the variety of scientific expertise available here, it's been easy to find experts to help with all the challenges involved."

In other process control work, MDF researchers are developing methods to monitor for defects on the subsurface of builds and to detect porosity that may form in deeper layers, including the use of photodiodes and high-speed cameras.

"We've been doing welding for hundreds of years, but additive has only been around for a couple of decades and we don't know what the problems look like in some cases," Scime said. "Machine learning techniques allow us to collect and analyze a lot of data quickly. We can then identify those problems and gain the knowledge we need to better understand and prevent anomalies."

BIRMINGHAM, Ala. - Why is the COVID-19 virus deadly, while many other coronaviruses are fairly innocuous and just cause colds?

A team of University of Alabama at Birmingham and Polish researchers propose an answer -- the COVID-19 virus acts as a microRNA "sponge." This action modulates host microRNA levels in ways that aid viral replication and stymies the host immune response.

This testable hypothesis results from analysis of current literature and a bioinformatic study of the COVID-19 virus and six other coronaviruses. It is published as a perspective in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

Human microRNAs, or miRNAs, are short, non-coding RNAs with about 22 bases. They act to regulate gene expression by their complementary pairing with specific messenger RNAs of the cell. That pairing silences the messenger RNA, preventing it from being translated into a protein. Thus, miRNAs are a fine-tuned controller of cell metabolism or the cell's response to stress and adverse challenges, like infection by a virus.

The miRNAs are only about 0.01 percent of total human cell and tissue RNA, while replicating viral RNA of a virus like the COVID-19 virus may reach 50 percent of the total cellular RNA. So, the UAB and Polish researchers say, if the COVID-19 virus has binding sites for specific miRNAs -- and these sites are different from the binding sites for miRNAs found on coronaviruses that cause colds -- the more pathogenic COVID-19 virus may selectively sponge up certain miRNAs to dysregulate the cell in ways that make it a dangerous human coronavirus.

The sponge idea is not novel. Viral RNA sponges have been shown capable of removing host miRNA by the Epstein-Barr virus, and sponge activity has also been shown for the herpes and hepatitis C viruses.

There were two human coronaviruses prior to the COVID-19 virus -- whose formal name is SARS-CoV-2 -- that foreshadowed the devastating consequences of the COVID-19 virus. The first was the severe acute respiratory coronavirus, or SARS virus, in 2002; the second was the Middle East respiratory syndrome coronavirus, or MERS virus, in 2012. Neither had the high infectivity of the COVID-19 virus; but both were dangerous, causing 774 and 866 deaths, respectively, according to the National Institutes of Health.

In the present study, the researchers used computer-aided bioinformatic analysis to find potential miRNA target sites for 896 mature human miRNA sequences on seven different coronavirus genomes. These genomes included the three pathogenic coronaviruses -- the SARS, MERS and COVID-19 viruses -- and four non-pathogenic coronaviruses.

The researchers found that the number of target sites was elevated in the pathogenic viruses compared to the non-pathogenic strains. Furthermore, they found that pathogenic human coronaviruses attracted sets of miRNAs that differ from the non-pathogenic human coronaviruses. In particular, a set of 28 miRNAs were unique for the COVID-19 virus; the SARS and MERS viruses had their own unique sets of 21 and 24 miRNAs, respectively.

Focusing on the 28 unique miRNAs for the COVID-19 virus, the researchers found that the majority of these miRNAs are well expressed in bronchial epithelial cells, and their dysregulation has been reported in human lung pathologies that include lung cancers, chronic obstructive pulmonary disease, cystic fibrosis and tuberculosis. Furthermore, many of the miRNAs have been proposed to act as tumor suppressors that target the pathways for programmed cell death, or apoptosis, that are supposed to make a cell kill itself when infected, mutated or stressed in other ways. Reduction of those miRNAs has been associated with poor cancer prognosis.

"Hence, the COVID-19 virus -- by its potential reduction of the host's miRNA pool -- may promote infected cell survival and thus continuity of its replication cycle," the researchers said.

The authors gave a detailed explanation of how the virus replicates inside an infected cell, including how the cell assists protein folding and how the virus begins assembly in the cell's endoplasmic reticulum and Golgi system. They also described many of the cellular proteins involved in these steps. This viral replication is known to produce stress and can provoke an unfolded protein response that causes a cell to undergo programmed death.

"Taken together," the researchers said, "the viral strategies to increase the endoplasmic reticulum membranes and endoplasmic reticulum folding capacity and block unfolded protein response-associated translational attenuation, inflammatory responses and apoptosis are critical components for virus production."

The authors then showed, by citing literature, that nine of the specific cellular miRNAs that potentially are sponged by the COVID-19 virus could help achieve those viral needs.

"The host miRNAs potentially controlled by the pathogenic human coronaviruses may be the key to gaining control over a very limited and specific set of miRNAs targets," they said. The researchers used computer-assisted gene ontology programs to find the genes and cellular pathways affected by the pathogenic human coronaviruses, and by the COVID-19 virus in particular.

The pathways they found "further supports the hypothesis that pathogenic human coronaviruses -- including the COVID-19 virus -- utilize the host miRNAs to adjust cellular processes in order to facilitate their viral protein production."

"Our hypothesis will require validations," they said, "starting with the assessment of these miRNA levels in infected tissues and ending with restoring the host miRNA balance with miRNA analogs. Furthermore, completely understanding how viruses take advantage of the endoplasmic reticulum and unfolded protein response pathway may also lead to the novel therapeutic strategies."

This hypothesis by the UAB and Polish researchers, who all contributed equally to the paper, may explain some other biological oddities of the COVID-19 virus.

One is the varying susceptibilities to infection seen among patients, including a more severe morbidity and mortality for older patients. There may be individual differences among patient miRNA profiles, they said, and one "recent study has suggested that COVID-19 virulence in aged patients may be due to a lower abundance of miRNAs, and this may be a contributing factor in disease severity."

Another biological question is how the virus co-exists in its normal animal source -- bats. "Notably," the researchers said, "a recent study proposed that bats, considered as host of origin for the COVID-19 virus, have tolerance to potentially deadly viruses because of specific miRNAs."

The European Union aims to achieve climate neutrality by 2050 and is relying largely on renewable electricity to reach this goal. The implementation of this energy transition is the subject of heated debate: A continental-scale system that concentrates energy generation infrastructure in the most suitable locations would provide the most affordable solution but many citizens favour smaller, more dispersed supply networks. A new study prepared by researchers in Potsdam and Zurich shows that the implementation of such systems would not incur significant additional costs.

The researchers examined the technical feasibility and economic viability of renewable electricity generation at the continental, national, and regional levels. The study aimed to learn whether smaller electricity supply systems are indeed significantly more expensive than a continental-scale system, explains lead author Tim Tröndle (Institute for Advanced Sustainability Studies, Potsdam/ETH Zurich): "Proponents of a continental system argue that large-scale solutions are more affordable, enable suppliers to balance fluctuations, and facilitate the efficient use of resources regardless of their location. While these advantages are undeniable, political interests and public acceptance play a significant role in shaping the energy transition. As a result, proper consideration must also be given to smaller systems."

Smaller scale systems incur a cost penalty of less than 20%

Modelling conducted as part of the study confirmed that the most affordable solution would involve the creation of an interconnected European grid to distribute electricity generated at locations across Europe with the best solar and wind resources. But the cost penalties incurred by smaller systems remain low if suppliers are able to balance fluctuations in electricity generation across countries and regions. In this case, grid operators can cooperate with partners at the national and regional levels to balance fluctuations by sharing electricity with neighbouring grids rather than deploying costly storage technologies or curtailing electricity generation from wind and solar plants.

The creation of a well performing European energy market could reduce cost penalties incurred by small-scale systems to below 20 percent compared with a continental supply system. According to the authors, this finding supports current efforts to establish a European electricity market and expand the network of cross-border interconnectors linking national systems, which help to balance fluctuations.

Infrastructure requirements vary significantly

According to the study, the location of electricity generation infrastructure does not significantly affect the cost of a completely renewable electricity supply. "However, location significantly impacts infrastructure choices, especially with respect to the question of whether more generation or transmission infrastructure is required. In light of this, the preferred size of power generation systems should be clarified quickly in order to accelerate the energy transition," recommends co-author Johan Lilliestam (IASS Potsdam/University of Potsdam). Several solutions are feasible, ranging from a more continental system in which electricity generation is concentrated in the best locations through to numerous smaller, local systems in which electricity is generated close to consumers.

Even as studies have shown that the uneven distribution of urban heat islands, urban tree canopy cover, and urban environmental hazards, for example, are strongly dictated by structural racism and classism in cities, relatively few studies have addressed the varied contributions of social factors like race to ecological heterogeneity in cities. Here, Christopher J. Schell and colleagues integrate findings from ecology, evolution, and the social sciences to underscore such relationships. Their findings, they say, are necessary to conserve biodiversity, improve human health, and promote justice in nature and society. They start with a well-known hypothesis called the luxury effect - which suggests that urban biodiversity, and plant diversity in particular, is positively correlated with neighborhood wealth. A direct effect of the luxury effect is that poorer-income neighborhoods usually have less tree cover - and thus more heat. These neighborhoods are also typically located closer to pollution sources. "Work on heat islands and pollution support the idea that inequality in neighborhood wealth leads not only to a diversity of environmental hazards," the authors say, "but that these hazards compound to create unique, challenging environmental patches." They also cite research that has shown that neighborhood racial composition can be a stronger predictor of urban socio-ecological patterns than wealth. Neighborhoods that were "redlined" decades ago - by a policy that segregated urban residential neighborhoods principally by race - have on average 21 percent less tree canopy, for example. Knowing where these cities are could help to identify and predict geographic regions with compounding anthropogenic disturbances that require more sustained stewardship, the authors say. "Our capacity to understand urban ecosystems and non-human organisms necessitates a more thorough integration of the natural and social parameters of our cities," Schell and colleagues write. "We cannot generalize human behavior in urban ecosystems without dealing with systemic racism and other inequities."

WASHINGTON (Aug. 13, 2020) -- Fingolimod, an FDA-approved immunosuppressive drug used to treat multiple sclerosis flare-ups, may be used to block HIV infection and reduce the latent reservoir. Researchers at the George Washington University (GW) published their novel findings in PLOS Pathogens.

"While antiretroviral drugs have been effective in treating HIV thus far, drug resistance, negative side effects of antiretroviral therapy, and its varying efficacy underscore the need to develop alternative treatment and prevention options," said Alberto Bosque, PhD, MBA, assistant professor of microbiology, immunology, and tropical medicine at the GW School of Medicine and Health Sciences. "For the first time, our research team found that by targeting the receptors to the signaling molecule Sphingosine-1-phosphate (S1P), we could effectively block HIV infection and cell-to-cell transmission of the virus and consequently reduce the seeding of the latent virus in the test tube."

Treatment for HIV is lifelong, due to a latent reservoir of HIV-infected cells that may reactivate at any time. In addition to other drawbacks, current antiretroviral therapies do not specifically target latent infection. Finding ways to not only target infection, but also reduce the latent reservoir would have a great impact on the nearly 40 million people living with HIV worldwide.

Fingolimod, known also as Gilenya, works by acting as a functional antagonist of S1P receptors. By observing human immune cells, Bosque and his research team found that HIV infection was blocked by targeting S1P receptors with Fingolimod. The team discovered that the HIV life cycle was impacted at multiple levels. First, the drug reduced the surface density of the HIV receptor in T-cells, inhibiting viral binding and fusion. Secondly, Fingolimod activated the antiviral restriction factor SAMHD1, leading to a reduction in levels of total and integrated HIV.

"We believe this compound may be a promising novel therapy for HIV treatment and prevention," said Bosque.

"Fingolimod inhibits multiple stages of the HIV-1 life cycle," was published in PLOS Pathogens and is available at https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008679.

Mitochondria are small organelles that provide the energy critical for each cell in our body, in particular in the high fuel-consuming brain. In this week's edition of Science, a Belgian team of researchers led by Pierre Vanderhaeghen (VIB-KU Leuven, ULB) finds that mitochondria also regulate a key event during brain development: how neural stem cells become nerve cells. Mitochondria influence this cell fate switch during a precise period that is twice as long in humans compared to mice. The seminal findings highlight an unexpected function for mitochondria that may help explain how humans developed a bigger brain during evolution, and how mitochondrial defects lead to neurodevelopmental diseases.

Our brains are made up of billions of incredibly diverse neurons. They first arise in the developing brain when stem cells stop self-renewing and differentiate into a particular type of neuron. This process, called neurogenesis, is precisely regulated to give rise to the enormous complex structure that is our brain. It is thought that small differences in the way neural stem cells generate neurons are at the origin of the dramatic increase in the size and complexity of our brain.

To gain insight in this complex process, prof. Pierre Vanderhaeghen (VIB-KU Leuven, ULB) and his colleagues examined the mitochondria, small organelles that provide energy in every cell in the body, including the developing brain.

"Diseases caused by defects in mitochondria lead to developmental problems in many organs, in particular the brain," explains Vanderhaeghen, a specialist in stem cell and developmental neurobiology. "We used to think that this was related to the crucial function of mitochondria to provide energy to the cells, but this is only part of the story: recent work in stem cells suggests that mitochondria have a direct influence on organ development. We have tested whether and how this could be the case in the brain."

Fission and fusion

Together with his team, he explored whether and how mitochondrial remodeling is coupled with neuronal fate commitment during neurogenesis. "Mitochondria are highly dynamic organelles, that can join together (fusion) or split up (fission), and we know these dynamics are associated with fate changes in various types of stem cells," says Vanderhaeghen.

Ryohei Iwata, a postdoctoral researcher in the Vanderhaeghen lab, developed a new method to watch mitochondria in great detail as the neural stem cells are 'caught in the act' to become neurons. "We found that shortly after stem cells divide, the mitochondria in daughter cells destined to self-renew will fuse, while those in daughter cells that become neurons show high levels of fission instead," says Ryohei Iwata.

But this was not just a coincidence: indeed, the researchers could show that increased mitochondrial fission in fact promotes differentiation to a neuronal fate, while mitochondrial fusion after mitosis redirects daughter cells towards self-renewal.

Time window

So mitochondrial dynamics are important to become a neuron--but there is more.

"We found that the influence of mitochondrial dynamics on cell fate choice is limited to a very specific time window, right after cell division," says Pierre Casimir, a PhD student in Vanderhaeghen's lab. "Interestingly, the restricted time window is twice as long in humans compared to mice."

"Previous findings were primarily focused on fate decision of neural stem cells before they divide, but our data reveal that cell fate can be influenced for a much longer period, even after neural stem cell division," says Vanderhaeghen. This may have interesting implications in the emerging field of cell reprogramming, where scientists try to convert non-neuronal cells directly in neuronal cells for therapeutic purposes for instance.

"Since this period of plasticity is much longer in human cells compared to mouse cells, it is tempting to speculate that it contributes to the increased self-renewal capacity of human progenitor cells, and thus to the uniquely developed brain and cognitive abilities of our species. It is fascinating to think that mitochondria, small organelles that have evolved in cells more than a billion years ago, might have contributed to the recent evolution of the human brain."

What The Study Did: Excess deaths in New York during the peak of the 1918 influenza pandemic were compared with those during the initial period of the COVID-19 outbreak in this study.

Authors: Jeremy S. Faust, M.D., M.S., of Brigham and Women's Hospital and Harvard Medical School in Boston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.17527)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: COVID-19-related outcomes in French nursing homes that implemented voluntary staff confinement with residents are investigated in this study.

Authors: Joel Belmin, M.D., Ph.D., of the Hopital Charles Foix in  Ivry-sur-Seine, France, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.17533)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: National Cancer Database data from 2004 to 2014 were used to examine the association between overall survival and timing of radiotherapy relative to androgen deprivation therapy in patients with prostate cancer.

Authors: Vinayak Muralidhar, M.D., M.Sc., of the Dana-Farber Cancer Institute/Brigham and Women's Hospital and Harvard Medical School in Boston is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamaoncol.2020.3545)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Viewpoint Says: This Viewpoint calls for greater attention to racial and socioeconomic health disparities affecting patients with cancer in the setting of COVID-19.

Authors: Onyinye D. Balogun, M.D., of Weill Cornell Medicine in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamaoncol.2020.3327)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.